Neurological disorders, encompassing neurodegenerative and neuroinflammatory conditions, present significant public health and clinical challenges. Recent research has elucidated the pivotal role of various enzymes in the onset and progression of these disorders. This review explores the therapeutic potential of targeting these enzymes with natural and synthetic molecules. Key enzymes, including acetylcholinesterase, monoamine oxidase, beta-secretase, tau kinases, caspases, and cyclooxygenase-2, are implicated in diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Modulating these enzymes can alleviate symptoms, slow disease progression, or reverse pathological changes. Natural molecules derived from plants, microbes, seaweeds, and animals have long been noted for their therapeutic potential. Their ability to interact with specific enzymes with high specificity and minimal side effects makes them promising candidates for treatment. These natural agents provide a foundation for developing targeted therapies with improved safety profiles. Simultaneously, the development of synthetic chemistry has resulted in molecules designed to inhibit neurodegenerative enzymes with precision. This review examines the progress in creating small molecules, peptides, and enzyme inhibitors through sophisticated drug design techniques. It evaluates the efficacy, safety, and mechanisms of these synthetic agents, highlighting their potential for clinical application. The review offers a comprehensive overview of recent advancements in enzyme-targeted therapies for neurological disorders, covering both natural and synthetic molecules investigated in preclinical and clinical settings. It discusses the mechanisms through which these molecules exert their effects, the challenges faced in their development, and future research directions. By synthesizing current knowledge, this paper aims to illuminate the potential of enzyme-targeted interventions in managing neurological disorders, showcasing both the promise and limitations of these approaches.

We report the coencapsulation of fluorocoxib Q (FQ) and chemocoxib A (CA) in micellar nanoparticles (FQ-CA-NPs) of a new PPS135-b-POEGA17 diblock polymer, which exhibited a hydrodynamic diameter of 109.2 ± 4.1 nm and a zeta potential (ζ) of -1.59 ± 0.3 mV. The uptake of FQ-CA-NPs by 4T1 mouse mammary cancer cells and intracellular cargo release were assessed by fluorescence microscopy that resulted in increased fluorescence in 4T1 cells compared to cells pretreated with celecoxib. The viability of primary human mammary epithelial cells (HMECs) or 4T1 mouse mammary carcinoma cells treated with FQ-CA-NPs were assessed, which showed decreased growth of 4T1 breast cancer cells but showed no effect on the growth of primary human mammary epithelial cells (HMECs). Intravenous dosing of FQ-CA-NPs in mice enabled ROS-induced cargo (FQ and CA) release and fluorescence activation of FQ and resulted in increased fluorescence in breast tumors compared to the tumors of animals pretreated with tempol or celecoxib, and minimum fluorescence was detected in the tumors of animals treated with nothing or empty-NPs. In addition, tumor tissues from treated animals were analyzed ex vivo by liquid chromatography-mass spectrometry (LC-MS)/MS, and identified increased levels of cargo delivery and retention in the tumor compared to tempol- or celecoxib-pretreated animal tumors. These in vivo and ex vivo results confirmed the targeted delivery of loaded NPs followed by ROS-mediated cargo release and fluorescence activation for targeted visualization of drug delivery in breast tumors and CA-induced therapeutic effect in an in vivo tumor growth inhibition assay and an ex vivo hematoxylin and eosin (H&E) staining of tumor tissues. Thus, coencapsulation of FQ and CA into polymeric micellar nanoparticles (FQ-CA-NPs) enabled their ROS-sensitive release followed by fluorescence activation and COX-2-dependent tumor targeting and retention in the visualization of CA delivery in solid breast tumors.

Neutrophil-based drug delivery systems for targeted therapy of cancer have been studied widely in the recent past. Chemotactic cytokines including colony-stimulating factors (CSFs) recruit various immune cells including the neutrophils to the tumor microenvironment (TME) leading to enhanced metastasis. These cytokines can be targeted effectively by immunotherapeutic agents such as checkpoint inhibitors and mAbs that can lead to systemic toxicity. To minimize the systemic adverse effects, camouflaged nanoparticles can be used significantly as alternative therapeutic agents. The neutrophil-interacting NPs and neutrophil membrane coated NPs have been exploited recently for their antitumor properties in vitro and pose limited systemic adverse effects in vivo. Neutrophil-derived exosomes derived from immune cells can efficiently escape immune-surveillance and pass through the blood-brain barrier. They possess several intrinsic properties in drug delivery as they are nano-sized, extremely biocompatible, non-immunogenic, biodegradable, stable and can carry targeting agents with limited toxicity and display antitumor properties. Also, neutrophil-based nanotherapy is dependent on factors such as neutrophil kinetics and the physicochemical properties of NPs such as size, shape, and surface chemistry. Therefore, neutrophil-based drug delivery for cancer therapy via the use of polymer nanoparticles is widely studied as their clinical appliance in nanomedicine is still at its infancy.

Trichinellosis is a global zoonotic disease affecting humans and nearly all animal species. The intestinal (enteric) phase of trichinellosis is critical, as it determines the course and prognosis of the disease. The medications used in the management of trichinellosis demonstrate inadequate bioavailability, along with a significant level of resistance. Therefore, there is a need for the development of novel agents that enhance the bioavailability of administered medications. Nanobiotechnology has emerged as a significant strategy in treating parasitic diseases. This study examined the use of solid lipid nanoparticles (SLNs) to improve the efficacy of oral ivermectin (IVM) in treating the enteric phase of trichinellosis. Thirty-five Swiss albino mice were divided into seven equal groups as follows: negative control, positive control, albendazole, ivermectin, SLNs, ivermectin loaded on solid lipid nanoparticles (IVM-SLNs), and a combination of IVM-SLNs and albendazole. Mice were sacrificed on the seventh day post-infection. The drugs' effects were assessed using parasitological, biochemical, histological, histochemical and immunohistochemical analyses. The co-administration of albendazole and IVM-SLNs resulted in a significant decrease in adult burden, inflammatory cell infiltration, and apoptosis. Furthermore, a significant reduction in Cyclooxygenase-2 (COX-2) expression was observed compared to the infected untreated control group, along with improved liver and kidney function indices. In conclusion, the potent trichinocidal effect of a single oral dose of IVM-SLNs against Trichinella adults makes them a promising alternative or adjunct to existing nematicidal agents.

