Adverse events of anticancer treatment were common and debilitating in cancer patients. Traditional Chinese medicine injection (TCMI) plays an important role in the comprehensive treatment of cancer in China.

To explore whether TCMI can reduce adverse events of anticancer treatment in patients with cancer.

Ten databases (i.e., Embase, Web of Science, PubMed, ClinicalTrials.gov, the Cochrane Library, CBM, Scoups, CNKI, Wangfang Database and VIP) were searched up to July 2, 2024. RCT was included if it assessed TCMI in cancer patients and reported any type of adverse events. Data were extracted from eligible studies, and risk of bias was assessed using the RoB2 tool. Certainty of evidence was evaluated by the GRADE tool. Meta analysis was conducted by using random effects model. Subgroup and sensitivity analyses were performed for primary outcomes. The publication bias was evaluated for outcomes reported by more than 10 trials using funnel plots and Egger's test.

A total of 76 eligible RCTs involving 9862 patients with cancer and 45 type of adverse events were included. Meta-analysis revealed that compared with anticancer therapy alone, combination treatment with TCMI had lower risk for adverse events in bone marrow suppression (RR 0.60; 95 % CI,0.51, 0.70) and gastrointestinal issues (RR 0.69; 95 % CI, 0.63, 0.76). Also, TCMI was associated with decreased risk of leukopenia (RR 0.67; 95 % CI, 0.61, 0.74), thrombocytopenia (RR 0.66; 95 % CI, 0.57, 0.77), hemoglobin reduction (RR 0.76; 95 % CI, 0.68, 0.86), neutropenia (RR 0.74; 95 % CI,0.59, 0.93), anemia (RR 0.57; 95 % CI, 0.48, 0.68), liver adverse events (RR 0.63; 95 % CI, 0.54, 0.74), renal adverse events (RR 0.55; 95 % CI, 0.43, 0.70), neurotoxicity (RR 0.70; 95 % CI, 0.61, 0.81), cardiovascular toxicity (RR 0.42; 95 % CI, 0.23, 0.77), radiation-induced injuries (RR 0.43; 95 % CI, 0.34, 0.54]), oral mucositis (RR 0.46; 95 % CI, 0.36, 0.58), fatigue (RR 0.66; 95 % CI, 0.48, 0.90), fever (RR 0.52; 95 % CI, 0.32, 0.85), infection (RR 0.48; 95 % CI, 0.32, 0.72) and chemotherapy toxicity (RR 0.95; 95 % CI, 0.36, 0.86). GRADE assessment indicated high certainty for evidence in bone marrow suppression, hemoglobin reduction, liver adverse events, renal adverse events and oral mucositis.

TCMI can reduce adverse events of anticancer treatment and serve as an adjuvant therapy. It is necessary to strengthen the mechanism research of TCMI and carry out more large-scale, multi-center and well-designed clinical studies to evaluate the synergistic effects of TCMI in the future.

The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.

It is crucial to explore ways to increase the sensitivity of hepatocellular carcinoma cells to sorafenib.

The HepG2 and Huh7 cell lines with overexpressed HIF-2α were constructed. The cells were treated with Xuanfu Hua Tang (Xuanfu HT) containing serum and sorafenib separately and by using both of them, the cell viability and other cell biology functions were detected by CCK-8 and other assays. The mechanism of quercetin was investigated by thermal stability assay and dual luciferase reporter gene assay, and the effects of Xuanfu HT on the transcript and protein levels of Notch1 pathway genes were evaluated by qPCR and Western Blot. The effects of Xuanfu HT in tumor growth was investigates by mice subcutaneous tumor implantation model.

The Xuanfu HT increased sensitivity of HepG2 and Huh7 cell lines with overexpressed HIF-2αto sorafenib, and enhanced inhibition of cell proliferation, migration, invasion and angiogenesis by sorafenib. The component quercetin of Xuanfu HT containing serum could inhibit the binding between HIF-2α and the promoter of the transcription factor FOXP3 to inhibit the expression of FOXP3, so as to inhibit the activation of Notch1 pathway and angiogenesis. The expression of FOXP3 counteracted the decrease in Notch1 and VEGF expression, and angiogenic capacity induced by the combined treatment with Xuanfu HT and sorafenib. The tumor growth inhibitory effects of Xuanfu HT and sorafenib in mice were proved by constructing a subcutaneous tumor model.

Xuanfu HT can increase sorafenib sensitivity of hepatocellular carcinoma cells by antagonizing the Notch1 pathway through quercetin-binding HIF-2α.

Human hepatocellular carcinoma (HCC) is recognized as one of the leading causes of death globally and is resistant to several anticancer drugs. As a result, it is critical to identify more effective druggable therapies. Metal oxide nanoparticles (MO-NPs), especially nanocomposites, have recently received much attention owing to their potential applications in cancer therapy. In this study, we synthesized zinc oxide (ZnO) and copper oxide (CuO) nanocomposites in different ratios (N1, N2, and N3). We evaluated their cytotoxicity against two HCC cell lines (HepG2 and HuH-7) and one normal liver cell (BNL), compared with Sorafenib as a standard therapy. Then, we investigated the potential underlying mechanisms of anticancer action employing flow cytometry, migration assay, and western blot. The results showed that the nanocomposite with an equal ratio of both ZnO and CuO-NPs (N1) exhibited the highest cytotoxic activity on the HuH7 cell line while exerting no detrimental impact on normal rat liver epithelial cells. Further investigation into the toxicity mechanisms of N1 revealed three modalities of induced cell death (apoptotic, necrotic, and autophagic) along with S- and G2/M cell cycle arrest, suggesting mitotic catastrophe. Furthermore, N1 displayed potent anti-migratory activity, surpassing sorafenib, upregulated the protein level of autophagy marker beclin-1, while downregulated the protein level of EMT-marker vimentin. Overall, our findings showed that combining ZnO-NPs and CuO-NPs is more intriguing in combating HCC, providing prospective guidance for evolving liver cancer therapy employing bimetallic NPs.

Sorafenib is a synthetic compound and an orally administered multichines inhibitor that targets growth signaling and angiogenesis. It is widely recognized as the standard of care for advanced hepatocellular carcinoma (HCC) but has toxic side effects. Deinoxanthin, purified from the radioresistant bacterium Deinococcus radiodurans, has strong antioxidant characteristics. In this study, the protective effect of deinoxanthin against sorafenib-induced nephrotoxicity was investigated in a rat model of hepatocellular carcinoma. In this regard, the expressions of DDAH1, KIM1, and INOS genes were examined, histopathological and immunohistochemical analyses were performed, and various parameters such as SOD, MDA, GST, CAT, TAS, and TOS were tested biochemically. BUN and creatinine levels were measured in renal tissues. RT-qPCR, Western blot, and ELISA methods were used for all these analyses. As a result, the analyses show that deinoxanthin, which has a high antioxidant capacity, reduces kidney injury and can be used as a protective agent. The primary objective of this study is to evaluate the potential of deinoxanthin as a protective agent against the nephrotoxic side effects of sorafenib in HCC. Our study identified the potential synergistic effects of sorafenib and deinoxanthin on nephrotoxicity in rats with hepatocellular carcinoma.

RTA-408, also referred to as Omaveloxolone, is a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2) and has been demonstrated with protective effects against oxidative stress-induced injury. Oxidative stress is closely associated with the pathogenesis of hepatic ischemia reperfusion injury (HIRI). The aim of this study is to elucidate the impact and underlying mechanisms of RTA-408 in the process of HIRI. In the HIRI mice models, we found that RTA-408 improved liver function of HIRI mice and attenuated the HIRI-induced oxidative stress in vivo. Moreover, the neutrophil infiltration in liver tissues of HIRI mice was alleviated by the administration of RTA-408. RTA-408 treatment also rescued the elevated apoptosis in the liver tissues of HIRI mice. Furthermore, we demonstrated that RTA-408 treatment activated the Nrf2/HO-1 signaling pathway in liver tissues of HIRI mice. Furthermore, the HIRI mice models were developed using Nrf2-deficient mice to explore whether the protective effect of RTA-408 on HIRI was achieved through the activation of Nrf2. The results indicated that RTA-408 did not significantly alleviate the liver injury in Nrf2-deficient mice. Collectively, our results suggest that RTA-408 attenuates HIRI by improving liver function, and attenuating oxidative stress damage, apoptosis and inflammatory response possibly via the Nrf2/HO-1 pathway, which may provide a novel treatment strategy for HIRI patients.

