Cadmium (Cd) is a highly toxic environmental pollutant, which can accumulate in the kidney, induce cell damage and trigger inflammatory responses. However, the specific regulation mechanism of nephrotoxicity induced by Cd remains unclear. This study was conducted to investigate the toxic effects of Cd on human embryonic kidney 293 (HEK293) cells and explore its potential mechanisms. Cell viability was assessed with MTT assay. Reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were evaluated through DCFH-DA staining and Rhodamine staining. Apoptosis was detected with Hoechst 33258 staining. The expression of the DNA damage biomarker 8-hydroxy-2'-deoxyguanosine (8-OHdG) was detected with the 8-OHdG ELISA kit. Senescence-associated secretory phenotype (SASP) factors and signaling pathways were analyzed by Western blot. The results showed that Cd exposure could induce oxidative stress and cellular inflammation. It could also impair MMP, contribute to cell apoptosis and activate MAPK and NF-κB signaling pathways. Finally, exposure to Cd triggered DNA damage and SASP production. However, NF-κB inhibitor BAY11-7082 and antioxidant NAC could inhibit these effects by suppressing NF-κB and MAPK signaling pathways. The present study revealed the specific mechanisms of Cd toxicity in HEK293 cells and provided useful information for elucidating the nephrotoxicity of Cd.

Immunotherapy is an emerging strategy that awakens the intrinsic immune system for cancer treatment. Generally, successful immunotherapy of malignant tumours relies on the effective production of tumour-associated antigens and their lymph node delivery, antigen processing and presentation for T-cell activation, and the dismantling of the immunosuppressive tumour microenvironment. Toll-like receptor (TLR) agonists are potent stimulants in cancer immunotherapy, which can directly activate antigen-presenting cells (APCs) and further induce T cell activation for antitumour immune response and convert immunosuppressive tumour microenvironment to an immunogenic one for cooperative tumour ablation. However, TLR agonists for effective cancer immunotherapy have encountered essential challenges, such as insufficient immune activation and systemic side effects. In recent years, nano-immunomodulators with TLR agonists have been employed for tumour- and/or lymph node-targeted immune activation to improve the antitumour immune response and alleviate their systemic toxicities, providing a promising strategy for enhanced cancer immunotherapy. Herein, we introduce the recent progress in developing various TLR nano-immunomodulators for cancer immunotherapy via APC activation and tumour microenvironment remodelling. Upon elucidating the rational design principles of nano-immunomodulators, we elucidate the advancement of TLR nanoagonists to break the barriers in effective and safe Toll-like receptor stimulation for potent cancer immunotherapy.

This study aims to compare variations in 18 trace elements (Al, Na, K, Mg, Ca, Ti, Ba, Sn, Cr, Mn, Fe, Cu, Zn, Se, Mo, Cd, Sr, and Tl) between benign and malignant thyroid tissues. Post-operative thyroid tissue samples were collected from 106 patients (34 benign, 72 malignant), and elemental concentrations were quantified using inductively coupled plasma mass spectrometry. Spearman's correlation analysis revealed positive correlations among these trace elements. Notably, the malignant group exhibited significantly higher concentrations in eight elements (Mg, Al, Fe, Cr, Ti, Sr, Sn, and Ba) compared to the benign group, while levels of six elements (Na, Mn, Cu, Zn, Cd, and Mo) were significantly lower. Orthogonal partial least squares discriminant analysis distinguished three elements (Al, Ti, Sn) for the malignant group and six elements (Na, Mn, Cu, Zn, Cd, and Mo) for the benign group. Multivariate logistic regression further revealed associations between thyroid cancer and levels of Al, Cr, Ti, Sr, Sn, Ba, Mn, Cu, Zn, and Cd. Considering with each elemental biological funcions, these findings suggest that Cu, Mn, and particularly Zn may act as essential antitumor elements with synergistic effects, whereas elevated Ba, Cr, and Al levels are closely related to thyroid malignancies. However deficiencies and excesses of elements may be the consequences of malignant tissues. In conclusion, benign and malignant thyroid tumors exhibit different trace-element profiles.

The nuclear factor kappa B (NF-κB) is a critical pathway that regulates various cellular functions, including immune response, proliferation, growth, and apoptosis. Furthermore, this pathway is tightly regulated to ensure stability in the presence of immunogenic triggers or genotoxic stimuli. The lack of control of the NF-κB pathway can lead to the initiation of different diseases, mainly autoimmune diseases and cancer, including Renal cell carcinoma (RCC). RCC is the most common type of kidney cancer and is characterized by complex genetic composition and elusive molecular mechanisms.

The current review summarizes the mechanism of NF-κB dysregulation in different subtypes of RCC and its impact on pathogenesis.

This review highlights the prominent role of NF-κB in RCC development and progression by driving the expression of multiple genes and interplaying with different pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. In silico analysis of RCC cohorts and molecular studies have revealed that multiple NF-κB members and target genes are dysregulated. The dysregulation includes receptors such as TLR2, signal-transmitting members including RelA, and target genes, for instance, HIF-1α. The lack of effective regulatory mechanisms results in a constitutively active NF-κB pathway, which promotes cancer growth, migration, and survival. In this review, we comprehensively summarize the role of dysregulated NF-κB-related genes in the most common subtypes of RCC, including clear cell RCC (ccRCC), chromophobe RCC (chRCC), and papillary RCC (PRCC).

The expression of TIMM8A, a molecular chaperone involved in mitochondrial protein translocation, was observed to be significantly elevated in various tumor types. However, the specific role of TIMM8A in cancer development and its underlying molecular mechanism remains inadequately understood. In this study, our primary objective was to investigate the functional implications of TIMM8A in breast cancer development, while also assessing its expression levels and prognostic relevance in pan-cancer. Notably, TIMM8A exhibited high expression in nearly 33 different cancer types, which was consistently associated with unfavorable clinical outcomes. In breast cancer, TIMM8A exhibited a strong association with prognosis and demonstrated its potential as an independent prognostic indicator. Additionally, the inhibition of TIMM8A effectively impeded the proliferation of MCF-7 and MDA-MB-231 cells, while also suppressing their migratory and invasive capabilities in vitro. Mechanistically, the downregulation of NF-κB p65, upregulation of pro-apoptotic proteins, and regulation of EMT-related proteins were observed upon TIMM8A knockdown. Furthermore, the over-expression of miR-10b-5p effectively hindered the expression of TIMM8A. Collectively, TIMM8A, a critical oncogene, was regulated by miR-10b-5p and could activate NF-κB signaling cascade response, promote apoptosis inhibition and regulate EMT-related protein expression, thereby stimulating proliferation, migration, and invasion of breast cancer cells.