Macrophages, polarized into pro-inflammatory M1 or anti-inflammatory M2 states, are essential cellular elements of innate immunity. In the tumor microenvironment, owing to a paracrine manipulative program by cancerous cells, tumor-associated macrophages (TAMs) evolve, which can shift between M1-like and M2-like phenotypes. Since it is fairly unknown how the promising anticancer agents, silver (AgNPs) and gold nanoparticles (AuNPs) affect the bidirectional communication and reprogramming in the tumor stroma, we examined the behavior, the tumor-supporting functions, and the expression of polarization and functional marker genes of TAMs to reveal how these are modulated upon interaction with nanoparticle-exposed cancer cells.

We established co-cultures of murine immortalized J774 or primary bone marrow-derived macrophages with 4T1 breast cancer cells treated with AuNPs or AgNPs or with none of the nanoparticles. We assessed the expression of macrophage polarization and functional markers using RT-qPCR and Proteome Profiler Array and evaluated macrophage migration and matrix metalloproteinase activity by specific assays.

Protein and mRNA levels of most examined factors - except tumor necrosis factor-alpha - such as C-C-motif chemokine ligands 2 and 22, interleukin-23, inducible nitric oxide synthase, cyclooxygenase-2, the macrophage mannose receptor CD206, transforming growth factor-beta, and chitinase-like-3 protein decreased, and the expression of polarization markers revealed a shift towards M1-like phenotype in macrophages co-cultured with AgNP- or AuNP-treated 4T1 cells. Both nanoparticle treatments reduced the levels and activity of cell migration-related factors, such as C-C motif chemokine ligand 3, matrix metalloproteinases, and suppressed macrophage migration.

Both AuNPs and AgNPs showed a remarkable ability to influence macrophage-cancer cell communication, suppressed indirectly M2-like TAM polarization, and perturbed the migration behavior of TAMs that is critical for tumor invasion, indicating modulated immunological functions and debilitated cancer-promoting capabilities of TAMs in this microenvironment.

In recent years, precision medicine for non-small cell lung cancer (NSCLC) has made significant strides, particularly with advancements in diagnostic and therapeutic technologies. Targeted 7therapies and Anti-PD-(L)1 Therapies have emerged as vital treatment options, yet KRAS mutations, especially KRAS G12C, have been historically difficult to address. Due to the unique activation mechanism of KRAS G12C has led to the development of specific inhibitors, such as AMG 510 and MRTX849, which show promising therapeutic potential. However, results from the CodeBreaK 200 Phase III trial indicated that AMG 510 did not significantly improve overall survival compared to docetaxel. Resistance after prolonged use of KRAS G12C inhibitors continues to pose a challenge, prompting interest in new drugs and combination strategies. KRAS mutations can impair tumor-infiltrating T cell function and create an immunosuppressive tumor microenvironment, making the combination of KRAS G12C inhibitors with anti-PD-(L)1 therapies particularly appealing. Preliminary data suggest these combinations may enhance both survival and quality of life, though safety concerns remain a barrier. Ongoing research is crucial to refine treatment regimens and identify suitable patient populations. This review focuses on the development of KRAS G12C inhibitors in monotherapy and combination therapies for NSCLC, discussing major clinical trials and future research directions.

The arachidonic acid (AA) pathway promotes tumor progression by modulating the complex interactions between cancer and immune cells within the microenvironment. In this Review, we summarize the knowledge acquired thus far concerning the intricate mechanisms through which eicosanoids either promote or suppress the antitumor immune response. In addition, we will discuss the impact of eicosanoids on immune cells and how they affect responsiveness to immunotherapy, as well as potential strategies for manipulating the AA pathway to improve anticancer immunotherapy. Understanding the molecular pathways and mechanisms underlying the role played by AA and its metabolites in tumor progression may contribute to the development of more effective anticancer immunotherapies.

Inorganic polyphosphate (PolyP) is a high-molecular-weight polymer that plays multiple roles in regulating immune responses. However, the specific anti-inflammatory mechanisms of bacteria-derived PolyP are unclear. In the present study, PolyP was extracted from Lactobacillus plantarum (L. plantarum), and the chain length was estimated to be approximately 250 Pi residues. The immune regulatory functions of PolyP were investigated using a lipopolysaccharide (LPS)-induced RAW264.7 cell oxidative stress model, and dexamethasone was used as a positive control. The result revealed that both dexamethasone and PolyP were protective against oxidative stress by inhibiting macrophage M1 polarization and the production of several markers, such as nitric oxide (NO), reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2. In addition, PolyP suppressed inflammation progression by regulating the production of several cytokines, such as interleukin (IL)-1β, interferon (INF)-γ, tumor necrosis factor (TNF)-α, and IL-6, and inhibited the expressions of inhibitory κB kinase (IKK) α, IKKβ, and extracellular regulated protein kinases 2 (ERK2). Conclusively, PolyP derived from L. plantarum has the ability to protect cells from oxidative stress damage by inhibiting M1 polarization in macrophages. These findings provide insights into the function of PolyP and offer support for the potential application of PolyP in immune-related diseases.