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. While early-stage HCC can be effectively managed with surgical resection and other interventions, treatment options for advanced HCC are limited. Current systemic treatments for advanced HCC include VEGF-targeted tyrosine kinase inhibitors (Sorafenib, Lenvatinib), and the combination therapy of anti PD-1/PD-L1 and anti VEGF (Atezolizumab plus Bevacizumab, Camrelizumab plus Rivoceranib). However, the lack of response to these drugs and the emergence of acquired drug resistance significantly impairs their efficacy. Numerous studies have demonstrated that the tumor immune microenvironment (TIME) plays a crucial role in modulating the response to these therapies. Various immune cells and their secreted factors within the TIME play a pivotal role in the emergence of secondary drug resistance in HCC. This article reviews the mechanism of TIME promoting drug resistance, discusses the influence of current systemic HCC treatment drugs on TIME, and evaluates how these TIME changes affect the efficacy of treatment. A deeper understanding of the interaction between TIME and systemic treatment drugs may be beneficial to enhance the treatment effect, mitigate drug resistance of advanced HCC, and ultimately improve the prognosis of patients.

Coix lacryma-jobi, a highly regarded Asian herb widely used in traditional Chinese medicine, is recognized for its dual benefits in promoting overall health and treating various diseases. While it exhibits moderate anticancer efficacy when used alone, this study investigated the enhanced anticancer potential of raw and cooked Coix lacryma-jobi var. lacryma-jobi (CL) seed extracts in combination with sorafenib against HCT116 and HepG2 cancer cell lines. The combination of sorafenib with other anticancer agents, including natural extracts, has garnered significant attention as a promising strategy for developing more effective cancer therapies.

Dry powders of raw (R) and cooked (C) CL seeds, obtained from a local commercial source in Thailand, were extracted and fractionated using ethanol (E), dichloromethane (D), ethyl acetate (A), and water (W) to produce eight fractions: CLRE, CLCE, CLRD, CLCD, CLRA, CLCA, CLRW, and CLCW. The coixol content in raw and cooked seed extracts was quantified and expressed as μg of coixol per gram of extract. The cytotoxic effects of these fractions were evaluated against HCT116 and HepG2 cells using the MTT assay. Fractions demonstrating the most significant cytotoxic responses were combined with sorafenib to evaluate their synergistic effects. Apoptosis induction and mitochondrial membrane potential (MMP) were assessed, and the underlying mechanism of apoptosis was explored by analyzing reactive oxygen species (ROS) generation and antioxidant protein expression levels. Additionally, the combination treatment's effect on the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway was investigated.

One gram of CLCE and CLCD extracts contained higher coixol levels (7.02 μg and 9.69 μg, respectively) compared to CLRE and CLRD (2.66 μg and 5.96 μg, respectively). Coixol content in CLRA, CLRW, and CLCW fractions was undetectable under the study conditions. All extract fractions exhibited IC50 values exceeding 1 mg/mL after 24- and 48-hour incubations with HCT116 and HepG2 cells, indicating limited cytotoxicity when used independently. CLRD and CLCD fractions were selected for combination studies at a concentration of 1 mg/mL, combined with sub-IC50 concentrations of sorafenib to minimize its side effects. This combination significantly increased cytotoxicity, inducing apoptosis in HCT116 and HepG2 cells by elevating ROS levels and reducing the expression of superoxide dismutase 2 and catalase. Furthermore, the combination treatment downregulated the PI3K/AKT/mTOR pathway, indicating a targeted anticancer mechanism.

The combination of CLCD with sorafenib demonstrates significant potential as a strategy for future anticancer therapies. This CL seed extract, cultivated and commercially available in Thailand, shows promise as a natural supplement to enhance the efficacy of chemotherapy in upcoming clinical anticancer applications.

Recently, our group identified antimony (Sb) as a novel nerve pollutant, can lead to neuronal injure. However, Sb-associated neurotoxicological mechanisms yet remain unclear. Herein, we found Sb induced hippocampal neuronal ferroptosis in vivo and in vitro. Moreover, ferroptosis inhibition using ferrostatin-1 effectively attenuated Sb-induced neuronal damage in PC12 cells and mice hippocampal regions. Furthermore, iron chelator deferoxamine (DFO) also effectively attenuated ferroptosis and cytotoxicity in PC12 cells. In vitro, Sb treatment reduced expression of the heavy (H)- and light (L)-chain subunits of ferritin (FTH1 and FTL). Moreover, Sb accelerated FTH1 and FTL protein degradation, while ferritin overexpression by plasmid or hippocampal AAV injections dramatically weaken Sb-induced ferroptosis. Sb exposure accelerated autophagic flux, and autophagy inhibition with beclin1 knockdown effectively reduced Sb-mediated ferroptosis. 3-methyladenine treatment in Sb-exposed mice prevented the decrease of FTH1 and FTL protein, resulting in recovery of Sb-induced hippocampal ferroptosis as well as neuronal loss, suggesting that Sb triggered hippocampal neuronal ferritinophagy. Finally, we found Sb upregulated NCOA4 protein expression, while NCOA4 knockdown significantly attenuated Sb-triggered ferroptosis. Collectively, our results proved that Sb triggers hippocampal neuronal ferroptosis through NCOA4-dependent ferritinophagy.

Immune checkpoint inhibitors (ICIs) have altered the landscape of tumor immunotherapy, offering novel therapeutic approaches alongside surgery, chemotherapy, and radiotherapy and significantly improving survival benefits. However, their clinical efficacy is limited in some patients, and their use may cause immune-related adverse events (irAEs). Integrating traditional Chinese medicine (TCM) with ICIs has demonstrated the potential to boost sensitization and reduce toxicity. Clinical trials and experimental explorations have confirmed that TCM and its active components synergistically enhance the effectiveness of ICIs.

This narrative review summarizes the TCM practices that enhance the clinical efficacy and reduce irAEs of ICIs. This paper also summarizes the mechanism of experimental studies on the synergies of Chinese herbal decoctions, Chinese herbal preparation, and Chinese herbal active ingredients. Most of the studies on TCM combined with ICIs are basic experiments. We discussed the mechanism of TCM enhanced ICIs to provide reference for the research and development of TCM adjuvant immunotherapy.

We conducted a literature search using PubMed and Chinese National Knowledge Infrastructure databases, with a focus on herbal decoction, Chinese medicine preparations, and active ingredients that boost the effectiveness of ICIs and reduce irAEs. The search keywords were "ICIs and traditional Chinese medicine", "PD-1 and traditional Chinese medicine", "PD-L1 and traditional Chinese medicine", "CTLA-4 and traditional Chinese medicine", "IDO1 and traditional Chinese medicine", "Tim-3 and traditional Chinese medicine", "TIGIT and traditional Chinese medicine", "irAEs and traditional Chinese medicine". The search period was from May 2014 to May 2024. Articles involving the use of TCM or its components in combination with ICIs and investigating the underlying mechanisms were screened. Finally, 30 Chinese medicines used in combination with ICIs were obtained to explore the mechanism. In the part of immune checkpoint molecules other than PD-1, there were few studies on the combined application of TCM, so studies involving the regulation of immune checkpoint molecules by TCM were included.

TCM has been shown to boost the effectiveness of ICIs and reduce irAEs. Researchers indicate that TCM and its active components can work synergistically with ICIs by regulating immune checkpoints PD-1, PD-L1, CTLA-4, and IDO1, regulating intestinal flora, improving tumor microenvironment and more.

Combining TCM with ICIs can play a better anti-tumor role, but larger samples and high-quality clinical trials are necessary to confirm this. Many Chinese medicines and their ingredients have been shown to sensitize ICIs in experimental studies, which provides a rich choice for the subsequent development of ICI enhancers.

Understanding the molecular mechanisms of adaptive regulation in the tumor microenvironment is crucial for precision therapy in hepatocellular carcinoma (HCC). We hypothesized that cargo proteins carried by extracellular vesicles (EVs) released in a hypoxic microenvironment might promote HCC progression by remodeling tumor-associated macrophages (TAMs).

EV protein analysis by label-free proteomics mass spectrometry of HCC cell lines of different tumor grades was performed. The promotional effect if spermidine synthase（SRM） on M2 polarized TAMs was further investigated using various biological approaches.