Chronic kidney disease (CKD) and Alzheimer's disease (AD) are two prevalent and debilitating conditions that frequently coexist, with CKD contributing to cognitive decline and potentially exacerbating AD pathology. In CKD, irreversible changes in the structure or function of the kidneys are observed, while AD is primarily marked by amyloid deposition and tau pathology. Both conditions involve complex and multifactorial pathophysiology affecting brain functioning, highlighting the need for comprehensive research to understand their potential crosstalk. This review articulates the possible molecular mechanisms underlying both diseases, focusing on key pathways, including oxidative stress, inflammation, vascular dysfunction, hypertension, and uremic toxin accumulation. These interconnected mechanisms suggest a potential bidirectional relationship where kidney dysfunction accelerates cognitive decline and vice versa. Additionally, we examine critical risk factors implicated in both CKD and AD, for instance, vitamin D deficiency, erythropoietin dysregulation, endothelin action, klotho gene expression, and the role of the extracellular vesicle, which may influence disease progression through their effects on the kidney and brain, influencing cognitive function. Further, we emphasized potential biomarkers that could aid in diagnosing and monitoring disease progression in these comorbid conditions, like amyloid beta, tau, homocysteine, cystatin C, creatinine, proteinuria, and estimated glomerular filtration rate. Lastly, the review highlights treatment strategies for managing CKD and AD concurrently, focusing on therapeutic approaches that address common pathophysiological mechanisms. These strategies not only aim to address the underlying causes of both conditions but also offer the potential to slow or even prevent the progression of cognitive impairment. Moreover, we recommend further research to refine these approaches, execute correlational studies on disease progression, and design clinical trials that address both conditions, aiming to establish effective, tailored treatments for this dual burden of disease.

The sW196*(Stop) mutation of HBV is the rarest variant of sW196L. It is associated with rapid progression of chronic hepatitis B to end-stage liver disease and hepatocellular carcinoma. Information on proliferative vs. apoptotic cells and immunological manifestations related to the expression of HBV-associated cytokines in the presence of the lamivudine-resistant mutation sW196L and the rarest variant of sW196L, sW196*(Stop), has been limited. Therefore, the current investigation aimed to examine the molecular and immunological basis of lamivudine-resistant mutations with the help of transfection studies carried out in cell lines of hepatic origin. sW196*(Stop) transfected HepG2 cells showed IFN-gamma was extremely downregulated by 20.96 folds, and IL-6 was upregulated by 4.5 folds which had not been seen in any of the constructs. The current study reveals for the first time the underlying immunological processes that render detrimental effects to lamivudine-resistant rare mutations, in particular sW196*(Stop) of HBV that can be explained by downregulation of IFN-gamma, a known cytokine associated with efficient viral clearance, together with upregulation of IL-6 known to be associated with disease progression and HCC. Understanding the molecular and immunological mechanisms in such HBV mutations is furthered by the choreographed event of increased TNF-alpha expression, which is known to be linked to liver damage.

Metabolic associated steatohepatitis characterized by lipid accumulation, inflammation and fibrosis, is a growing global health issue, contributing to severe liver-related mortality. With limited effective treatments available, there is an urgent need for novel therapeutic strategies. Moringa oleifera, rich in antioxidants, offers potential for combating steatohepatitis, but its cytotoxicity presents challenges. Aloe vera, renowned for its cytocompatibility and anti-inflammatory effects, shows promise in mitigating these risks. Using infrared spectrometry and mass spectrometry, we identified 1586 metabolites from both plants across 84 chemical classes. By encapsulating these phytochemicals in nanoparticles, we achieved increased solubility, cytocompatibility, and gene modulation to hepatic stellate cells affected by steatohepatitis. Chemoinformatic analysis revealed bioactive metabolites, including hesperetin analogs, known to inhibit TGF-β. Our results demonstrate that these nanoparticles not only improved gene expression modulation related to metabolic associated steatohepatitis, particularly TGF-β and COL1A1, but also outperformed free compounds, highlighting their potential as a novel therapeutic approach.

Cervical cancer ranks among the most prevalent malignancies impacting women globally. Disulfidptosis represents a recently identified pathway of cellular demise, although its role in the context of cervical cancer is not well elucidated. This research investigates the significance of Disulfidptosis-Related Genes (DRGs) within cervical cancer. Furthermore, it aims to analyze the differences in prognosis and immune infiltration among different molecular subtypes.

We compiled genes associated with cervical cancer and disulfidptosis from a variety of databases to perform a differential expression analysis. Subsequently, the samples are grouped through consensus clustering. To evaluate immune cell infiltration, we employed CIBERSORT. Additionally, immune checkpoint genes (ICGs) were gathered from existing literature and databases, enabling statistical analyses of two subtype samples of cervical cancer (CESC). Following our analyses using GO, KEGG, and GSEA to compare the differences between the two subtypes. Lastly, a prognostic risk model was constructed using LASSO regression and validated using ROC.

This study identified seven key genes: PCBP3, ARNT, ANP32E, DSTN, CD2AP, EPAS1, and ACTN1.The consensus clustering analysis showed differences in immune cell infiltration and DFS(disease-free survival) among the various clusters. The immune checkpoint gene CXCL1 displayed highly significant statistical differences between subtype A (Cluster 1) and subtype B (Cluster 2) in cervical cancer (CESC) samples. The gene set enrichment analysis identified the negative regulation of peptidase activity and the IL-17 signaling pathway, which link to subtype-specific differentially expressed genes (DEGs).

Statistical analysis of the various subtypes of CESC samples highlighted the importance of subtype-specific therapeutic targets. Additionally, it seeks to enhance the accuracy of prognostic predictions, thereby establishing a foundation for the formulation of personalized treatment approaches.

Asthma is a common condition involving chronic airway inflammation that primarily affects women and boys. Estrogen levels correlate with the observed differences in the prevalence of asthma between the sexes, but the exact mechanism is unclear. This study established a castration mice (OVX) model through bilateral ovariectomy surgery, and subcutaneously injected estradiol (E2) into OVX asthmatic mice to analyze the effect of E2 on the onset of asthma. Then, airway inflammation was evaluated in the mice using airway resistance measurements, lung tissue hematoxylin and eosin staining, and eosinophil counts. Furthermore, the proportion of CD206-positive cells and the expression of M2 polarization markers, such as Arg1 and YM1, were detected in alveolar macrophages (AMs). The effects of different concentrations of E2 on M2 polarization of AMs were examined in vitro, and the types of estrogen receptors (ERs) involved were investigated. Transcriptome analysis combined with volcano plots and heatmaps were used to compare the differentially expressed genes to investigate the mechanism by which E2 affects M2 polarization of AMs. The results showed that female asthmatic mice had more severe airway inflammation and higher airway responsiveness than male asthmatic mice. E2 increased airway inflammation and airway resistance in asthmatic mice. E2 not only promoted M2 polarization of AMs in asthmatic mice in vivo, but also increased the expression of M2 markers, such as Arg1 and YM1, by AMs in vitro. The use of ERα antagonist AZD9496 reduced the effect of E2 on the promotion of M2 polarization in AMs. Analysis of transcriptome differences indicated that E2 upregulated expression of M2 breast cancer metastasis suppressor gene 1 (Brms1) in AMs. Notably, antagonism of ERα inhibited this upregulation of Brms1 gene expression. Interference with Brms1 mRNA production reduced the gene expression of Arg1 and YM1 in AMs undergoing M2 polarization after E2 stimulation. In summary, E2 exacerbates airway inflammation in asthmatic mice and binds to ERα, upregulating Brms1 expression and mediating M2 polarization of AMs.