Growth hormone-releasing hormone (GHRH) antagonists exert antitumor functions in different experimental cancers. However, their role in combination with radiotherapy in non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the radiosensitizing effect of GHRH antagonists in NSCLC. A549 and H522 NSCLC cell lines were exposed to ionizing radiation (IR) and GHRH antagonists MIA-602 and MIA-690, either individually or in combination. Cell viability and proliferation were evaluated by MTT, BrdU, flow cytofluorimetry, and clonogenic assays; gene and protein expression, signaling pathways, and apoptosis were analyzed by real-time PCR, Western blot, annexin staining, and caspase-3 assay. GHRH antagonists showed antitumor effects alone and potentiated IR-induced inhibition of cell viability and proliferation. The combination of MIA-690 and IR decreased the expression of GHRH receptor, its oncogenic splice variant 1, and IGF1 mRNA levels. Additionally, cell cycle inhibitors and proapoptotic markers were upregulated, whereas cyclins, oncogenic MYC, and the antiapoptotic protein Bcl-2 were downregulated. Radioresistance was prevented by MIA-690, which also blunted epithelial-mesenchymal transition by enhancing E-cadherin and reducing mesenchymal, oxidative, and proangiogenic effectors. Finally, both MIA-602 and MIA-690 enhanced radiosensitivity in primary human NSCLC cells. These findings highlight the potential of GHRH antagonists as radiosensitizers in NSCLC treatment.

The efficacy of cancer immunotherapy is significantly influenced by the heterogeneity of individual tumors and immune responses. To investigate this phenomenon, a microfluidic platform is constructed for profiling immune-cancer cell interactions at the single-cell proteomics level for the first time. Based on the platform, a comprehensive workflow is proposed for achieving accurate single-cell pairing of an immune cell and a cancer cell with low cell damage and high success rate up to 95%, cell pair co-culture, and real-time microscopic monitoring of the cell-pair interactions, cell pair retrieval, mass spectrometry-based proteomic analysis of singe cell pairs, and decoupling of the proteomic information for each cell within the cell pair with the stable-isotope labeling method. With the workflow, the interactions of single natural killer (NK) cells and single K562 tumor cells are investigated based on real-time images and single cell-pair proteomics. Notably, an identification depth of over 1000 protein groups in a single cell-pair is achieved, leading to the discovery of sub-clusters of NK cells with different functions and the identification of important biomarkers for cancer treatments. This demonstrates the unique capability of the present platform in providing substantial and comprehensive datasets for profiling immune-cancer cell interactions, discovering heterogeneous immune responses, and predicting biomarkers in the study of cancer immunotherapy.

Metabolic reprogramming is one of the major biological features of malignant tumors, playing a crucial role in the initiation and progression of cancer. The tumor microenvironment consists of various non-cancer cells, such as hepatic stellate cells, cancer-associated fibroblasts (CAFs), immune cells, as well as extracellular matrix and soluble substances. In liver cancer, metabolic reprogramming not only affects its own growth and survival but also interacts with other non-cancer cells by influencing the expression and release of metabolites and cytokines (such as lactate, PGE2, arginine). This interaction leads to acidification of the microenvironment and restricts the uptake of nutrients by other non-cancer cells, resulting in metabolic competition and symbiosis. At the same time, metabolic reprogramming in neighboring cells during proliferation and differentiation processes also impacts tumor immunity. This article provides a comprehensive overview of the metabolic crosstalk between liver cancer cells and their tumor microenvironment, deepening our understanding of relevant findings and pathways. This contributes to further understanding the regulation of cancer development and immune evasion mechanisms while providing assistance in advancing personalized therapies targeting metabolic pathways for anti-cancer treatment.

Medicines, food packaging, personal care products, and cosmetics extensively use polyethylene terephthalate nanoplastics (PET-NaPs). However, they also have harmful impacts on several organs. Betaine demonstrates potent antioxidant and anti-inflammatory characteristics. Our goal was to investigate the detrimental impact of PET-NaPs on the mouse brain and evaluate the neuroprotective properties of betaine. We allocated 40 completely mature male Swiss albino mice into four distinct groups: control group, betaine group, PET-NaPs group, and betaine-co-treated group. Following a 30-day duration, euthanasia was performed on the mice, and analyzed tissue samples were obtained from the cerebrum, cerebellum, and hippocampus. PET-NaPs resulted in an elevated level of malondialdehyde and upregulated cyclooxygenase-2 and interleukin-1 beta (IL-1β) expression while significantly reducing the levels of glutathione and downregulating acetylcholinesterase. The PET-NPs also caused significant changes in the histopathology of the brain tissue, and there was a demonstrable rise in the immunostaining of IL-1β and glial fibrillary acidic proteins. Consequently, betaine effectively alleviated the negative consequences of PET-NaPs. Therefore, betaine possesses the capacity to mitigate the neurotoxic consequences induced by PET-NaPs.

Neuroinflammation is associated with the development of postoperative cognitive dysfunction (POCD). Parecoxib has powerful anti-inflammatory and analgesic effects, which may reduce the occurrence of POCD. We hypothesized that parecoxib could reduce the incidence of POCD and relieve postoperative pain without increasing postoperative complications in elderly patients with gastrointestinal cancer. The study analyzed the effect of parecoxib on elderly patients undergoing elective radical resection of gastrointestinal tumors. Patients were divided into the NSAIDs group and the non-NSAIDs group according to whether parecoxib was administered. Demographic and clinical data were collected and compared. The incidence of POCD was set as the primary outcome, and postoperative pain as the secondary outcome. Among the 440 enrolled patients, the POCD incidence rates within 7 days after surgery in the NSAIDs and non-NSAIDs groups were 42.60% and 40.30%, respectively, with no statistically significant difference (P > 0.05). Patients in the NSAIDs group experienced significantly less pain on the first and second days after surgery compared to the non-NSAIDs group (P < 0.05). There were no statistically significant differences in postoperative adverse events between the two groups (P > 0.05). Parecoxib had no significant negative effect on early postoperative cognitive function, effectively alleviating early postoperative acute pain without increasing postoperative complications. The findings have implications for the broader use of parecoxib in postoperative pain management in elderly patients undergoing major surgery.