SRM expression was positively correlated with liver cancer progression in HCC cell lines, liver cancer samples, and nude mouse models. In a mouse model, SRM expression was positively correlated with TAM infiltration and liver cancer progression. Pan-cancer dataset analysis confirmed that SRM overexpression in HCC tumors is correlated with poor patient prognosis. However, a hypoxic microenvironment is an internal driving factor for exosomal SRM that participates in microenvironmental modifications. Moreover, we defined a hitherto unknown pattern of microenvironmental crosstalk involving SRM in EVs, whereby macrophages complete the phenotypic fate of M2 tumor-associated macrophages through SRM uptake.

SRM regulation within the immune microenvironment is metabolically driven. By upregulating spermidine, which serves as a substrate for eIF5A hypusination, excessive oxidative phosphorylation (OXPHOS) assembly is achieved. This, in turn, leads to the expression of immunosuppressive marker molecules and ultimately promotes liver cancer progression. SRM, which is enriched in the EVs of HCC cells under hypoxic conditions, acts as a potent regulator linking polyamine and energy metabolism in TAMs, thereby promoting liver cancer progression.

Fritillaria cirrhosa D. Don (FCD) is a traditional Chinese medicine used to treat respiratory disorders, known for its effects in clearing heat, moistening the lungs, resolving phlegm, and relieving cough. Additionally, the total alkaloids extracted from FCD can alleviate asthma symptoms and reduce airway inflammation. However, no studies have investigated the effects of total alkaloids on lung macrophages.

This study explored whether the total alkaloids of FCD (TAs-FCD) reduce M2 macrophage polarization and, consequently, attenuate airway remodeling in asthmatic mice. This study further elucidated its mechanism of action in treating allergic asthma.

The extracted TAs-FCD was analyzed for its composition using UPLC-Q-TOF/MS. Network pharmacology was employed to identify the active ingredients and potential mechanisms of TAs-FCD in the treatment of allergic asthma. A mouse model of ovalbumin-induced allergic asthma was established, adopted, and validated through in vivo experiments. Hematoxylin-eosin staining (H&E), immunohistochemistry (IHC), immunofluorescence staining (IF), enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), and real-time fluorescence quantitative polymerase chain reaction (q-PCR) were used to investigate the role of TAs-FCD in inhibiting M2 macrophage polarization in the context of allergic asthma.

A total of 66 active ingredients were screened from 116 compounds using SWISSADME. The targets of these 66 compounds were predicted by SwissTargetPrediction, resulting in 808 unique drug targets after excluding duplicates. Additionally, 1756 targets related to allergic asthma were identified from the DisGeNET, Genecard, and OMIM databases. This led to 267 cross-targets between the active ingredient targets and allergic asthma targets, including interleukin (IL)-1β, tumor necrosis factor (TNF), and STAT3. Animal experiments demonstrated that TAs-FCD improved histopathological injury in mouse lungs, reduced peri-airway collagen fiber accumulation, airway mucus secretion, and airway smooth muscle proliferation. TAs-FCD also lowered IL-1β, TNF-α and IL-4 levels in lung tissues and alleviated airway inflammation. Furthermore, TAs-FCD significantly reduced levels of Arg1 and CD206, which are closely associated with M2 macrophages, and downregulated the expression of p-STAT3 and p-JAK2.

TAs-FCD may inhibit M2 macrophage polarization by regulating the JAK2/STAT3 pathway, thereby alleviating airway remodeling and inflammation in allergic asthmatic mice.

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally. Despite advancements in immunotherapy, the prognosis for patients with HCC continues to be poor. As oxidative stress plays a significant role in the onset and progression of various diseases, including metabolism-related HCC, comprehending its mechanism in HCC is critical for effective diagnosis and treatment.

This study utilized the TCGA dataset and a collection of oxidative stress genes to identify the expression of oxidative stress-related genes in HCC and their association with overall survival using diverse bioinformatics methods. A novel prognostic risk model was developed, and the TCGA cohort was divided into high-risk and low-risk groups based on each tumor sample's risk score. Levels of immune cell infiltration and the expression of immune checkpoint-related genes in different risk subgroups were analyzed to investigate the potential link between tumor immunity and oxidative stress-related features. The expression of model genes in actual samples was validated through immunohistochemistry, and their mRNA and protein expression levels were measured in cell cultures.

Four oxidative stress-related genes (EZH2, ANKZF1, G6PD, and HMOX1) were identified and utilized to create a predictive risk model for HCC patient overall survival, which was subsequently validated in an independent cohort. A correlation was found between the expression of these prognostic genes and the infiltration of tumor immune cells. Elevated expression of EZH2, ANKZF1, G6PD, and HMOX1 was observed in both HCC tissues and cell lines.

The combined assessment of EZH2, ANKZF1, G6PD, and HMOX1 gene expression can serve as an oxidative stress risk model for assessing HCC prognosis. Furthermore, there is a correlation between the expression of these risk model genes and tumor immunity.

Sorafenib is currently the first choice for the treatment of patients with advanced hepatocellular carcinoma, but its therapeutic effect is still limited.

This study aims to examine whether WEE family kinase inhibitors can enhance the anticancer effect of sorafenib.

We analyzed the expression levels of PKMYT1 kinase and WEE1 kinase in HCC, studied the inhibitory effect of PKMYT1 kinase inhibitor RP-6306, WEE1 kinase inhibitor adavosertib combined with sorafenib on the proliferation of HCC cells, and detected the effect of drug combination on CDK1 phosphorylation.

We found that PKMYT1 and WEE1 were upregulated in HCC and were detrimental to patient survival. Cell experiments showed that both RP-6306 and adavosertib (1-100 μM) inhibited the proliferation of HCC cell lines in a dose-dependent manner alone, and the combination of the two drugs had a synergistic effect. In HCC cell lines, sorafenib combined with RP-6306 or adavosertib showed a synergistic antiproliferation effect and less toxicity to normal cells. Sorafenib combined with RP-6306 and adavosertib further inhibited the proliferation of HCC cells and caused complete dephosphorylation of CDK1.

Taken together, our findings provide experimental evidence for the future use of sorafenib in combination with RP-6306 or adavosertib for the treatment of HCC.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce serious adverse effects in gastrointestinal (GI) mucosa, increasing intestinal permeability and leading to mitochondrial dysfunction, oxidative stress, apoptosis and inflammation. As proton pump inhibitors are effective in protecting against NSAID-induced gastropathy but not NSAID-induced enteropathy, current research is focused on natural products as protective substances for therapy and prevention of intestinal injury. Herein, through the use of an in vitro model based on intestinal epithelial cell (Caco-2) damage caused by indomethacin (INDO), we examined the protective activity of a commercially available standardized extract (OFI+OE) from Opuntia ficus-indica (L.) Mill. cladodes and Olea europaea L. leaves. Pre-treatment with OFI+OE prevented INDO-induced intestinal epithelial barrier damage, as demonstrated by TEER measurement, fluorescein permeability, and tight junction protein expression. The extract showed positive effects against INDO-induced oxidative stress and correlated activation of apoptosis, decreasing pro-apoptotic markers BAX and Caspase-3 and increasing anti-apoptotic factor Bcl-2. Moreover, the extract inhibited the NF-κB pathway and pro-inflammatory cascade. In conclusion, these data support the use of OFI+OE extract as a natural strategy for therapy and prevention of intestinal mucosal damage, demonstrating its beneficial effects against INDO-induced intestinal damage, through modulation of oxidative, apoptotic, and inflammatory pathways.

Yajieshaba (YJSB), approved by the Yunnan Provincial Food and Drug Administration in 2008, are known for their anti-inflammatory, antiviral, and pro-apoptotic properties, effectively treating Hepatic fibrosis (HF). However, its mechanism of action remains unclear.

The objective of this investigation is to explore how YJSB influences the TGF-β1/Smad signaling pathway as a strategy for reducing HF.

The establishment of a HF model in mice involved ligation of the common bile duct, followed by administration of YJSB. Body and liver weights were measured, and the liver index calculated. Serum levels of ALT, AST, ALP, TBA, and TBIL were assessed using colorimetric methods. Additionally, liver homogenates were analyzed for PIIINP, Col-IV, LN, HA, and Hyp, as well as TGF-β1 activity, using ELISA. Histological analyses of liver sections, stained with H&E, Ag, and Masson's trichrome, were performed to examine inflammation and the accumulation of collagen and reticular fibers. These studies aimed to elucidate the pharmacodynamic effects of YJSB on HF in mice with bile duct obstruction. The target pathways of YJSB were preliminarily identified through immunofluorescence detection of TGF-β1, P-Smad2L, P-Smad2C, P-Smad3L, P-Smad3C, and Smad4 proteins. In vitro experiments included the induction of hepatic stellate cell (HSC-T6) activation by H2O2. A cell injury model was established for HSC-T6, and the CCK-8 assay was used to determine the optimal YJSB concentration and treatment duration. After pirfenidone (PFD) administration, which inhibits the TGF-β1/Smad pathway, the effects of YJSB on HSC-T6 cell proliferation were observed. ELISA assays quantified Col-III, α-SMA, and Col-I in cell lysates to assess YJSB's impact on collagen synthesis in HSC-T6 cells. Western blot analysis was performed to assess the protein levels within the TGF-β1/Smad signaling cascade.