Tumor necrosis factor receptor-associated factor-6 (TRAF6) is a well-established upstream regulator of the IKK complex, essential for the modulation of the NF-κB (nuclear factor kappa B) signaling pathway. Aberrant activation of TRAF6 has been strongly implicated in the pathogenesis of various cancers, including hepatocellular carcinoma (HCC). The speckle type BTB/POZ protein (SPOP), an E3 ubiquitin ligase substrate-binding adapter, constitutes a significant component of the CUL3/SPOP/RBX1 complex, which is closely linked to tumorigenesis. In this study, we demonstrated that the E3 ubiquitin ligase SPOP shielded TRAF6 from proteasomal degradation, leading to the hyperactivation of the NF-κB pathway. Notably, a liver cancer-associated S119N mutation in SPOP resulted in a failure to mediate the ubiquitination and subsequent degradation of TRAF6. Moreover, both gain-of-function and loss-of-function experiments revealed that SPOP inhibits the proliferation and invasion of HCC cells through the TRAF6-NF-κB axis in vitro and in vivo. Taken together, our findings elucidate the underpinning mechanism by which SPOP negatively regulates the stability of the TRAF6 oncoprotein, thus offering a new therapeutic target for HCC intervention.

Ganoderic acid A (GAA, C30H44O7) is one of the most abundant and active components of Ganoderic acids (GAs). GAs are highly oxidized tetracyclic triterpenoid compounds mainly derived from Ganoderma lucidum (Curtis) P. Karst (Chinese: ). GAA is primarily isolated from the fruiting body of Ganoderma lucidum. Modern pharmacological investigations have established the broad pharmacological effects of GAA, highlighting its notable influence on managing various conditions, including inflammatory diseases, neurodegenerative diseases, and cancer. This review provides a comprehensive summary of GAA's pharmacological activities.

The literature in this review were searched in PubMed and China National Knowledge Infrastructure (CNKI) using the keywords "Ganoderic acid A″, "Pharmacology" and "Pharmacokinetics". The literature cited in this review dates from 2000 to 2024.

According to the data, GAA exerts anti-inflammatory, antioxidant, antitumor, neuropsychopharmacological, hepatoprotective, cardiovascular, renoprotective, and lung protective effects by regulating a variety of signal transduction pathways, such as nuclear factor kappa-B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), Toll-like receptor 4 (TLR4), nuclear factor erythroid 2-related factor-2 (Nrf2), phosphoinositide-3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and Notch. Given its promising pharmacological activity, GAA holds excellent potential for treating human diseases. The pharmacokinetic properties of GAA have also been reviewed, revealing low bioavailability but high absorption and elimination rates. In addition, network pharmacology and molecular docking analyses verified that GAA plays a role in multiple diseases through MAPK3, tumor necrosis factor (TNF), caspase-3 (CASP3), peroxisome proliferator-activated receptor gamma (PPARG), and β-catenin (CTNNB1) signaling pathways.

GAA plays a pivotal role in various pathological and physiological processes, boasting broad application prospects. Furthermore, the network pharmacological results reveal the mechanisms of GAA in the treatment of multiple diseases. In the future, it is necessary to conduct further experiments to elucidate its specific mechanism of action, thus laying the foundation for the scientific utilization of GAA.

Endogenous retroviruses (ERVs) shape human genome functionality and influence disease pathogenesis, including cancer. ERVK-7, a significant ERV, acts as an immune modulator and prognostic marker in lung adenocarcinoma (LUAD). Although ERVK-7 overexpression has been linked to the amplification of the 1q22 locus in approximately 10% of LUAD cases, it predominantly arises from alternative regulatory mechanisms. Our findings indicate that the canonical 5' long terminal repeat (LTR) of ERVK-7 is methylated and inactive, necessitating the use of alternative upstream promoters. We identified two novel transcripts, ERVK-7.long and ERVK-7.short, arising from distinct promoters located 2.8 kb and 13.8 kb upstream of the 5'LTR of ERVK-7, respectively. ERVK-7.long is predominantly overexpressed in LUAD. Through comprehensive epigenetic mapping and single-cell transcriptomics, we demonstrate that ERVK-7.long activation is predetermined by cell lineage, specifically in small airway epithelial cells (SAECs), where its promoter displays tumor-specific H3K4me3 modifications. Single-cell RNA sequencing further reveals a distinct enrichment of ERVK-7.long in LUAD tumor cells and alveolar type 2 epithelial cells, underscoring a cell-type-specific origin. Additionally, inflammatory signaling significantly influences ERVK-7 expression; TNF-α enhances ERVK-7.long, while interferon signaling preferentially augments ERVK-7.short by differential recruitment of NF-κB/RELA and IRF to their respective promoters. This differential regulation clarifies the elevated ERVK-7 expression in LUAD compared to lung squamous cell carcinoma (LUSC). Our study elucidates the complex regulatory mechanisms governing ERVK-7 in LUAD and proposes these transcripts as potential biomarkers and therapeutic targets, offering new avenues to improve patient outcomes.

Cuscuta chinensis Lam. (CCL), is made from the dried mature seeds of a plant in the Convolvulaceae family. Predominantly distributed in China and several Asian countries, it has long been used to treat osteoporosis (OP) and other aging-related diseases. However, studies on the mechanisms of anti-OP compounds in CCL remain limited.

The objective of this study is to determine the bioactive constituents present in CCL and to elucidate their mechanisms of action in the prevention and treatment of postmenopausal osteoporosis (PMOP). This will be achieved by investigating the modulation of bone marrow macrophage polarization via the Nuclear Factor Kappa B (NF-κB)/Inhibitor of Kappa B Alpha (IκBα) signaling cascade.

CCL's chemical components were identified using UPLC-Q-TOF-MS. Blood components were analyzed for targets using databases. Pathway enrichment was performed via network pharmacology. We used an ovariectomy (OVX)-induced OP rat model to assess the effects of CCL extracts in comparison to a positive control drug. Osteogenic markers were analyzed. We utilized flow cytometry to assess macrophage marker expression, while quantitative PCR (qPCR) and Western blotting were employed to identify targets within the signaling pathways.