Cancer is characterized by unregulated cell proliferation, enabling it to invade and spread to different organs and tissues in the body. Cancer progression is intricately influenced by the complex dynamics within the tumor microenvironment (TME). The TME is a composite and dynamic network comprising cancer cells and various immune cells, including tumor-associated macrophages. Exosomes facilitate the communication between different cancer cells as well as other types of cells. This review particularly focuses on exosomal proteins derived from different cancer cells in mounting the complex crosstalk between cells of cancer and macrophages within the TME. Most cancer-derived exosomal proteins polarize macrophages towards M2 phenotype, promoting cancer aggressiveness, while a few have role switching towards the M1 phenotype, inhibiting cancer proliferation, respectively. In this review, we summarize, for the first time, the dual impact of cancer cell-derived exosomal proteins on macrophage polarization and the associated signaling pathways, offering valuable insights for developing innovative therapeutic strategies against diverse cancer types.

Inflammation is an important physiological response of the organism to restore homeostasis upon pathogenic or damaging stimuli. However, the persistence of the harmful trigger or a deficient resolution of the process can evolve into a state of low-grade, chronic inflammation. This condition is strongly associated with the development of several increasingly prevalent and serious chronic conditions, such as obesity, cancer, and cardiovascular diseases, elevating overall morbidity and mortality worldwide. The current pandemic of chronic diseases underscores the need to address chronic inflammation, its pathogenic mechanisms, and potential preventive measures to limit its current widespread impact. The present review discusses the current knowledge and research gaps regarding the association between low-grade chronic inflammation and chronic diseases, focusing on obesity, cardiovascular diseases, digestive diseases, and cancer. We examine the state of the art in selected aspects of the topic and propose future directions and approaches for the field.

Colorectal cancer (CRC) poses a significant global health burden, being the third most prevalent cancer and the second most significant contributor to cancer-related deaths worldwide. Preventive strategies are crucial to combat this rising incidence. 6-shogaol, derived from ginger, has shown promise in preventing and treating various cancers. This study investigated the preventive effects of 6-shogaol on azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CRC in mice. Forty male BALB/c mice were randomly divided into control, 6-shogaol, AOM + DSS, and 6-shogaol + AOM + DSS. Mice in the control group received corn oil for 16 weeks, while those in the 6-Shogaol group were administered 20 mg/kg of 6-shogaol for 16 weeks. The AOM + DSS group received a single intraperitoneal dose (ip) of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The 6-shogaol + AOM + DSS group received both 6-shogaol for 16 weeks and a single ip of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The AOM + DSS-treated mice exhibited reduced food consumption, colon weight, and colon length, along with increased tumor formation. Co-administration of 6-shogaol effectively reversed these changes, inhibiting CRC development. Histopathological analysis revealed protective effects of 6-shogaol against colonic insults and modulation of inflammatory responses. 6-shogaol significantly reduced Carcinoembryonic antigen and Kiel 67 levels, indicating inhibition of tumor cell proliferation. Mechanistically, 6-shogaol promoted apoptosis by upregulating protein 53 and caspase-3 expression, and it effectively restored the balance of the Wingless-related integration site signaling pathway by regulating β-catenin and adenomatous polyposis coli levels. Moreover, 6-shogaol demonstrated anti-inflammatory effects, reducing myeloperoxidase, Tumor necrosis factor alpha, and cyclooxygenase-2 levels in AOM/DSS-treated mice. Additionally, 6-shogaol restored redox homeostasis by reducing lipid peroxidation and nitrosative stress and enhancing antioxidant enzyme activities. The findings suggest that 6-shogaol inhibits cell proliferation, induces apoptosis, regulates Wnt signaling, suppresses inflammation, and restores redox homeostasis, providing comprehensive insights into its potential therapeutic benefits for CRC.

Targeting oxidative stress and inflammatory signaling pathways is an effective cancer prevention and therapy approach. The mechanism of action of synthesized salicylidene-based compounds was investigated in regulating key molecular targets of breast cancer development. Compounds (1), (4), (5), and (7) were found to be more cytotoxic to MCF-7 and 4T1 cells compared to non-cancerous Chang liver cells, while these compounds were cytotoxic to MDA-MB-231 cells, but with poor selectivity. The colony formation assay indicated that bioactive compounds induced significant damage to breast cancer cells, as observed by a reduction in the number of colonies compared to control cells. By inducing a concentration and time-dependent increase of luminescence and fluorescence of phosphatidylserine, and activating the expression of caspases-3, -7, -8, -9 in breast cancer cells, (1) and (7) have shown to induce caspase-dependent apoptosis. The downregulation of NF-kB-p65 and an upregulation of TP53 expression after exposure to bioactive compounds, demonstrated the suppression of two key targets of breast cancer development. Molecular docking studies revealed that selected protein targets strongly interact with bioactive compounds, and the estimated inhibition constants (Ki) of JAK2, STAT3, COX-2, HPV31 E6, EGFR1, TP53, and PARP1 were significantly decreased compared to acetylsalicylic acid. This could be a clear indication that these protein targets are implicated with antiproliferative efficacy, thereby warranting the potential of (1) and (7) to be used as anti-breast cancer drug candidates.