In the HF mouse model, administration of YJSB notably augmented the body weight and reduced the liver index. Concurrently, there was an elevation in serum concentrations of ALP, AST, ALT, TBA, and TBIL. Similarly, in the liver homogenates of HF mice, increases were observed in the levels of HA, PIIINP, Col-IV, LN, Hyp, and TGF-β1. Histological assessments using H&E, Ag, and Masson stains indicated a substantial diminution in liver tissue damage. Through immunofluorescence analysis, it was discerned that YJSB modulated the expression of TGF-β1, P-Smad2L, P-Smad2C, and P-Smad3L downwards, while elevating P-Smad3C and Smad4 protein expressions. Additional investigations revealed a significant reduction in α-SMA, Col-I, and Col-III levels in cell culture fluids, suggesting a decrease in collagen synthesis and a protective role against cellular damage. Western blot analyses demonstrated that the TGF-β1/Smad pathway inhibitor, PFD, acted in synergy with YJSB, enhancing its regulatory effects on this pathway, decreasing levels of TGF-β1, P-Smad2L, P-Smad2C, P-Smad3L, and promoting the expression of P-Smad3C.

YJSB demonstrates a pharmacodynamic effect against HF, enhancing liver functionality and effectively mitigating the damage associated with bile duct obstruction. The proposed action mechanism of YJSB involves modulation of the TGF-β1/Smad signaling pathway. Research indicates that YJSB might play a role in suppressing the movement, programmed cell death, and activation of HSC-T6, potentially decelerating the advancement of hepatic fibrosis.

Topoisomerase is a ubiquitous enzyme in the control of DNA chain topology. There have been extensive research on topoisomerase inhibitors derived from natural sources, which act as partial inducers of tumor cell apoptosis. However, their specific efficacy in treating hepatocellular carcinoma is relatively unexplored. Hence, this comprehensive review focuses on the structural characteristics and anti-cancer properties of topoisomerase inhibitors in hepatocellular carcinoma. Furthermore, this review is also elucidating the mechanism of action, structure-activity relationships, therapeutic limitations, stage of clinical trials of described classes of natural bioactive compounds as well as their potential application in cancer chemotherapies. This broad understanding of topoisomerase medical biology will provide indispensable framework for enhancing the efficiency of rational anti-hepatocellular carcinoma drug discovery.

Rheumatoid arthritis, a chronic autoimmune disorder characterized by joint inflammation, is thought to be exacerbated by bacterial infections, notably Proteus mirabilis. This study explores the combined effects of quercetin, a potent antioxidant and anti-inflammatory flavonoid, and chondroitin sulfate, known for its cartilage-protective properties, as a potential therapeutic approach. Molecular docking analyses revealed favourable interactions between these compounds and key pro-inflammatory cytokines IL-6 and TNF-α, suggesting their potential to disrupt inflammation-related signaling pathways. In vitro assays demonstrated that the quercetin-chondroitin sulfate combination (1:1 ratio) significantly inhibited oxidative stress and hemolysis, highlighting its enhanced anti-inflammatory and membrane-protective effects. The free radical scavenging assays further confirmed the antioxidant potential of this combination, which demonstrated strong radical scavenging activity. Antimicrobial assays showed notable antibacterial effects, with an increased inhibition zone against P. mirabilis when quercetin and chondroitin sulfate were combined, suggesting a synergistic antimicrobial action. In vivo, zebrafish subjected to bacterial stress showed improved survival rates with the quercetin and chondroitin sulfate combination treatment, along with enhanced mineralization and significant modulation of alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activities, indicating its protective role in maintaining joint health. Furthermore, gene expression analysis revealed a substantial reduction in pro-inflammatory markers, including TNF-α and IL-6, demonstrating the quercetin and chondroitin sulfate combination's ability to mitigate inflammation. Together, these findings suggest that the quercetin and chondroitin sulfate combination hold significant therapeutic potential in reducing oxidative stress, inflammation, and microbial-induced RA exacerbations.

Sangju Cold Granule (SJCG) is a classical traditional Chinese medicine (TCM) prescription described in "Item Differentiation of Warm Febrile Diseases". Historically, SJCG was employed to treat respiratory illnesses. Despite its popular usage, the alleviating effect of SJCG on influenza A virus infection and its mechanisms have not been fully elucidated.

Influenza is a severe respiratory disease that threatens human health. This study aims to assess the therapeutic potential of SJCG and the possible molecular mechanism underlying its activity against influenza A virus in vitro and in vivo.

Ultrahigh-performance liquid chromatography (UPLC)-Q-Exactive was used to identify the components of SJCG. The 50% cytotoxic concentration of SJCG in MDCK and A549 cells were determined using the CCK-8 assay. The activity of SJCG against influenza A virus H1N1 was evaluated in vitro using plaque reduction and progeny virus titer reduction assays. RT-qPCR was performed to obtain the expression levels of inflammatory mediators and the transcriptional regulation of RIG-I and MDA5 in H1N1-infected A549 cells. Then, the mechanism of SJCG effect on viral replication and inflammation was further explored by measuring the expressions of proteins of the RIG-I/NF-kB/IFN(I/III) signaling pathway by Western blot. The impact of SJCG was explored in vivo in an intranasally H1N1-infected BALB/c mouse pneumonia model treated with varying doses of SJCG. The protective role of SJCG in this model was evaluated by survival, body weight monitoring, lung viral titers, lung index, lung histological changes, lung inflammatory mediators, and peripheral blood leukocyte count.

The main SJCG chemical constituents were flavonoids, carbohydrates and glycosides, amino acids, peptides, and derivatives, organic acids and derivatives, alkaloids, fatty acyls, and terpenes. The CC50 of SJCG were 24.43 mg/mL on MDCK cells and 20.54 mg/mL on A549 cells, respectively. In vitro, SJCG significantly inhibited H1N1 replication and reduced the production of TNF-α, IFN-β, IL-6, IL-8, IL-13, IP-10, RANTES, TRAIL, and SOCS1 in infected A549 cells. Intracellularly, SJCG reduced the expression of RIG-I, MDA5, P-NF-κB P65 (P-P65), P-IκBα, P-STAT1, P-STAT2, and IRF9. In vivo, SJCG enhanced the survival rate and decreased body weight loss in H1N1-infected mice. Mice with H1N1-induced pneumonia treated with SJCG showed a lower lung viral load and lung index than untreated mice. SJCG effectively alleviated lung damage and reduced the levels of TNF-α, IFN-β, IL-6, IP-10, RANTES, and SOCS1 in lung tissue. Moreover, SJCG significantly ameliorated H1N1-induced leukocyte changes in peripheral blood.

SJCG significantly reduced influenza A virus and virus-mediated inflammation through inhibiting the RIG-I/NF-kB/IFN(I/III) signaling pathway. Thus, SJCG could provide an effective TCM for influenza treatment.

Metastasis contributes to the increased mortality rate of cancer, but the intricate mechanisms remain unclear. Cancer cells from a primary tumor invade nearby tissues and access the lymphatic or circulatory system. If these cells manage to survive and extravasate from the vasculature into distant tissues and ultimately adapt to survive, they will proliferate and facilitate malignant tumor formation. Traditional two-dimensional (2D) cell cultures offer a rapid and convenient method for validating the efficacy of anticancer drugs within a reasonable cost range, but their utility is limited because of tumors' high heterogeneity in vivo and spatial complexities. Three-dimensional (3D) cell cultures that mimic the physiological conditions of cancer cells in vivo have gained considerable interest. In these cultures, cells assemble into spheroids through gravity, magnetic forces, or their low-adhesion to the plates. Although these approaches address some of the limitations of 2D cultures, they often require a considerable amount of time and cost. Therefore, this study aims to enhance the effectiveness of 3D culture techniques by using microfluidic systems to provide a high-throughput and sensitive pipeline for drug screening. Using these systems, we studied the effects of lanthanide elements, which have garnered interest in cancer treatment, on spheroid formation and cell spreading. Our findings suggest that these elements alter the compactness of cell spheroids and decrease cell mobility.