Seventeen chemical components were identified in CCL extracts, of which 14 were identified as prototype compounds absorbed into the bloodstream. Pathway enrichment analysis revealed that CCL's therapeutic effects on PMOP were closely associated with the NF-κB signaling pathway, specifically targeting NF-κB and IκBα proteins. Animal studies showed that high-dose CCL significantly lowered serum levels of tartrate-resistant acid phosphatase (TRACP) and c-terminal telopeptide of type I collagen (CTX) (p < 0.01) and increased levels of bone-specific alkaline phosphatase (BALP) and procollagen I c-terminal propeptide (PICP) (p < 0.01), indicating effective inhibition of bone resorption and promotion of bone formation. CCL treatment improved the microstructure of trabecular bone at the distal femur by reducing bone cavity spaces, increasing trabecular thickness, and enhancing trabecular alignment. CCL markedly enhanced the expression levels of osteoprotegerin (OPG), runt-related transcription factor 2 (Runx2), and alkaline phosphatase (ALP) genes and their corresponding proteins in the tibial tissue (p < 0.01), promoting osteoblast differentiation and function. Flow cytometry analysis showed that CCL modulated immune cell markers CD86 and CD163, supporting its anti-inflammatory effects in PMOP treatment. Furthermore, CCL regulated the NF-κB/IκBα signaling pathway by significantly decreasing NF-κB expression and increasing IκBα expression, thereby modulating inflammatory responses and bone metabolism.

The active components in CCL effectively prevent and treat PMOP by modulating bone marrow macrophage polarization through the NF-κB/IκBα signaling pathway.

Pooled optical screens have enabled the study of cellular interactions, morphology, or dynamics at massive scale, but they have not yet leveraged the power of highly plexed single-cell resolved transcriptomic readouts to inform molecular pathways. Here, we present a combination of imaging spatial transcriptomics with parallel optical detection of in situ amplified guide RNAs (Perturb-FISH). Perturb-FISH recovers intracellular effects that are consistent with single-cell RNA-sequencing-based readouts of perturbation effects (Perturb-seq) in a screen of lipopolysaccharide response in cultured monocytes, and it uncovers intercellular and density-dependent regulation of the innate immune response. Similarly, in three-dimensional xenograft models, Perturb-FISH identifies tumor-immune interactions altered by genetic knockout. When paired with a functional readout in a separate screen of autism spectrum disorder risk genes in human-induced pluripotent stem cell (hIPSC) astrocytes, Perturb-FISH shows common calcium activity phenotypes and their associated genetic interactions and dysregulated molecular pathways. Perturb-FISH is thus a general method for studying the genetic and molecular associations of spatial and functional biology at single-cell resolution.

Helicobacter pylori (H. pylori) infection and the resulting gastric inflammation are major contributors to gastric cancer development. Probiotics, particularly Lactobacillus, are promising for their anti-inflammatory potential, yet their exact mechanisms in inhibiting H. pylori-induced inflammation are unclear. In our previous study, Lactiplantibacillus plantarum ZJ316 (L. plantarum ZJ316) demonstrated strong anti-inflammatory effects against H. pylori infection in vivo, but its precise mechanisms were not fully understood. Here, we aimed to investigate how L. plantarum ZJ316 inhibits the inflammatory response to H. pylori infection. Our results demonstrated that L. plantarum ZJ316 effectively reduced the expression of pro-inflammatory cytokines in H. pylori-infected AGS cells. Mechanistically, L. plantarum ZJ316 inhibited the NF-κB signaling pathway by preventing the degradation of IκBα, suppressing p65 phosphorylation, and blocking the nuclear translocation of phosphorylated p65. Treatment with the NF-κB inhibitor BAY 11-7082 further decreased tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and interleukin-1β (IL-1β) levels, confirming the inhibitory effect of L. plantarum ZJ316 on the NF-κB pathway. In H. pylori-infected mice, oral administration of L. plantarum ZJ316 significantly alleviated inflammatory cell infiltration, reduced TNF-α and pepsinogen II (PGII) levels, and increased interleukin-10 (IL-10) levels in serum. A comparative metagenomic analysis of the gastric microbiota revealed a decrease in Prevotella and Desulfovibrio, alongside an increase in Ligilactobacillus and Akkermansia, supporting the protective effects of L. plantarum ZJ316 and correlating with their decreased inflammatory response. In summary, administration of L. plantarum ZJ316 demonstrated robust anti-inflammatory effects against H. pylori infection by suppressing NF-κB signaling and promoting favorable changes in the gastric microbiota composition. Therefore, L. plantarum ZJ316 holds promise as a novel functional food for protecting the body against H. pylori infection.

Colorectal cancer (CRC) is a significant global health concern, often challenging to treat effectively with conventional methods and burdened by adverse effects. Scorpion venoms offer a unique avenue for exploration, given their ability to disrupt the cell cycle, inhibit growth, and trigger apoptosis. This study delves into the impact of Mesobuthus eupeus (M. eupeus) scorpion venom on the proliferation and progression of colorectal cancer at the molecular level. The total protein concentration in the venom (607.5 µg/mL) also emphasized the rich composition and potential for therapeutic applications. The study reveals that M. eupeus venom effectively reduced the proliferation of DLD-1 and HT-29 colorectal cancer cells in a dose-dependent manner with IC50 values of 4.32 and 7.61 µg/mL, respectively. The venom also impedes cell migration, diminishes colony formation, and triggers apoptosis in the cancer cells. The venom also induced early and late apoptosis in the two cancer cell lines. The human colorectal cancer and apoptotic pathways were clarified at the molecular level using pathway panels, which revealed that 16 genes involved in colorectal cancer increased while 23 decreased. In the HT-29 cell line, 57 genes increased, and 1 decreased following venom treatment. Besides, the mRNA expression of 19 genes involved in the apoptotic pathway was increased, while 22 were reduced in DLD-1 cells. This study underscores the potential of M. eupeus venom as a natural therapeutic approach in the quest for cancer treatments.

Gliomas, including both glioblastoma multiforme (GBM) and lower-grade glioma (LGG), present a substantial challenge in neuro-oncology because of genetic heterogeneity and unsatisfactory prognosis. This study aimed to conduct a comprehensive multi-omics analysis of gliomas using various bioinformatics approaches to identify potential therapeutic targets and prognostic markers. A comprehensive analysis was conducted on 1327 sequencing data samples alongside their relevant clinical information sourced from The Cancer Genome Atlas (TCGA) pertaining to glioblastoma (GBM), low-grade glioma (LGG), the Chinese Glioma Genome Atlas (CCGA) and University of California Santa Cruz Xena (UCSC Xena) datasets. These tools were employed for gene expression profiling, survival analysis, and cell communication mapping. Spatial transcriptomics revealed the localization of mesenchymal (MES)-like malignant tumors, and drug sensitivity analysis was performed to evaluate responses to quinpirole and meropenem. Additionally, the Tumor Immune Dysfunction and Exclusion (TIDE) framework was utilized to gauge the responsiveness to immunotherapy. The MES-like malignant and monocyte/macrophage (mono/macro) cell subsets showed high hallmark scores, playing key roles in the tumor microenvironment. MES-like malignant marker gene scores correlated with overall survival across datasets, whereas mono/macro marker gene scores were significant in the TCGA-LGG and CCGA datasets. Key interactions between these cell types were found, especially with CD14-ITGB2, LGALS1-CD69, and APOE-TREM2. The mono/macro cell subset demonstrated better immune therapy responsiveness, as indicated by lower TIDE scores. Spatial transcriptomics revealed that MES-like malignant tumors are predominantly localized in four distinct regions, with the marker genes CHI3L1 and ADM confirming these locations. Drug sensitivity analysis revealed differential responses of the MES-like malignant cell subset to quinpirole and meropenem. Our results offer fresh perspectives on the differential roles of MES-like malignant and monocyte/macrophage cell subsets in tumor progression and immune modulation, providing novel insights into glioma biology.