CA102N is a novel anticancer drug developed by covalently linking H-Nim (N-(4-Amino-2-phenoxyphenyl methanesulfonamide) to Hyaluronic Acid to target CD44 receptor-rich tumors. The proposed approach seeks to enhance the efficacy and overcome limitations associated with H-Nim, including poor solubility and short half-life.

The study aimed to evaluate the pharmacokinetics, biodistribution, metabolism, and tumor permeability of [14C] CA102N in xenograft mice following a single intravenous dose of 200 mg/kg. Liquid scintillation counting analysis was used for the pharmacokinetics and mass balance analysis. Metabolite profiling was assessed by HPLC-MS coupled with a radio flow-through detector. Quantitative Whole-Body Autoradiography was used to determine tissue distribution. Concentrations of CA102N and its metabolites were measured using total radioactivity data from urine, feces, and tissue samples.

About 94.9% of the administered dose was recovered at 240 h post-dose. The primary route of radioactivity elimination was through urine, accounting for an average of 77% of the dose with around 13.2% excreted in the feces. Tissue distribution showed rapid accumulation within 0.5 h post-administration, followed by a fast decline in most tissues except for the tumor, where slow elimination was observed. CA102N/metabolites exhibited a two-phase pharmacokinetic profile, characterized by an initial rapid distribution phase and a slower terminal elimination, with a half-life (t1/2) of 22 h. The mean maximum concentration (Cmax) of 1798.586 µg equivalents per ml was reached at 0.5 h (Tmax). Most of the radioactivity in plasma was attributed to CA102N, while small-molecule hydrolysis products dominated the excreta and tissue samples. Metabolite profiling revealed two major hydrolysis products: H-Nim-disaccharide and H-Nim-tetrasaccharide. No unchanged [14C] CA102N was detected in urine or feces, suggesting that CA102N undergoes extensive metabolism before excretion.

The current data provided valuable insights into the pharmacokinetics, metabolism, and tissue/tumor distribution of CA102N in mice. These findings demonstrated that metabolic clearance is the primary elimination pathway for CA102N and that the drug exhibits tumor retention, supporting its development as an anticancer therapy. Our results provided a strong pharmacological basis for the advancement of CA102N into the clinic.

Prostate cancer (Pca) is a deadly disease prevalent among men, and it accounts for about 7-8 % of mortality globally. Synthetic drugs have proved effective but have limitations and severe side effects. There is, therefore, a need to discover a less expensive, natural therapeutic agent with no side effects in treating the ailment.

The study aims to investigate the anti-prostate cancer activity of extracts of Indigofera macrophylla (I. macrophylla) at the physiological and molecular levels in experimental animals.

Polyphenol-rich extract of I. macrophylla was subjected to HPLC analysis to identify the plant's phytochemical constituent. Adult Wistar rats were orally administered 2mls of 50, 100 and 200 PPM of the cacodylic acid solution for 28 days to induce prostate cancer, while treatment was carried out by orally administering extract of I. macrophylla at doses of 50, 100 and 200 mg/kg for up to 28 days. The anti-inflammatory and apoptotic properties of the extract in experimental animals were investigated by the expression levels of various genetic biomarkers such as Bax-2, TNF-α, IL-6, COX2, IL-1β, β-Catenin, APC, Bcl2, CEA, Caspase 3 and β-Catenin using reverse transcriptase polymerase chain reaction (RT-PCR).

HPLC analysis shows that I. macrophylla has 21 bioactive components which are categorized into seven groups: flavonoid, terpenes, phenols, isoflavonoid, phytosterols, quinone and glycosides. Administration of the drug shows inconsistencies in the mean body weights of the experimental animals. Further investigation revealed that I. macrophylla increased TNF-α upregulation and expression, significantly downregulated IL-1β, significantly decreased IL-6 expression, ameliorated COX2 expression, downregulated β-catenin expression and significantly reduced the expression of the APC gene. These results show that the drug activity modulates the investigated inflammatory and apoptotic genes in the prostate gland of PCa-induced rats, thus demonstrating its anti-PCa potential.

The results of this study suggest the potential of a novel treatment protocol of I. macrophylla plant extract to improve therapeutic outcomes for patients with aggressive PCa, which reportedly claims hundreds of thousands of lives yearly.

Triple-negative breast cancer (TNBC) lacks the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), rendering it unresponsive to endocrine therapy and HER2 targeted treatments. Though certain chemotherapeutics targeting the cell cycle have shown efficacy to a certain extent, the presence of chemotherapy-resistant cancer stem cells (CSCs) presents a significant challenge in tackling TNBC. Multiple lines of evidence suggest the upregulation of neuropeptide Substance P (SP), its NK-1 receptor (NK1R) and the Cyclooxygenase-2 (COX-2) enzyme in TNBC patients. Upregulation of the SP/NK1R system and COX-2 influences major signalling pathways involved in cell proliferation, growth, survival, angiogenesis, inflammation, metastasis and stem cell activity. The simultaneous activation and crosstalk between the pathways activated by SP/NK1R and COX-2 consequently increase the levels of key regulators of self-renewal pathways in CSCs, promoting stemness. The combination therapy with NK1R antagonists and COX-2 inhibitors can simultaneously target TNBC cells and CSCs, thereby enhancing treatment efficacy and reducing the risk of recurrence and relapse. This review discusses the rationale for combining NK1R antagonists and COX-2 inhibitors for the better management of TNBC and a novel strategy to deliver drug cargo precisely to the tumour site to address the challenges associated with off-target binding.