Every cell in the human body is vital because it maintains equilibrium and carries out a variety of tasks, including growth and development. These activities are carried out by a set of instructions carried by many different genes and organized into DNA. It is well recognized that some lifestyle decisions, like using tobacco, alcohol, UV, or multiple sexual partners, might increase one's risk of developing cancer. The advantages of natural products for any health issue are well known, and researchers are making attempts to separate flavonoid-containing substances from plants. Various parts of plants contain a phenolic compound called flavonoid. Quercetin, which belongs to the class of compounds known as flavones with chromone skeletal structure, has anti-cancer activity.

The study was aimed at investigating the therapeutic action of the flavonoid quercetin on various cancer cells.

The phrases quercetin, anti-cancer, nanoparticles, and cell line were used to search the data using online resources such as PubMed, and Google Scholar. Several critical previous studies have been included.

Quercetin inhibits various dysregulated signaling pathways that cause cancer cells to undergo apoptosis to exercise its anticancer effects. Numerous signaling pathways are impacted by quercetin, such as the Hedgehog system, Akt, NF-κB pathway, downregulated mutant p53, JAK/STAT, G1 phase arrest, Wnt/β-Catenin, and MAPK. There are downsides to quercetin, like hydrophobicity, first-pass effect, instability in the gastrointestinal tract, etc., because of which it is not well-established in the pharmaceutical industry. The solution to these drawbacks in the future is using bio-nanomaterials like chitosan, PLGA, liposomes, and silk fibroin as carriers, which can enhance the target specificity of quercetin. The first section of this review covers the specifics of flavonoids and quercetin; the second section covers the anti-cancer activity of quercetin; and the third section explains the drawbacks and conjugation of quercetin with nanoparticles for drug delivery by overcoming quercetin's drawback.

Overall, this review presented details about quercetin, which is a plant derivative with a promising molecular mechanism of action. They inhibit cancer by various mechanisms with little or no side effects. It is anticipated that plant-based materials will become increasingly relevant in the treatment of cancer.

Edible and medicinal herbs1 (EMHs) refer to a class of substances with dual attribution of food and medicine. These substances are traditionally used as food and also listed in many international pharmacopoeias, including the European Pharmacopoeia, the United States Pharmacopoeia, and the Chinese Pharmacopoeia. Some classical formulas that are widely used in traditional Chinese medicine include a series of EMHs, which have been shown to be effective with obvious characteristics and advantages. Notably, these EMHs and Chinese classical prescriptions2 (CCPs) have also attracted attention in international herbal medicine research because of their low toxicity and high efficiency as well as the rich body of experience for their long-term clinical use.

Our purpose is to explore the potential therapeutic effect of EMHs with immune-inflammatory modulation for the study of modern cancer drugs.

In the present study, we present a detailed account of some EMHs used in CCPs that have shown considerable research potential in studies exploring modern drugs with immune-inflammatory modulation.

Approximately 500 publications in the past 30 years were collected from PubMed, Web of Science and ScienceDirect using the keywords, such as natural products, edible and medicinal herbs, Chinese medicine, classical prescription, immune-inflammatory, tumor microenvironment and some related synonyms. The active ingredients instead of herbal extracts or botanical mixtures were focused on and the research conducted over the past decade were discussed emphatically and analyzed comprehensively.

More than ten natural products derived from EMHs used in CCPs are discussed and their immune-inflammatory modulation activities, including enhancing antitumor immunity, regulating inflammatory signaling pathways, lowering the proportion of immunosuppressive cells, inhibiting the secretion of proinflammatory cytokines, immunosuppressive factors, and inflammatory mediators, are summarized.

Our findings demonstrate the immune-inflammatory modulating role of those EMHs used in CCPs and provide new ideas for cancer treatment in clinical settings.

Lung adenocarcinoma stands as a leading global cause of cancer-related fatalities, with current therapeutic approaches remaining unsatisfactory. Given the association between elevated oxidative markers and the aggressive nature of cancer cells (including multidrug resistance and metastatic potential) that can predict poor outcome of lung adenocarcinoma patients, any compounds that interfere with their aberrant redox biology should be rationally explored as innovative intervention strategies. This study was designed to screen potential anticancer activities within nine newly synthesized organochalcogen - compounds characterized by the presence of oxygen, sulfur, or selenium elements in their structure and exhibiting antioxidant activity - and systematically evaluated their performance against cisplatin, the cornerstone therapeutic agent for lung adenocarcinoma. Our methodology involved the establishment of optimal conditions for generating single tumor spheroids using A549 human lung adenocarcinoma cell line. The initiation interval for spheroid formation was determined to be four days in vitro (DIV), and these single spheroids demonstrated sustained growth over a period of 20 DIV. Toxic dose-response curves were subsequently performed for each compound after 24 and 48 h of incubation at the 12th DIV. Our findings reveal that at least two of the synthetic organochalcogen compounds exhibited noteworthy anticancer activity, surpassing cisplatin in key parameters such as lower LD (Lethal Dose) 50, larger drug activity area, and maximum amplitude of effect, and are promising drugs for futures studies in the treatment of lung adenocarcinomas. Physicochemical descriptors and prediction ADME (absorption, distribution, metabolism, and excretion) parameters of selected compounds were obtained using SwissADME computational tool; Molinspiration server was used to calculate a biological activity score, and possible molecule targets were evaluated by prediction with the SwissTargetPrediction server. This research not only sheds light on novel avenues for therapeutic exploration but also underscores the potential of synthetic organochalcogen compounds as agents with superior efficacy compared to established treatments.

Current chemotherapeutic agents have several limitations, including lack of selectivity, the development of undesirable side effects, and chemoresistance. As a result, there is an unmet need for the development of novel small molecules with minimal side effects and the ability to specifically target tumor cells. A new series of 3-phenoxybenzoic acid derivatives, including 1,3,4-oxadiazole derivatives (4a-d) and benzamides derivatives (5a-e) were synthesized; their chemical structures were confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectra; and various physicochemical properties were determined. The antiproliferative activities of the new derivatives were evaluated by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Three compounds (4b, 4c, and 4d) exhibited cytotoxicity against two of the three cell lines tested, five compounds (3, 4a, 5a, 5b, and 5e) were toxic to one cell line, while two compounds (5c and 5d) were not cytotoxic to any of the three cell lines tested in the current study. Based on docking scores, MTT assay findings, and vascular endothelial growth factor receptor 2 (VEGFR-2) kinase activity data, Compound 4d was selected for further biological investigation. Flow cytometry was used to determine the mode of cell death (apoptosis vs. necrosis) and the effect on cell cycle progression. Compound 4d arrested HepG2 hepatocellular carcinoma cells in the G2/M phase and activated both the intrinsic and extrinsic apoptosis pathways. In conclusion, Compound 4d has shown promising results for future research as a potent VEGFR-2 tyrosine kinase inhibitor.

An FDA-approved kinase inhibitor called sorafenib (SOR) is used to treat primary kidney and liver cancer as well as to stop the spread of advanced breast cancer. Side effects from SOR, such as palmar-plantar erythrodysesthesia syndrome, can negatively impact an individual's quality of life. There are a lot of data supporting the importance of lycopene (LYC) in preventing cancer. The antitumor properties of the combination of sorafenib and lycopene were examined in this study. A viability test against MDA-MB-231 was used to assess the anticancer efficacy of sorafenib, lycopene, and their combination in vitro. Moreover, a cell cycle analysis and Annexin-V/PI double staining were performed by using flow cytometry. In addition, the protein level of JNK-1, ERK-1, Beclin-1, P38, and P53 of the MDA-MB-231 cell line was estimated using ELISA kits. In addition, mice with SEC were divided into four equal groups at random (n = 10) to investigate the possible processes underlying the in vivo antitumor effect. Group IV (SEC-SOR-LYC) received SOR (30 mg/kg/day, p.o.) and LYC (20 mg/kg/day, p.o.); Group I received the SEC control; Group II received SEC-SOR (30 mg/kg/day, p.o.); and Group III received SEC-LYC (20 mg/kg/day, p.o.). The findings demonstrated that the combination of sorafenib and lycopene was superior to sorafenib and lycopene alone in causing early cell cycle arrest, suppressing the viability of cancer cells, and increasing cell apoptosis and autophagy. Likewise, the combination of sorafenib and lycopene demonstrated inhibition of the levels of Bcl-2, Ki-67, VEGF, IL-1β, and TNF-α protein. Otherwise, the quantities of the proteins BAX, P53, and caspase 3 were amplified. Furthermore, the combined treatment led to a substantial increase in TNF-α, caspase 3, and VEGF gene expression compared to the equivalent dosages of monotherapy. The combination of sorafenib and lycopene enhanced apoptosis and reduced inflammation, as seen by the tumor's decreased weight and volume, hence demonstrating its potential anticancer effect.