Background/Objectives: The diversity of the oral microbiota exerts its effects in maintaining dental and overall health. The unique genetic profile of each individual influences the composition of the oral microbiota, determining susceptibility to certain diseases. The aim is to observe its role by highlighting the pathogenic mechanisms involved in oral dysbiosis and identify genetic determinism's influence in maintaining balance. Methods: This study was designed as a narrative review of the oral microbiota, utilizing some of the principles and guidelines of systematic review to increase methodological rigor. We examined 121 articles such as reviews, meta-analyses, editorials, and observational studies, which met the inclusion and exclusion criteria. The inclusion criteria for studies were as follows: (1) studies that evaluated the impact of the microbiota in oral or/and systemic diseases; (2) studies that observed pathogenic mechanisms in the oral microbiota; (3) studies that evaluated the interaction of the microbiota with the immune system (4); studies that evaluated genetic implications in the microbiota. Results: Host genes regulate inflammatory and immunological reactions that play a role in microbiological balance. This explains the increased resistance of some to diseases, including gingivitis or periodontitis. Also, the implications of oral dysbiosis are reflected not only locally, but also generally, being associated with various systemic conditions. Conclusions: Understanding the pathogenic mechanisms and genetic determinants involved in oral dysbiosis may help create individualized therapies for preventing and managing oral and systemic disorders. A healthy lifestyle and adequate oral hygiene can facilitate a diverse and balanced microbiome, crucial for overall health.

Colorectal cancer (CRC) is a significant worldwide health issue, ranking second in women and third in men. Predictions estimate a rise to 2.5 million cases by 2035, with CRC being the fourth deadliest cancer due to delayed diagnosis and the scarcity of effective treatment options. Over 60% of CRC cases involve MAPK-activated signal pathways, particularly driven by RAS oncogene mutations, which hinder treatment responses, making them 'undruggable.' This study conducts a two-sample Mendelian randomization protein quantitative trait loci (pQTL) analysis to investigate the causal association between plasma proteins and MAPK-activated CRCs. The study indicates that four plasma proteins-MHC class I polypeptide-related sequence B (MICB), complement C4A, C4B, and interleukin-21 (IL-21) are associated with an increased risk of MAPK-activated CRCs. These findings highlight the possibility of utilizing plasma proteins as therapeutic targets and diagnostic markers to advance the fight against CRCs, indicating promising results for more effective interventions. To ascertain and expand upon these discoveries, further research is imperative to fully harness the potential of these discoveries.

In aquatic ecosystems, metal and ammonia pollution pose major concern as they contaminate the environment and induces toxicity in fish. The present study addresses the toxicity induced by chromium (Cr) and ammonia (NH3) toxicity in fish and investigates the potential of dietary curcumin in mitigating the effects of concurrent exposure to theses stressors in Pangasianodon hypophthalmus. Three isonitrogenous and isocaloric diets were formulated: a control diet (0% curcumin) and two curcumin-supplemented diets containing 0.1% and 0.2% curcumin. Four experimental groups were designed in a completely randomized design: (1) control, (2) concurrent exposure to Cr and NH3 toxicity and fed with control diet, (3) 0.1% curcumin with Cr and NH3 exposure, and (4) 0.2% curcumin with Cr and NH3 exposure. Fish fed with 0.2% curcumin diet, followed by the 0.1% curcumin diet under Cr and NH3 stress, exhibited significantly reduced cortisol levels compared to the control and Cr + NH3 groups. Similarly, the expression of HSP70 and iNOS genes in liver tissue was significantly downregulated in the 0.1% and 0.2% curcumin-fed groups compared to other groups. Concurrent exposure to Cr and NH3 led to a considerable increase in oxidative stress enzyme in liver and kidney tissues, including glutathione S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD). However, dietary supplementation with 0.1% curcumin significantly reduced oxidative stress enzyme activities. The stressors markedly reduced acetylcholinesterase (AChE) activity, but supplementation with 0.1% curcumin restored AChE activity. The expression of stress-related genes such as cytochrome P450 (CYP450), caspase-3a (Cas3a), and tumor necrosis factor-alpha (TNF-α) was noticeably downregulated in the curcumin-fed groups, reducing the impact of Cr + NH3 stress. Furthermore, total immunoglobulin (Ig) levels and growth-related gene expression, including growth hormone (GH) and growth hormone receptor 1 (GHR1), were significantly upregulated in the 0.1% curcumin-fed group under Cr + NH3 stress compared to all other groups. Additionally, myostatin (MYST) gene expression was significantly downregulated in the 0.1% curcumin-fed group. Activities of cellular metabolic and digestive enzymes were significantly improved with curcumin supplementation, mitigating the adverse effects of Cr + NH3 stress compared to the control and other groups. Moreover, Cr bioaccumulation in different fish tissues was reduced in the 0.1% curcumin-fed group. This study highlights the potential of dietary curcumin in mitigating the adverse effects of concurrent Cr and NH3 exposure through gene regulation, thereby improving the physiological and productive performance of Pangasianodon hypophthalmus.

Omentin-1, a novel adipocytokine predominantly secreted by visceral adipose tissue, has emerged as a significant factor in cardiovascular health, particularly regarding hypertension (HTN) and heart failure (HF). This manuscript investigates the multifaceted roles of omentin-1 in these conditions, emphasizing its protective effects on vascular function and its potential as both a biomarker and therapeutic target. Clinical studies indicate that reduced circulating levels of omentin-1 are associated with metabolic syndrome (MetS) and increased cardiovascular risk, while animal studies demonstrate its ability to ameliorate endothelial dysfunction and lower blood pressure. Omentin-1 exerts its beneficial effects through various signaling pathways, including AMP-activated protein kinase (AMPK) and protein kinase B (Akt), thereby promoting vasodilation, enhancing insulin sensitivity, and mitigating inflammation. In the context of HF, particularly heart failure with preserved ejection fraction (HFpEF), omentin-1 levels exhibit a negative correlation with diastolic dysfunction and inflammatory markers, suggesting its role in cardiac protection. Additionally, the manuscript discusses the implications of omentin-1 in managing obesity-related cardiovascular diseases and its potential utility as a prognostic marker for adverse outcomes in HF patients. Collectively, omentin-1 represents a promising avenue for research in cardiovascular health, with the potential to inform novel therapeutic strategies aimed at improving outcomes in patients with HTN and HF. Further research is necessary to elucidate the details of omentin-1 function and evaluate its potential in the treatment of cardiovascular disease.