Breast cancer (BC) is the most frequently diagnosed malignancy among women. It is characterized by a high level of heterogeneity that emerges from the interaction of several cellular and soluble components in the tumor microenvironment (TME), such as cytokines, tumor cells and tumor-associated immune cells. Tumor necrosis factor (TNF) receptor 2 (TNFR2) appears to play a significant role in microenvironmental regulation, tumor progression, immune evasion, drug resistance, and metastasis of many types of cancer, including BC. However, the significance of TNFR2 in BC biology is not fully understood. This review provides an overview of TNFR2 biology, detailing its activation and its interactions with important signaling pathways in the TME (e.g., NF-κB, MAPK, and PI3K/Akt pathways). We discuss potential therapeutic strategies targeting TNFR2, with the aim of enhancing the antitumor immune response to BC. This review provides insights into role of TNFR2 as a major immune checkpoint for the future treatment of patients with BC.

Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.

This study aimed to investigate the effects of combined exposure to noise (85 dB(A)) and inhaled Toluene (300 ± 10 ppm) on rat lung health. It also aimed to assess the potential therapeutic effects of Olea europaea L. leaves extract (OLE) (40 mg/kg/day) using biochemical, histopathological, and immunohistochemical (IHC) analyses, as well as determination of pro-inflammatory cytokines (TNF-α and IL-1β), and in silico Docking studies. The experiment involved forty-two male Wistar rats divided into seven groups, each exposed to a 6-week/6-hour/day regimen of noise and Toluene. The groups included a control group, rats co-exposed to noise and Toluene, and rats co-exposed to noise and Toluene treated with OLE for different durations. The results indicated that noise and Toluene exposure led to structural damage in lung tissue, oxidative harm, and increased levels of pro-inflammatory cytokines (TNF-α and IL-1β). However, the administration of OLE extract demonstrated positive effects in mitigating these adverse outcomes. OLE treatment reduced lipid peroxidation and enhanced the activities of catalase and superoxide dismutase, indicating its anti-oxidant properties. Furthermore, OLE significantly decreased the levels of pro-inflammatory cytokines compared to the groups exposed to noise and Toluene without OLE treatment. Moreover, the in silico investigation substantiated a robust affinity between COX-2 and OLE components, affirming the anti-inflammatory activity. Overall, our findings suggest that OLE possesses anti-inflammatory and anti-oxidative properties that mitigate the adverse effects of concurrent exposure to noise and Toluene.

Hepatobiliary cancers, including hepatocellular carcinoma and cancers of the biliary tract, share high mortality and rising incidence rates. They may also share several risk factors related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and rates of obesity. Recent data also suggest a role for the gut microbiome in the development of hepatobiliary cancer and other liver pathologies. The gut microbiome and the liver interact bidirectionally through the "gut-liver axis," which describes the interactive relationship between the gut, its microbiota, and the liver. Here, we review the gut-liver interactions within the context of hepatobiliary carcinogenesis by outlining the experimental and observational evidence for the roles of gut microbiome dysbiosis, reduced gut barrier function, and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to hepatobiliary cancer development. We also outline the latest findings regarding the impact of dietary and lifestyle factors on liver pathologies as mediated by the gut microbiome. Finally, we highlight some emerging gut microbiome editing techniques currently being investigated in the context of hepatobiliary diseases. Although much work remains to be done in determining the relationships between the gut microbiome and hepatobiliary cancers, emerging mechanistic insights are informing treatments, such as potential microbiota manipulation strategies and guiding public health advice on dietary/lifestyle patterns for the prevention of these lethal tumors.

Globally, colorectal cancer is a major health problem that ranks in third place in terms of occurrence and second in terms of mortality worldwide. New cases increase annually, with the absence of effective therapies, especially for metastatic colorectal cancer, emphasizing the need for novel therapeutic approaches. Although conventional treatments are commonly used in oncotherapy, their success rate is low, which leads to the exploration of novel technologies. Recent efforts have focused on developing safe and efficient cancer nanocarriers. With their nanoscale properties, nanocarriers have the potential to utilize internal metabolic modifications amid cancer and healthy cells. Drug repurposing is an emerging strategy in cancer management as it is a faster, cheaper, and safer method than conventional drug development. However, most repurposed drugs are characterized by low-key pharmacokinetic characteristics, such as poor aqueous solubility, permeability, retention, and bioavailability. Nanoparticles formulations and delivery have expanded over the past few decades, creating opportunities for drug repurposing and promises as an advanced cancer modality. This review provides a concise and updated overview of colorectal cancer treatment regimens and their therapeutic limitations. Furthermore, the chemotherapeutic effect of various FDA-approved medications, including statins, non-steroidal anti-inflammatory drugs, antidiabetic and anthelmintic agents, and their significance in colorectal cancer management. Along with the role of various nanocarrier systems in achieving the desired therapeutic outcomes of employing these redefined drugs.

Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. Cyclooxygenase-2 (COX-2) is a key enzyme involved in inflammatory signaling. While being transiently upregulated upon inflammatory stimuli, COX-2 has been found to be consistently overexpressed in human colorectal cancer and several other malignancies. The association between chronic inflammation and cancer has been revisited: cancer can arise when inflammation fails to resolve. Besides its proinflammatory functions, COX-2 also catalyzes the production of pro-resolving as well as anti-inflammatory metabolites from polyunsaturated fatty acids. This may account for the side effects caused by long term use of some COX-2 inhibitory drugs during the cancer chemopreventive trials. This review summarizes the latest findings highlighting the dual functions of COX-2 in the context of its implications in the development, maintenance, and progression of cancer.