San Huang Pill (SHP) is a prescription in Dunhuang Ancient Medical Prescription, which has the efficacy of heat-clearing and dampness-drying, and is a traditional formula for the treatment of gastrointestinal diseases. However, its efficacy and mechanism in treating ulcerative colitis (UC) are still unclear.

To investigate the protective effects of SHP and its bioactive compounds against Dextran Sulfate Sodium (DSS)-induced intestinal damage using the Drosophila melanogaster model, and to detect the molecular mechanism of SHP in the treatment of UC.

Survival rate, locomotion, feeding, and excretion were used to explore the anti-inflammatory effects of SHP. The pharmacotoxicity of SHP was measured using developmental analysis. Intestinal integrity, intestinal length, intestinal acid-base homeostasis, and Tepan blue assay were used to analyze the protective effect of SHP against DSS-induced intestinal damage. The molecular mechanism of SHP was detected using DHE staining, immunofluorescence, real-time PCR, 16 S rRNA gene sequencing, and network pharmacology analysis. Survival rate, intestinal length, and integrity analysis were used to detect the protective effect of bioactive compounds of SHP against intestinal damage.

SHP supplementation significantly increased the survival rate, restored locomotion, increased metabolic rate, maintained intestinal morphological integrity and intestinal homeostasis, protected intestinal epithelial cells, and alleviated intestinal oxidative damage in adult flies under DSS stimulation. Besides, administration of SHP had no toxic effect on flies. Moreover, SHP supplementation remarkably decreased the expression levels of genes related to JAK/STAT, apoptosis, and Toll signaling pathways, increased the gene expressions of the Nrf2/Keap1 pathway, and also reduced the relative abundance of harmful bacteria in DSS-treated flies. Additionally, the ingredients in SHP (palmatine, berberine, baicalein, wogonin, rhein, and aloeemodin) had protection against DSS-induced intestinal injury, such as prolonging survival rate, increasing intestinal length, and maintaining intestinal barrier integrity.

SHP had a strong anti-inflammatory function, and remarkably alleviated DSS-induced intestinal morphological damage and intestinal homeostatic imbalance in adult flies by regulating JAK/STAT, apoptosis, Toll and Nrf2/Keap1 signaling pathways, and also gut microbial homeostasis. This suggests that SHP may be a potential complementary and alternative medicine herb therapy for UC, which provides a basis for modern pharmacodynamic evaluation of other prescriptions in Dunhuang ancient medical prescription.

Objective: Here, we aimed to explore the effect of LBP in combination with Oxaliplatin (OXA) on reversing drug resistance in colon cancer cells through in vitro and in vivo experiments. We also aimed to explore the possible mechanism underlying this effect. Finally, we aimed to determine potential targets of Lycium barbarum polysaccharide (LBP) in colon cancer (CC) through network pharmacology and molecular docking. Methods: The invasion ability of colon cancer cells was assessed using the invasion assay. The migration ability of these cells was assessed using the migration assay and wound healing assay. Cell cycle analysis was carried out using flow cytometry. The expression levels of phosphomannose isomerase (PMI) and ATP-binding cassette transport protein of G2 (ABCG2) proteins were determined using immunofluorescence and western blotting. The expression levels of phosphatidylinositol3-kinase (PI3K), protein kinase B (AKT), B-cell lymphoma 2 (Bcl-2), and BCL2-Associated X (Bax) were determined using western blotting. Forty BALB/c nude mice purchased from Weitong Lihua, Beijing, for the in vivo analyses. The mice were randomly divided into eight groups. They were administered HCT116 and HCT116-OXR cells to prepare colon cancer xenograft models and then treated with PBS, LBP (50 mg/kg), OXA (10 mg/kg), or LBP + OXA (50 mg/kg + 10 mg/kg). The tumor weight and volume of treated model mice were measured, and organ toxicity was evaluated using hematoxylin and eosin staining. The expression levels of PMI, ABCG2, PI3K, and AKT proteins were then assessed using immunohistochemistry. Moreover, PMI and ABCG2 expression levels were analyzed using immunofluorescence and western blotting. The active components and possible targets of LBP in colon cancer were explored using in silico analysis. GeneCards was used to identify CC targets, and an online Venn analysis tool was used to determine intersection targets between these and LBP active components. The PPI network for intersection target protein interactions and the PPI network for interactions between the intersection target proteins and PMI was built using STRING and Cytoscape. To obtain putative targets of LBP in CC, we performed GO function enrichment and KEGG pathway enrichment analyses. Results: Compared with the HCT116-OXR blank treatment group, both invasion and migration abilities of HCT116-OXR cells were inhibited in the LBP + OXA (2.5 mg/mL LBP, 10 μΜ OXA) group (p < 0.05). Cells in the LBP + OXA (2.5 mg/mL LBP, 10 μΜ OXA) group were found to arrest in the G1 phase of the cell cycle. Knockdown of PMI was found to downregulate PI3K, AKT, and Bcl-2 (p < 0.05), while it was found to upregulate Bax (p < 0.05). After treatment with L. barbarum polysaccharide, 40 colon cancer subcutaneous tumor models showed a decrease in tumor size. There was no difference in the liver index after LBP treatment (p > 0.05). However, the spleen index decreased in the OXA and LBP + OXA groups (p < 0.05), possibly as a side effect of oxaliplatin. Immunohistochemistry, immunofluorescence, and western blotting showed that LBP + OXA treatment decreased PMI and ABCG2 expression levels (p < 0.05). Moreover, immunohistochemistry showed that LBP + OXA treatment decreased the expression levels of PI3K and AKT (p < 0.05). Network pharmacology analysis revealed 45 active LBP components, including carotenoids, phenylpropanoids, quercetin, xanthophylls, and other polyphenols. It also revealed 146 therapeutic targets of LBP, including AKT, SRC, EGFR, HRAS, STAT3, and MAPK3. KEGG pathway enrichment analysis showed that the LBP target proteins were enriched in pathways, including cancer-related signaling pathways, PI3K/AKT signaling pathway, and IL-17 signaling pathways. Finally, molecular docking experiments revealed that the active LBP components bind well with ABCG2 and PMI. conclusion: Our in vitro experiments showed that PMI knockdown downregulated PI3K, AKT, and Bcl-2 and upregulated Bax. This finding confirms that PMI plays a role in drug resistance by regulating the PI3K/AKT pathway and lays a foundation to study the mechanism underlying the reversal of colon cancer cell drug resistance by the combination of LBP and OXA. Our in vivo experiments showed that LBP combined with oxaliplatin could inhibit tumor growth. LBP showed no hepatic or splenic toxicity. LBP combined with oxaliplatin could downregulate the expression levels of PMI, ABCG2, PI3K, and AKT; it may thus have positive significance for the treatment of advanced metastatic colon cancer. Our network pharmacology analysis revealed the core targets of LBP in the treatment of CC as well as the pathways they are enriched in. It further verified the results of our in vitro and in vivo experiments, showing the involvement of multi-component, multi-target, and multi-pathway synergism in the drug-reversing effect of LBP in CC. Overall, the findings of the present study provide new avenues for the future clinical treatment of CC.

Chronic liver diseases mainly include chronic viral liver disease, metabolic liver disease, cholestatic liver disease (CLD), autoimmune liver disease, and liver fibrosis or cirrhosis. Notably, the compound formulas of traditional Chinese medicine (TCM) is effective for chronic liver diseases in clinical trials and basic research in vivo, which provide evidence of chronic liver disease treatment with integrated TCM and traditional Western medicine.

This paper aims to provide a comprehensive review of the compound formulas of TCM for treating different chronic liver diseases to elucidate the composition, main curative effects, and mechanisms of these formulas and research methods.