Identification of metastasis drivers of triple-negative breast cancer (TNBC) is a multifaceted challenge. Here, we identified TATA-box binding protein associated factor 7 (TAF7) as a candidate to modulate TNBC metastasis. TAF7 exhibited high expression in metastatic TNBC patients, and its elevated expression showed a negative correlation with overall survival in TNBC patients. The knockdown of TAF7 suppressed the migration and invasion of TNBC, suggesting TAF7 plays a role in the metastatic processes. Further, TAF7 was enhancing serum amyloid A1 (SAA1) transcription by binding to a specific motif in the SAA1 gene promoter. The elevated SAA1 in TNBC cells directly increased E-cadherin and N-cadherin phosphorylation thereby regulating cell adhesion. Mechanistically, TAF7 modulated cell invasion, migration, and lung metastasis through an SAA1-dependent manner in vitro and in vivo experiments. Taken together, it is likely that TAF7 could directly act on the SAA1 gene promoter, upregulating SAA1 and consequently promoting TNBC metastasis.

Lichen planus (LP) and oral lichen planus (OLP) share clinical and histological similarities, yet their distinct immunopathological mechanisms make differentiation and management challenging. Clarifying these differences is essential for accurate diagnosis and treatment. This study aimed to investigate the systemic immune profile of OLP using single-cell transcriptomics, identifying distinct immune cell subsets and signaling pathways contributing to its chronic inflammatory state. Additionally, it sought to compare the inflammatory lesion microenvironments of OLP and LP by analyzing key immune pathways and cellular interactions.

Peripheral blood mononuclear cells (PBMCs) were obtained from 16 OLP patients and 5 healthy controls. Single-cell transcriptomic data from PBMCs and lesion tissues of OLP and LP were analyzed to profile immune and inflammatory signatures. Key molecular findings were validated using independent datasets and enzyme-linked immunosorbent assays (ELISA).

Prostaglandin D2 synthase (PTGDS), a pivotal enzyme in prostaglandin metabolism, emerged as a diagnostic marker with elevated expression in NK cells from OLP patients. Additionally, a novel CXCR4 high-TSC22D3 high CD4 cytotoxic T cell subset with enhanced cytotoxicity was identified, potentially contributing to OLP pathogenesis. OLP blood samples also demonstrated significant upregulation of TNF and TLR signaling in NK cells, indicating a heightened chronic inflammatory state. Comparative tissue analysis revealed intensified TNF-driven inflammation and a disrupted HIF1A- vascular endothelial growth factor (VEGF) interactions in OLP, contrasting with LP's robust VEGF-mediated angiogenesis.

These findings highlight distinct immunopathogenic mechanisms between OLP and LP. The upregulation of PTGDS in NK cells and CXCR4 high-TSC22D3 high CD4 cytotoxic T cells in PBMCs indicates systemic immune dysregulation in OLP, while tissue-level differences suggest impaired vascular remodeling and chronic inflammation. These insights underscore the need for targeted immunomodulatory therapies.

This study identifies distinct immune signatures that differentiate OLP from LP, highlighting potential therapeutic targets that require further validation for personalized treatment strategies.

Chronic inflammation and oral dysbiosis are common features of oral squamous cell carcinoma (OSCC). The commensal streptococci, S. anginosus, is increased in oral diseases including OSCC. Our previous work revealed that S. anginosus promotes inflammatory responses from macrophage cell lines, however the molecular mechanism by which S. anginosus interacts with macrophages to instigate this response remains to be investigated. Here, we expand on our previous findings by investigating the effects of S. anginosus infection of primary bone marrow derived macrophages (BMMs) and during in vivo infection. We found S. anginosus activated primary BMMs, which presented an enlarged cellular area, increased NF-κB activation and downstream inflammatory cytokines TNF⍰, IL-6 and IL-1β at 24 hours post infection. S. anginosus viability was dispensable for NF-κB activation, but essential for the induction of downstream inflammatory proteins and cytokines. S. anginosus persisted intracellularly within BMMs and induced the expression of inflammasome sensors AIM2, NLRC4 and NLRP3. Further, BMMs lacking the inflammasome adapter protein ASC ( Asc -/- ) had significantly diminished IL-1β production compared to wild type BMMs, indicating that S. anginosus activated the inflammasome. S. anginosus primarily triggered the inflammasome through NLRP3 as S. anginosus -infected Nlrp3 -/- BMMs and NLRP3 inhibitor (MCC950)-treated wild type BMMs displayed diminished IL-1β production compared to wild type controls. Lastly, S. anginosus -infected Asc -/- and Nlrp3 -/- mice displayed reduced weight loss compared to C57BL/6 mice. These overall findings indicate that S. anginosus replicates within macrophages and promotes a proinflammatory response in part through activation of the NLRP3 inflammasome. brief summary sentence: S. anginosus replicates intracellularly within macrophages and is sensed by the NLRP3 inflammasome to promote proinflammatory response.

The DNA damage repair kinase ATM is phosphorylated by the NF-κB pathway kinase IKKα, resulting in enhanced DNA damage repair through the nonhomologous end-joining pathway. Thus, inhibition of IKKα enhances the efficacy of cancer therapy based on inducing DNA damage. Here, we found a role for the IKK regulatory subunit NEMO in DNA damage repair mediated by ATM and IKKα. Exposure to damaging agents induced the interaction of NEMO with a preformed ATM-IKKα complex, which was required to target active ATM and IKKα to chromatin for efficient DNA damage repair but not for activating ATM. Recognition of damaged DNA by the IKKα-NEMO-ATM complex was facilitated by the interaction between NEMO and histones and depended on the ADP ribosylation of histones by the enzyme PARP1. NEMO-deficient cells showed increased activity of the kinase ATR, and inhibition of ATR potentiated the effect of chemotherapy in cells lacking NEMO or IKKα. Bioinformatic analysis of colorectal cancer datasets demonstrated that the expression of genes encoding IKKα, NEMO, and ATM correlated with poor patient prognosis, suggesting that the mechanism linking these three elements may be clinically relevant.

Flavonoids represent a class of natural plant secondary metabolites with multiple activities including antioxidant, antitumor, anti-inflammatory, and antimicrobial properties. However, due to their structural characteristics, they often exhibit low bioavailability in vivo. In this review, we focus on the in vivo study of flavonoids, particularly the effects of gut microbiome on flavonoids, including common modifications such as methylation, acetylation, and dehydroxylation, etc. These modifications aim to change the structural characteristics of the original substances to enhance absorption and bioavailability. In order to improve the bioavailability of flavonoids, we discuss two feasible methods, namely dosage form modification and chemical modification, and hope that these approaches will offer new insights into the application of flavonoids for human health. In this article, we also introduce the types, plant sources, and efficacy of flavonoids. In conclusion, this is a comprehensive review on how to improve the bioavailability of flavonoids.