Esophageal Cancer (EC) ranks among the most common malignancies worldwide. Most EC patients acquire drug resistance to chemotherapy either intrinsically or acquired after T-DM1 treatment, which shows that increasing or decreasing the expression of particular genes might influence chemotherapeutic sensitivity or resistance. Therefore, gaining a deeper understanding of the altered expression of genes involved in EC drug resistance and developing new therapeutic methods are essential targets for continued advancement in EC therapy.

The present study aimed to find critical regulatory genes/pathways in the progression of T-DM1 resistance in OE-19 EC cells. Expression datasets were extracted from GEO omnibus. Gene interactions were analyzed, and the protein-protein interaction network was drawn. Then, enrichment analysis of the hub genes and network cluster analysis of the hub genes was performed. Finally, the genes were screened in the DrugBank database as therapeutic targets and molecular docking analysis was done on the selected targets.

In the current study, nine hub genes were identified in TDM-1-resistant EC cells (CTGF, CDH17, THBS1, CXCL8, NRP1, ITGB5, EDN1, FAT1, and PTGS2). The KEGG analysis highlighted the IL-17 signaling pathway and ECM-receptor interaction pathway as the most critical pathways; cluster analysis also showed the significance of these pathways. Therefore, the genes involved in these two pathways, including CXCL8, FSCN1, PTGS2, SERPINE2, LEF1, THBS1, CCN2, TAGLN, CDH11, and ITGA6, were searched in DrugBank as therapeutic targets. The DrugBank analysis suggests a potential role for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in reducing T-DM1 drug resistance in EC. The docking results revealed that NSAIDs, including Diclofenac, Mefenamic acid, Celecoxib, Naproxen, and Etoricoxib, significantly suppress resistant cancer cells.

This comprehensive bioinformatics analysis deeply explains the molecular mechanisms governing TDM-1 resistance in EC. The identified hub genes and their associated pathways offer potential targets for therapeutic interventions. Moreover, the possible role of NSAIDs in mitigating T-DM1 resistance presents an intriguing avenue for further investigation. This research contributes significantly to the field and establishes a basis for further research to enhance treatment efficacy for EC patients.

Hepatocellular carcinoma (HCC) is one of the most serious types of cancer that accounts for numerous cancer deaths worldwide. HCC is poorly prognosed and is a highly chemotherapy-resistant tumor. Therefore, new treatments are urgently needed. Exopolysaccharides (EPS-1) produced from the novel Bacillus sonorensis strain was found to exhibit chemopreventive effects against cancer.

Evaluating the anti-cancer cytotoxic effect of exopolysaccharides (EPS-1) produced by the newly studied Bacillus sonorensis strain SAmt2.

The cytotoxic activity was investigated through cell cycle, apoptosis, and autophagy analyses using flow cytometry technique. Also, the effect of EPS-1 on Huh7 release of COX-2 was examined using ELISA.

Our results revealed that EPS-1exhibit an anti-proliferative effect on Huh7 cells through decreasing the percentage of cells at the S-phase and G2 phase, while increasing the cell population at the sub-G1 and G1 phases. Apoptosis analysis showed that EPS-1 increased necrotic and apoptotic cell fractions in EPS-1 treated Huh7. In addition, it induced significant autophagic cell death in the Huh7.Finally, antiproliferative and apoptosis induction results were supportedby ELISA assay results where the protein level of COX-2 was declined.

: In conclusion, EPS-1 derived from B. sonorensis SAmt2, is a promising proliferation inhibitor of Huh7 cells with potential anticancer effects.

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) usage has been associated with pancreatic ductal adenocarcinoma (PDAC) prevention, though epidemiological data have not reliably demonstrated this. The aim of this study is to identify if aspirin and other NSAIDs are effective in the primary prevention of PDAC in a large UK prospective cohort.

A nested case-control study was conducted using the UK Biobank cohort. Incident PDAC cases (n = 1129 of whom 239 (21.2 %) were using aspirin) were age and sex-matched with cancer-free controls (n = 8822 of whom 1752 (19.9 %) were using aspirin). Conditional logistic regression models were used to generate odds ratios (ORs) and 95 % confidence intervals (CI) for risk of PDAC with and without regular use of aspirin, non-aspirin NSAIDs and all NSAIDs respectively. Exploratory analyses were carried out assessing interactions with diabetes mellitus (DM) as a condition with increased pancreatic cancer risk.

Regular aspirin use at initial recruitment was independently associated with a decreased risk of PDAC (OR [95 % CI] = 0.80 [0.68-0.95] P = 0.01). Regular non-aspirin NSAID use was not associated with a risk reduction of PDAC (OR [95 % CI] = 1.01 [0.84-1.23] P = 0.88). Exploratory analyses showed that in those with DM; regular aspirin use reduced risk of PDAC (OR [95 % CI] = 0.60 [0.42-0.85] P = 0.004) compared to non-use.

Regular aspirin use is associated with a reduction in risk of PDAC. The reduced risk is more apparent in participants with DM.

Pituitary neuroendocrine tumor is the third most common primary intracranial tumor. Its main clinical manifestations include abnormal hormone secretion symptoms, symptoms caused by tumor compression of the surrounding pituitary tissue, pituitary stroke, and other anterior pituitary dysfunction. Its pathogenesis is yet to be fully understood. Surgical treatment is still the main treatment. Despite complete resection, 10%-20% of tumors may recur. While dopamine agonists are effective in over 90% of prolactinomas, prolonged use and individual variations can lead to increased drug resistance and a gradual decline in efficacy, which ultimately requires surgical intervention. Nonsteroidal anti-inflammatory drugs reduce the production of inflammatory mediator prostaglandins by inhibiting the activity of cyclooxygenase and exert antipyretic, analgesic, antiplatelet, and anti-inflammatory effects. In recent years, many in-depth studies have confirmed the potential of nonsteroidal anti-inflammatory drugs as a preventive and antitumor agent. It has been extensively utilized in the prevention and treatment of various types of cancer. However, their specific mechanisms of action still need to be fully elucidated. This article summarizes recent research progress on the expression of cyclooxygenase in pituitary neuroendocrine tumors and the treatment of nonsteroidal anti-inflammatory drugs. It provides a feasible theoretical basis for further research on pituitary neuroendocrine tumors and explores potential therapeutic targets.

Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identified mechanisms by which oncogenic KRAS promotes immune evasion, most notably via upregulation of immunosuppressive COX2 in cancer cells. Oncogenic KRAS potently induced COX2 in both mouse and human lung cancer, which was suppressed using KRAS inhibitors. COX2 acted via prostaglandin E2 (PGE2) to promote resistance to immune checkpoint blockade (ICB) in lung adenocarcinoma. Targeting COX2/PGE2 remodeled the tumor microenvironment by inducing proinflammatory polarization of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX2 expression contributed to tumor relapse after prolonged KRAS inhibition. These results provide the rationale for testing COX2/PGE2 pathway inhibitors in combination with KRASG12C inhibition or ICB in patients with KRAS-mutant lung cancer. Significance: COX2 signaling via prostaglandin E2 is a major mediator of immune evasion driven by oncogenic KRAS that promotes immunotherapy and KRAS-targeted therapy resistance, suggesting effective combination treatments for KRAS-mutant lung cancer.

Ferroptosis is a form of nonapoptotic cell death that involves iron-dependent phospholipid peroxidation induced by accumulation of reactive oxygen species, and results in plasma membrane damage and the release of damage-associated molecular patterns. Ferroptosis has been implicated in aging and immunity, as well as disease states including intestinal and liver conditions and cancer. To date, several ferroptosis-associated genes and pathways have been implicated in liver disease. Although ferroptotic cell death is associated with dysfunction of the intestinal epithelium, the underlying molecular basis is poorly understood. As the mechanisms regulating ferroptosis become further elucidated, there is clear potential to use ferroptosis to achieve therapeutic benefit.

Breast cancer is the most prevalent cancer among women worldwide and is a well-known cause for cancer mortality in females. COX-2 (cyclooxygenase) plays a vital role in development of some human cancers such as lung, colon and breast. It is a potent enzyme that is important for the conversion of arachidonic acid into prostaglandins. These prostaglandins mediate cellular proliferation, apoptosis and angiogenesis which contributes to carcinogenesis. Overexpression of COX-2 has been detected in several malignancies including breast cancer. COX-2 overexpression is regarded as a poor prognostic marker of breast cancer.The present study will aim to study the immunohistochemical expression of COX-2 in breast cancer and compare it with known histopathological parameters thus assessing its prognostic value.

This will be an observational study conducted in the Department of Pathology, JNMC, Wardha (Sawangi). Radical mastectomy specimens will be studied for COX-2 expression by immunohistochemistry in patients diagnosed with breast carcinoma. COX-2 expression will be quantified as immunohistochemical score and results will be correlated with various histopathological parameters.

The expected result of our study will suggest an association of COX-2 expression to the factors associated with poor prognosis in breast carcinoma. A positive correlation is expected between larger tumor size, positive lymph node status, higher T stage and N stage and lymphovascular invasion.

Conclusions will be drawn from the obtained results of the immunohistochemical study by using COX-2- for detection of overexpression of COX-2 when evaluated with TNM staging, histological grading and molecular types of breast cancer.

Artonin E (AA2) and artobiloxanthone (AA3) were extracted and purified from the acetone extract of the stem bark of Artocarpus altilis (Parkinson) Fosberg. Preliminary investigations of both candidates revealed promising cytotoxic effects in oral cancer cells. Moreover, these candidates modulated the expression of pivotal proteins linked to oral cancer progression, eliciting apoptosis through caspase-3 and caspase-9 activation. Additionally, our results showed that AA2 and AA3 suppressed several proteins linked with oral cancer, such as Bcl-2, COX-2, VEGF, and MMP-9, and modulated the cell signaling pathways, such as Akt/mTOR and STAT-3, offering valuable insights into the underlying mechanism of action of these compounds. These findings were robustly validated in silico using molecular docking and molecular dynamic simulations. To our knowledge, these findings have not been previously reported, and the continued exploration and development of these natural products may offer a potential avenue for the effective management of this malignancy.

Caspase-4 (CASP4) is a member of the inflammatory caspase subfamily and promotes inflammation. Here, we report that CASP4 in lung adenocarcinoma cells contributes to both tumor progression via angiogenesis and tumor hyperkinesis and tumor cell killing in response to high interferon (IFN)-γ levels. We observe that elevated CASP4 expression in the primary tumor is associated with cancer progression in patients with lung adenocarcinoma. Further, CASP4 knockout attenuates tumor angiogenesis and metastasis in subcutaneous tumor mouse models. CASP4 enhances the expression of genes associated with angiogenesis and cell migration in lung adenocarcinoma cell lines through nuclear factor kappa-light chain-enhancer of activated B cell signaling without stimulation by lipopolysaccharide or tumor necrosis factor. CASP4 is induced by endoplasmic reticulum stress or IFN-γ via signal transducer and activator of transcription 1. Most notably, lung adenocarcinoma cells with high CASP4 expression are more prone to IFN-γ-induced pyroptosis than those with low CASP4 expression. Our findings indicate that the CASP4 level in primary lung adenocarcinoma can predict metastasis and responsiveness to high-dose IFN-γ therapy due to cancer cell pyroptosis.