Different keywords related to chronic liver diseases and keywords related to the compound formulas of TCM were used to search the literature. PubMed, Scopus, Web of Science, and CNKI were searched to screen out original articles about the compound formulas of TCM related to the treatment of chronic liver diseases, mainly including clinical trials and basic in vivo research related to Chinese patent drugs, classic prescriptions, proven prescriptions, and hospital preparations. We excluded review articles, meta-analysis articles, in vitro experiments, articles about TCM monomers, articles about single-medicine extracts, and articles with incomplete or uncertain description of prescription composition. Plant names were checked with MPNS (http://mpns.kew.org).

In this review, the clinical efficacy and mechanism of compound formulas of TCM were summarized for the treatment of chronic viral hepatitis, nonalcoholic fatty liver disease, CLD, and liver fibrosis or cirrhosis developed from these diseases and other chronic liver diseases. For each clinical trial and basic research in vivo, this review provides a detailed record of the specific composition of the compound formulas of TCM, type of clinical research, modeling method of animal experiments, grouping methods, medication administration, main efficacy, and mechanisms.

The general development process of chronic liver disease can be summarized as chronic hepatitis, liver fibrosis or cirrhosis, and hepatocellular carcinoma. The compound formulas of TCM have some applications in these stages of chronic liver diseases. Owing to the continuous progress of medical technology, the benefits of the compound formulas of TCM in the treatment of chronic liver diseases are constantly changing and developing.

The effectiveness of chemotherapeutic agents for hepatocellular carcinoma (HCC) is unsatisfactory because of tumor heterogeneity, multidrug resistance, and poor target accumulation. Therefore, multimodality-treatment with accurate drug delivery has become increasingly popular. Herein, a cell penetrating peptide-aptamer dual modified-nanocomposite (USILA NPs) was successfully constructed by coating a cell penetrating peptide and aptamer onto the surface of sorafenib (Sora), ursolic acid (UA) and indocyanine green (ICG) condensed nanodrug (USI NPs) via one-pot assembly for targeted and synergistic HCC treatment. USILA NPs showed higher cellular uptake and cytotoxicity in HepG2 and H22 cells, with a high expression of epithelial cell adhesion molecule (EpCAM). Furthermore, these NPs caused more significant mitochondrial membrane potential reduction and cell apoptosis. These NPs could selectively accumulate at the tumor site of H22 tumor-bearing mice and were detected with the help of ICG fluorescence; moreover, they retarded tumor growth better than monotherapy. Thus, USILA NPs can realize the targeted delivery of dual drugs and the integration of diagnosis and treatment. Moreover, the effects were more significant after co-administration of iRGD peptide, a tumor-penetrating peptide with better penetration promoting ability or programmed cell death ligand 1 (PD-L1) antibody for the reversal of the immunosuppressive state in the tumor microenvironment. The tumor inhibition rates of USILA NPs + iRGD peptide or USILA NPs + PD-L1 antibody with good therapeutic safety were 72.38 % and 67.91 % compared with control, respectively. Overall, this composite nanosystem could act as a promising targeted tool and provide an effective intervention strategy for enhanced HCC synergistic treatment.

Hepatocellular carcinoma (HCC) is among the main causes of death by cancer worldwide, representing about 80-90% of all liver cancers. Treatments available for advanced HCC include atezolizumab, bevacizumab, sorafenib, among others. Atezolizumab and bevacizumab are immunological options recently incorporated into first-line treatments, along with sorafenib, for which great treatment achievements have been reached. However, sorafenib resistance is developed in most patients, and therapeutical combinations targeting cancer hallmark mechanisms and intracellular signaling have been proposed. In this review, we compiled evidence of the mechanisms of cell death caused by sorafenib administered alone or in combination with valproic acid and metformin and discussed them from a molecular perspective.

To construct a new diethylnitrosamine (DEN)-induced rat hepatocellular carcinoma (HCC) model with short induction time, high incidence, and survival rate.

60 male Sprague-Dawley rats were randomly divided into 4 groups: the control group, the model A (MA) group, the model B (MB) group, and the model C (MC) group. The control group was intraperitoneally injected with 0.9% saline for 6 weeks. The MA group was injected with the DEN solution at 30 mg/kg three times a week for 6 weeks. The MB group was injected with the DEN solution at 30 mg/kg three times a week for 6 weeks, and discontinued the induction for 2 weeks. The MC group was injected with the DEN solution at 30 mg/kg three times a week for 8 weeks. The levels of albumin (ALB), alanine transaminase (ALT), and aspartate aminotransferase (AST) in serum were assayed. Meanwhile, the pathological conditions, apoptosis of hepatocytes, expression of NF-κBp65, and the reactive oxygen species level were detected.

All rats in the control group and the MA group survived, and none of the rats occurred HCC. HCC occurred in rats of the MB group and the MC group. The serum ALB level in the MB group was higher than that in the MC group. The serum ALT and AST levels and the number of proliferating and apoptotic hepatocyte cells in the MB group were lower than those in the MC group. The expression of ROS- and NF-κBp6- positive cells in the MA group, MB group, and MC group were significantly higher than that of the control group.

This study developed a new DEN-induced rat HCC model with short induction time, high incidence, and survival rate. NF-κB pathway may be one of the main pathways involved in the development of this model.

Both ursolic acid (UA) and sorafenib (Sora) have been generally utilized in cancer treatment, and the combination of the two has also shown a good anti-tumor effect. However, single-agent therapy for Hepatocellular carcinoma (HCC) has the disadvantages of multi-drug resistance, poor water solubility and low bioavailability, and the application of traditional nanocarrier materials is limited due to their low drug loading and low carrier-related toxicity. Therefore, we prepared US NPs with different proportions of UA and Sora by solvent exchange method for achieving synergistic HCC therapy. US NPs had suitable particle size, good dispersibility and storage stability, which synergistically inhibited the proliferation of HepG2 cells, SMMC7721 cells and H22 cells. In addition, we also proved that US NPs were able to suppress the migration of HepG2 cells and SMMC7721 cells and reduce the adhesion ability and colony formation ability of these cells. According to the results, US NPs could degrade the membrane potential of mitochondrial, participate in cell apoptosis, and synergistically induce autophagy. Collectively, the carrier-free US NPs provide new strategies for HCC treatment and new ideas for the development of novel nano-drug delivery systems containing UA and Sora.

Pingchong Jiangni recipe (PJR) is often used in the treatment of endometriosis (EM). This formula has been clinically validated by the State Administration of Traditional Chinese Medicine Key Specialties Collaborative Group for its therapeutic efficacy. Recently, our research team also confirmed that PJR has a shrinking effect on ovarian chocolate cysts. Additionally, PJR was also found to have a shrinking effect on EM lesions; however, the mechanism by which this effect occurs remains unclear.

To explore the mechanisms by which PJR relieves pain in patients with EM.

A rat model of EM was established by autologous transplantation. PJR (3.78 g/kg, 7.56 g/kg, and 15.12 g/kg) was orally administered for 21 days. The rat grimace scale (RGS) score and paw withdrawal threshold (PWT) were measured at a fixed time during the experiment. Hematoxylin and eosin staining was performed to observe histopathological changes in EM rats after administration, enzyme-linked immunosorbent assay to evaluate the plasma expression of tumor necrosis factor-α (TNF-α) and nerve growth factor (NGF), and immunohistochemistry and western blotting to identify differences in the expression of pain-related factors in EM rats.

The medium-dose group of PJR (7.56 g/kg) had the best effect on relieving pain in EM rats by reducing RGS, increasing PWT, reducing the ectopic endometrium, improving the cellular structure of the lesion, and reducing TNF-α and NGF levels. However, PJR significantly decreased the expression of transient receptor potential vanilloid 1 (TRPV1), phosphorylated TRPV1 (p-TRPV1), protein kinase C (PKC), and NGF.

The mechanism by which PJR relieves EM pain may be through the downregulation of NGF, PKC, and TRPV1 expression.

Lobelia chinensis Lour. (LCL) is a common herb used for clearing heat and detoxifying, and it has antitumor activity. Quercetin is one of its important components, which may play an important role in the treatment of hepatocellular carcinoma (HCC).

To study the active ingredients of LCL, their mechanism of action on HCC, and lay the foundations for the development of new drugs for the treatment of HCC.