Depression is a pervasive mental disorder that poses a significant threat to human health globally. Asperuloside (ASP), an iridoid glycoside extracted from Herba Paederiae, exhibits a range of pharmacological activities, including anti-tumor and anti-inflammatory effects. This study aims to explore the function and molecular mechanisms of ASP in alleviating depression. Chronic unpredictable mild stress (CUMS) was employed to establish a rat model of depression. Behavioral tests were conducted to evaluate the antidepressant effects of ASP. Apoptosis in hippocampal tissues was assessed using TUNEL assay. Primary hippocampal neuron apoptosis was assessed using Annexin V/PI staining and flow cytometry, while cell death was detected via PI staining. The expression levels of target mRNAs and proteins were analyzed by quantitative PCR (qPCR) and western blotting, respectively. Additionally, the levels of O-GlcNAcylation and ubiquitination were determined by western blot analysis following immunoprecipitation. Molecular docking was performed to elucidate the interaction mode between ASP and its target protein, O-linked β-N-acetylglucosamine transferase (OGT). Our findings revealed that ASP treatment significantly ameliorated depression-like behaviors and cognitive dysfunction, as well as inhibited hippocampus apoptosis in CUMS-induced rats, Moreover, ASP inhibited LPS-induced neuronal cell apoptosis and suppressed the activation of the NF-κB signaling pathway. Mechanistically, we demonstrated that ASP promoted O-GlcNAcylation of IκBα, and suppressed its ubiquitination and phosphorylation, thereby stabilizing IκBα protein. In conclusion, ASP exerts antidepressant effects by enhancing IκBα O-GlcNAcylation, thus inhibiting its ubiquitination and phosphorylation. These findings provide a novel therapeutic target for the treatment of depression.

Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors, including non-small cell lung cancer (NSCLC). However, its detailed molecular mechanism has not been adequately demonstrated. In this research, it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft (PDX) model. Mechanistically, employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis (MST), microRNA-145-5p (miR-145-5p) was pinpointed as a critical target through which elemene exerts its anti-tumor effects. Interestingly, elemene serves as a binding stabilizer for miR-145-5p, demonstrating a strong binding affinity (dissociation constant (K D) = 0.39 ± 0.17 μg/mL) and preventing its degradation both in vitro and in vivo, while not interfering with the synthesis of the primary microRNA transcripts (pri-miRNAs) and precursor miRNAs (pre-miRNAs). The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA, subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated protein kinase kinase kinase 3 (MAP3K3)/nuclear factor kappaB (NF-κB) pathway. Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs.

Pancreatic cancer (PC) is a malignancy of gastrointestinal tract threatening the life of people around the world. In spite of the advances in the treatment of PC, the overall survival of this disease in advanced stage is less than 12%. Moreover, PC cells have aggressive behaviour in proliferation and metastasis as well as capable of developing therapy resistance. Therefore, highlighting the underlying molecular mechanisms in PC pathogenesis can provide new insights for its treatment. In the present review, inflammation and related pathways as well as role of gut microbiome in the regulation of PC pathogenesis are highlighted. The various kinds of interleukins and chemokines are able to regulate angiogenesis, metastasis, proliferation, inflammation and therapy resistance in PC cells. Furthermore, a number of molecular pathways including NF-κB, TLRs and TGF-β demonstrate dysregulation in PC aggravating inflammation and tumorigenesis. Therapeutic regulation of these pathways can reverse inflammation and progression of PC. Both chronic and acute pancreatitis have been shown to be risk factors in the development of PC, further highlighting the role of inflammation. Finally, the composition of gut microbiota can be a risk factor for PC development through affecting pathways such as NF-κB to mediate inflammation.

This study investigates the potential protective effects of chebulagic acid (CA) against endometritis and its underlying molecular mechanisms. Network pharmacology analysis identified 19 potential targets of CA related to endometritis, mainly associated with the mitogen-activated protein kinase (MAPK) signaling pathways. Molecular docking analysis further indicated that MAPK14 and MAPK3 are critical targets of CA, suggesting its potential role in modulating inflammatory responses. In vitro experiments demonstrated that CA at concentrations of 12.5, 25, and 50 µg/mL significantly inhibited the secretion of proinflammatory cytokines interleukin (IL)-1β and IL-6 in lipopolysaccharide (LPS)-stimulated bovine endometrial epithelial cells (bEECs), without affecting cell viability. In vivo, CA treatment mitigated uterine inflammation in an LPS-induced mouse model of endometritis by downregulating high-mobility group box protein 1 (HMGB1) expression and inhibiting the phosphorylation of key signaling molecules, including p65, extracellular signal-regulated kinase (ERK), and p38. These findings suggest that CA exerts significant anti-inflammatory effects in endometritis by modulating the MAPK/NF-κB signaling pathway. Given its potential to suppress excessive inflammatory responses, CA may serve as a promising candidate for the development of novel therapeutic strategies for endometritis.

The extract of Paspalum thunbergii, a native perennial herb in Korea belonging to the rice family, was investigated for its anti-inflammatory activity and the underlying mechanisms driving its effects. Fifteen chemical components of the P. thunbergii extract, including rosmarinic acid and isoquercitrin, were identified using LC-MS. The extract showed antioxidative activity through DPPH and ABTS cation radical scavenging activity. The P. thunbergii extract significantly inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW 264.7 cells. The extract inhibited the expression of lipopolysaccharide-induced iNOS and COX-2, which are inflammation-related enzymes. To explore the underlying anti-inflammatory mechanism, the expression levels of signal proteins related to MAPK, NF-κB, JAK/STAT, and Wnt/β-catenin signaling were measured. As a result, the P. thunbergii extract inhibited the expression of p-p38, and p-JNK increased by LPS in RAW 264.7 cells. Additionally, it decreased the expression of LPS-induced p-IKKβ and p-NF-κB p65 and prevented the migration of p-NF-κB into the nucleus caused by LPS. Notably, p-JAK1, p-STAT3, Wnt 3α, β-catenin, and p-GSK-3β protein expressions were also inhibited. Therefore, the prominent anti-inflammatory activity of the P. thunbergii extract may be via the MAPK, NF-κB, JAK/STAT, Wnt/β-catenin signal pathway.

Over the past few years, the tumor microbiome is increasingly recognized for its multifaceted involvement in cancer initiation, progression, and metastasis. With the application of 16S ribosomal ribonucleic acid (16S rRNA) sequencing, the intratumoral microbiome, also referred to as tumor-intrinsic or tumor-resident microbiome, has also been found to play a significant role in the tumor microenvironment (TME). Understanding their complex functions is critical for identifying new therapeutic avenues and improving treatment outcomes. This review first summarizes the origins and composition of these microbial communities, emphasizing their adapted diversity across a diverse range of tumor types and stages. Moreover, we outline the general mechanisms by which specific microbes induce tumor initiation, including the activation of carcinogenic pathways, deoxyribonucleic acid (DNA) damage, epigenetic modifications, and chronic inflammation. We further propose the tumor microbiome may evade immunity and promote angiogenesis to support tumor progression, while uncovering specific microbial influences on each step of the metastatic cascade, such as invasion, circulation, and seeding in secondary sites. Additionally, tumor microbiome is closely associated with drug resistance and influences therapeutic efficacy by modulating immune responses, drug metabolism, and apoptotic pathways. Furthermore, we explore innovative microbe-based therapeutic strategies, such as engineered bacteria, oncolytic virotherapy, and other modalities aimed at enhancing immunotherapeutic efficacy, paving the way for microbiome-centered cancer treatment frameworks.

Radiation therapy (RT) rarely induces tumor regression at untreated metastatic sites, the so-called abscopal effect. A syngeneic tumor (EG7) transplanted into a Th1-dominant mouse strain (C57BL/6) regressed significantly on the treated side and less on the contralateral side after RT. Additional subcutaneous administration of ARNAX, a non-inflammatory adjuvant, further accelerated tumor regression on the untreated side. This suggests that ARNAX after RT significantly enhances the tumor regression effect on the irrelevant tumor. Based on this setting, we next observed similar tumor shrinkage after RT and ARNAX by transplanting syngeneic breast cancer tumors (4T1) into a Th2-dominant mouse strain (BALB/c). The results were as follows: 1. ARNAX enhanced RT-mediated tumor shrinkage comparable to polyI:C; 2. In the Th2 mouse strain, little tumor regression occurred on the untreated side compared to tumor regression on the treated side after RT alone; 3. RT+ARNAX treatment caused additive regression on the treated side and induced slight tumor regression on the untreated side; 4. PD-L1 antibody + RT combination therapy caused tumor regression and further induced additive regression with ARNAX; 5. The combination of RT and ARNAX reduced the number and volume of lung metastases compared to RT alone. However, tumor regression was not always accompanied by a significant prolongation of survival in the mice receiving our regimen and protocol (one 10Gy radiation and a single ARNAX treatment). In conclusion, RT therapy promoted abscopal tumor regression in both Th2 and Th1 models with the addition of the non-inflammatory adjuvant ARNAX.

The human microbiome, which encompasses microbial communities and their genetic material, significantly influences health and disease, including cancer. The urogenital microbiota, naturally present in the urinary and genital tracts, interact with factors such as age, lifestyle, and health conditions to affect homeostasis and carcinogenesis. Studies suggest that alterations in this microbiota contribute to the development and progression of genitourinary cancers, emphasizing the concept of oncobiome, which refers to microbial genetic contributions to cancer. Similarly, gut microbiota can influence hormone levels and systemic inflammation, impacting cancers such as cervical and prostate cancer. Advanced studies indicate that microbial communities in genitourinary cancers have distinct profiles that may serve as diagnostic biomarkers or therapeutic targets. Dysbiosis of the urinary microbiota correlates with bladder and kidney cancer. Additionally, gut microbiota influence the effectiveness of cancer treatments. However, further research is necessary to clarify causality, the role of microbial metabolites, and hormonal regulation. The aim of this review is to understand that these dynamics present opportunities for innovative cancer diagnostics and therapies, highlighting the need for integration of microbiology, oncology, and genomics to explore the role of microbiota in genitourinary cancers. For this, a comprehensive search of relevant databases was conducted, applying specific inclusion and exclusion criteria to identify studies examining the association between microbiota and urogenital cancers. Research into the mechanisms by which microbiota influence urogenital cancers may pave the way for new diagnostic and therapeutic approaches, ultimately improving patient outcomes.

Insufficient dietary fiber intake has become a global public health issue, affecting the development and management of various diseases, including intestinal diseases and obesity. This study showed that dietary fiber deficiency enhanced the susceptibility of mice to colitis, which could be attributed to the disruption of the gut barrier integrity, activation of the NF-κB pathway, and oxidative stress. Undaria pinnatifida fucoidan (UPF) alleviated colitis symptoms in mice that fed with a fiber deficient diet (FD), characterized by increased weight gain and reduced disease activity index, liver and spleen indexes, and histological score. The protective effect of UPF against FD-exacerbated colitis can be attributed to the alleviation of oxidative stress, the preservation of the gut barrier integrity, and inhibition of the MAPK/NF-κB pathway. UPF ameliorated the gut microbiota composition, leading to increased microbiota richness, as well as increased levels of Muribaculaceae, Lactobacillaceae, and Bifidobacterium and reduced levels of Proteobacteria, Bacteroidetes, and Bacteroides. Metabolomics analysis revealed that UPF improved the profile of microbiota metabolites, with increased levels of carnitine and taurine and decreased levels of tyrosine and deoxycholic acid. This study suggests that UPF has the potential to be developed as a novel prebiotic agent to enhance human health.

Oncogenes are typically overexpressed in tumor tissues and often linked to poor prognosis. However, recent advancements in bioinformatics have revealed that many highly expressed genes in tumors are associated with better patient outcomes. These genes, which act as tumor suppressors, are referred to as "paradoxical genes." Analyzing The Cancer Genome Atlas (TCGA) confirmed the widespread presence of paradoxical genes, and KEGG analysis revealed their role in regulating tumor metabolism. Mechanistically, discrepancies between gene and protein expression-affected by pre- and post-transcriptional modifications-may drive this phenomenon. Mechanisms like upstream open reading frames and alternative splicing contribute to these inconsistencies. Many paradoxical genes modulate the tumor immune microenvironment, exerting tumor-suppressive effects. Further analysis shows that the stage- and tumor-specific expression of these genes, along with their environmental sensitivity, influence their dual roles in various signaling pathways. These findings highlight the importance of paradoxical genes in resisting tumor progression and maintaining cellular homeostasis, offering new avenues for targeted cancer therapy.

Leukemia inhibitory factor receptor (LIFR), in complex with glycoprotein 130 (gp130) as the receptor for leukemia inhibitory factor (LIF), can bind to a variety of cytokines and subsequently activate a variety of signaling pathways, including Janus kinase/signal transducer and activator of transcription 3. LIF, the most multifunctional cytokines of the interleukin-6 family acts as both a growth factor and a growth inhibitor in different types of tumors. LIF/LIFR signaling regulates a broad array of tumor-related processes including proliferation, apoptosis, migration, invasion. However, due to the activation of different signaling pathways, opposite regulatory effects are observed in certain tumor cells. Therefore, the role of LIFR in human cancers varies across different tumor and tissue, despite their recognized value in tumor treatment and prognosis observation is affirmed. Given its aberrant expression in numerous tumor cells and crucial regulatory function in tumorigenesis and progression, LIFR is considered as a promising targeted therapeutic agent. This review provides an overview of LIFR's initiating signaling pathway function as a cytokine receptor and summarize the current literature on the role of LIFR in cancer and its possible use in therapy.