Network pharmacology was used to examine the probable active ingredients and mechanisms of action of LCL in HCC treatment. Based on an oral bioavailability of ≥30% and a drug-likeness index of ≥0.18, relevant compounds were selected from the Traditional Chinese Medicine Systems Pharmacology database and TCM Database@Taiwan. HCC-related targets were identified using gene cards and the Online Mendelian Inheritance in Man (OMIM) database. A Venn diagram was created to assess the relationship between the intersection of disease and medication targets by creating a protein-protein interaction network, and the hub targets were selected by topology. Gene Ontology enrichment analyses were performed using the DAVID tool. Finally, in vivo and in vitro experiments (qRT-PCR, western blotting, hematoxylin and eosin staining, transwell assays, scratch tests, and flow cytometry assays) verified that LCL demonstrated notable therapeutic effects on HCC.

In total, 16 bioactive LCL compounds met the screening criteria. The 30 most important LCL therapeutic target genes were identified. Of these, AKT1 and MAPK1 were the most important target genes, and the AKT signaling pathway was identified as the key pathway. Transwell and scratch assays showed that LCL prevented cell migration, and flow cytometry tests revealed that the LCL-treated group showed a considerably higher rate of apoptosis than the control group. LCL reduced tumor formation in mice in vivo, and Western blot analysis of tumor tissues treated with LCL indicated variations in PTEN, p-MAPK and p-AKT1 levels. The results show that LCL may inhibit the progression of HCC through the PTEN/AKT signaling pathway to achieve the goal of treating HCC.

LCL is a broad-spectrum anticancer agent. These findings reveal potential treatment targets and strategies for preventing the spread of cancer, which could aid in screening potential traditional Chinese medicine for anticancer and clarifying their mechanisms.

The protein Solute Carrier Family 7 Member 11 (SLC7A11) plays a pivotal role in cellular redox homeostasis by suppressing disulfidptosis, which restricts tumor growth. Yet, its relevance in prognosis, immunity, and cancer treatment efficacy is not well understood.

We conducted a comprehensive analysis of the expression of SLC7A11 across 33 cancer types, employing datasets from public databases. Methods, such as Cox regression and survival analyses assessed its prognostic significance, while functional enrichment explored the biological processes tied to SLC7A11. The association between SLC7A11 expression, immune cell infiltration, and immune-related gene expression was also scrutinized.

Notably, SLC7A11 expression was more pronounced in cancerous compared to normal samples and correlated with higher tumor grades. Increased SLC7A11 expression was linked to poor outcomes, particularly in liver hepatocellular carcinoma (LIHC). This protein's expression also showcased significant relationships with diverse molecular and immune subtypes. Additionally, a prognostic nomogram was devised, integrating SLC7A11 expression and clinical variables. High SLC7A11 levels corresponded with cell growth and senescence pathways in various cancers and with lipid and cholesterol metabolism in LIHC. Furthermore, potential therapeutic compounds for LIHC with high SLC7A11 were identified. Real-time PCR (qPCR) and Western blot were conducted to explore the expression of SLC7A11 in tumor tissues and cancer cell lines.

In summation, this study emphasizes the prognostic and immunological importance of SLC7A11, spotlighting its potential as a therapeutic target in LIHC.

Sorafenib, an FDA-approved standard chemotherapy for advanced hepatocellular carcinoma, is associated with numerous adverse effects that significantly impact patients' physiological well-being. Consequently, identifying agents that mitigate these side effects while enhancing efficacy is crucial. Hesperetin, a flavone present in fruits and vegetables, possesses antioxidant, anti-inflammatory, and anti-cancer properties. This study aimed to investigate the hepatotoxic and neurotoxic effects of sorafenib and the potential protective role of hesperetin.

Swiss albino mice were orally administered sorafenib (100 mg/kg) alone or in combination with hesperetin (50 mg/kg) over 21 days. Behavioral assessments for anxiety and depressive-like behaviors were conducted. Additionally, evaluations encompassed apoptotic activity, mitochondrial integrity, liver enzyme levels, proliferation rates, and histopathological changes.

Combining hesperetin with sorafenib showed improvements in behavioral alterations, liver damage, brain mitochondrial dysfunction, and liver apoptosis compared to the sorafenib-only group in mice.

Hesperetin exhibits potential as an adjunct to sorafenib, mitigating its side effects by attenuating its toxicity, enhancing efficacy, and potentially reducing the occurrence of sorafenib-induced resistance through the downregulation of hepatocyte growth factor levels.

Nonalcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome in the liver and the leading cause of chronic liver disease worldwide. Digeda-4 decoction (DGD-4) is a commonly prescribed Mongolian herbal drug for treating acute and chronic liver injury and fatty liver. However, the mechanisms underlying the improvement of dislipidemia and liver injury via treatment with DGD-4 remain unclear. Disassembling a prescription is an effective approach to studying the effects and mechanisms underlying Mongolian medicine prescriptions. By disassembling a prescription, it is feasible to discover effective combinations of individual herbs to optimize a given prescription. Accordingly, we disassembled DGD-4 into two groups: the single Lomatogonium rotatum (L.) Fries ex Nym (LR) (DGD-1) and non-LR (DGD-3).

To study whether DGD-4 and its disassembled prescriptions have protective effects against tyloxapol (TY)-induced NAFLD and to explore the underlying mechanisms of action and compatibility of prescriptions.

NAFLD mice were developed by TY induction. Biochemical horizontal analyses, enzyme-linked immunosorbent assay, and liver histological staining were performed to explore the protective effects of DGD-4 and its disassembled prescriptions DGD-3 and DGD-1. Furthermore, we performed immunohistochemical analyses and Western blotting to further explore the expression of target proteins.

DGD-4 and its disassembled prescriptions could inhibit TY-induced dislipidemia and liver injury. In addition, DGD-4 and its disassembled prescriptions increased the levels of p-AMPKα and p-ACC, but decreased the levels of SREBP1c, SCD-1, SREBP-2, and HMGCS1 proteins. The activation of lipid metabolic pathways SIRT1, PGC-1α, and PPARα improved lipid accumulation in the liver. Moreover, DGD-4 could inhibit hepatocyte apoptosis and treat TY-induced liver injury by upregulating the Bcl-2 expression, downregulating the expression of Bax, caspase-3, caspase-8, and the ratio of Bax/Bcl-2, and positively regulating the imbalance of oxidative stress (OxS) markers (such as superoxide dismutase [SOD], catalase [CAT], malondialdehyde [MDA], and myeloperoxidase [MPO]). DGD-1 was superior to DGD-3 in regulating lipid synthesis-related proteins such as SREBP1c, SCD-1, SREBP-2, and HMGCS1. DGD-3 significantly affected the expression of lipid metabolic proteins SIRT1, PGC-1α, PPARα, apoptotic proteins Bcl-2, Bax, caspase-3, caspase-8, and the regulation of Bax/Bcl-2 ratio. However, DGD-1 showed no regulatory effects on Bax and Bcl-2 proteins.

This study demonstrates the protective effects of DGD-4 in the TY-induced NAFLD mice through a mechanism involving improvement of dyslipidemia and apoptosis by regulating the AMPK/SIRT1 pathway. Although the Monarch drug DGD-1 reduces lipid accumulation and DGD-3 inhibits apoptosis and protects the liver from injury, DGD-4 can be more effective overall as a therapy when compared to DGD-1 and DGD-3.

Cancer, an intricate and multifaceted disease, is characterized by the uncontrolled proliferation of cells that can lead to serious health complications and ultimately death. Conventional therapeutic strategies mainly target rapidly dividing cancer cells, but often indiscriminately harm healthy cells in the process. As a result, there is a growing interest in exploring novel therapies that are both effective and less toxic to normal cells. Herbs have long been used as natural remedies for various diseases and conditions. Some herbal compounds exhibit potent anti-cancer properties, making them potential candidates for nutraceutical-based treatments. However, despite their promising efficacy, there are considerable limitations in utilizing herbal preparations due to their poor solubility, low bioavailability, rapid metabolism and excretion, as well as potential interference with other medications. Nanotechnology offers a unique platform to overcome these challenges by encapsulating herbal compounds within nanoparticles. This approach not only increases solubility and stability but also enhances the cellular uptake of nutraceuticals, allowing for controlled and targeted delivery of therapeutic agents directly at tumor sites. By harnessing the power of nanotechnology-enabled therapy, this new frontier in cancer treatment presents an opportunity to minimize toxicity while maximizing efficacy. In conclusion, this manuscript provides compelling evidence for integrating nanotechnology with nutraceuticals derived from herbal sources to optimize cancer therapy outcomes. We explore the roadblocks associated with traditional herbal treatments and demonstrate how nanotechnology can help circumvent these issues, paving the way for safer and more effective cancer interventions in future oncological practice.