Search Results (2,671)

Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with RAS and BRAF wild-type cancer. Yet, primary and acquired resistance limit their benefit for many patients. A growing body of evidence reveals that resistance is not random but rather driven by a complex network of molecular alterations that sustain tumor growth independent of EGFR signaling. These include amplification of ERBB2 (HER2) and MET, activation of the PI3K and AKT pathways, EGFR extracellular domain mutations, and rare kinase fusions. The concept of negative hyperselection has emerged as a powerful strategy to refine patient selection by excluding tumors with these resistance drivers. Multiple clinical trials have consistently shown that patients who are hyperselected based on comprehensive molecular profiling achieve significantly higher response rates and improved survival compared to those selected by RAS and BRAF status alone. Liquid biopsy through circulating tumor DNA has further transformed this landscape, offering a noninvasive tool to capture tumor heterogeneity, monitor clonal evolution in real time, and guide rechallenge strategies after resistance emerges. Together, negative hyperselection, ctDNA-guided monitoring, and emerging therapeutics define a precision-oncology framework for identifying, tracking, and overcoming resistance to anti-EGFR therapy in mCRC, moving the field toward more effective and individualized care. Looking ahead, the development of innovative therapeutics such as bispecific antibodies, antibody drug conjugates, and RNA-based therapies promises to further expand in this challenging clinical scenario. These advances move precision oncology in colorectal cancer from concept to clinical reality, reshaping the standard of care through molecular insights. Full article

Acorus calamus, a traditional Tibetan medicine with potential antiviral activity but undefined mechanisms, was studied for its anti-respiratory syncytial virus (RSV) mechanisms using network pharmacology and molecular docking, given RSV’s substantial disease burden and lack of specific therapies. The primary active compounds were identified and analyzed through a literature search, the PubChem database, and the SwissADME. Relevant targets were sifted through the SwissTargetPrediction platform, OMIM, and GeneCards databases. Common targets underwent enrichment analysis using Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). Molecular docking and GEO datasets were used for further analysis. Among the screened data, 268 targets were associated with Acorus calamus compounds and 1633 with RSV. KEGG analysis of the shared targets revealed potential therapeutic roles via the PI3K–Akt and JAK–STAT signaling pathways. Molecular docking results demonstrated that CCND1, EGFR, and SRC exhibited relatively lower binding energies with compounds in comparison to other proteins, suggesting better interactions, and GEO-derived RSV datasets further validated CCND1’s significance. This study demonstrates Acorus calamus’s anti-RSV activity and its potential mechanism, providing a theoretical foundation for the effective active ingredients of Acorus calamus targeting CCND1 as a strategy to combat RSV infection. Full article

Noni juice polysaccharides demonstrate promising hypoglycemic activity, but their high molecular weight restricts bioavailability. This study established a controlled degradation approach to optimize the functional properties of Noni juice polysaccharides. Molecular characterization demonstrated that the degraded Noni juice polysaccharides (DNJPs, Mw 191.8 kDa) retained the core monosaccharide composition, while exhibiting enhanced solubility. In vitro experiments with insulin-resistant HepG2 cells showed that DNJPs (0.5–2 mg/mL) significantly enhanced glucose consumption (p < 0.01) and mitigated oxidative stress by upregulating antioxidant enzymes (SOD, CAT, and GSH-Px) and decreasing malondialdehyde (MDA) levels. DNJPs activated the PI3K/AKT-Nrf2-GSK3β signaling axis through a multifaceted mechanism involving the following: upregulating the phosphorylation levels of PI3K and AKT; enhancing Nrf2 nuclear translocation, which in turn promotes the expression of downstream targets such as HO-1 and NQO1; inhibiting GSK3β activity; and suppressing FOXO1-mediated gluconeogenesis. These findings underscore DNJPs as promising functional food ingredients that modulate two key pathways to improve glucose metabolism. Full article

Objective: Insulin resistance (IR) is a complex and multifactorial disorder that contributes to type 2 diabetes and cardiovascular disease. MicroRNAs (miRNAs) play important roles in diverse developmental and disease processes. However, the molecular mechanisms of IR are unclear. This paper aims to explore the role of miRNA in regulating IR and to elucidate the mechanisms responsible for these effects. Methods: IR models were created by feeding a high-fat diet (HFD) to mice or stimulating 3T3-L1 cells with palmitate. Twelve weeks of HFD trigger weight gain, leading to lipid accumulation and insulin resistance in mice. The expression profiles of miRNAs in adipose tissues (AT) from the HFD-induced mouse models were analyzed. The relationship between miR-221-3p and SOCS1 was determined using dual luciferase reporter gene assays. Metabolic alterations in AT were investigated by real-time PCR and Western blot. Results: miR-221-3p was significantly increased in AT. HFD-induced disturbances in glucose homeostasis were aggravated by miR-221-3p upregulation. The inhibition of miR-221-3p promoted insulin sensitivity including reduced lipid accumulation and the disruption of glucose metabolism. Of note, the 3′-UTR of SOCS1 was found to be a direct target of miR-221-3p. The SOCS1 inhibitor attenuated miR-221-3p-induced increases in IRS-1 phosphorylation, AKT phosphorylation, and GLUT4. miR-221-3p was considered to be involved in the PI3K/AKT signaling pathway, thus leading to increased insulin sensitivity and decreased IR in HFD-fed mice and 3T3-L1 adipocytes. Conclusions: The miR-221-3p/SOCS1 axis in AT plays a pivotal role in the regulation of glucose metabolism, providing a novel target for treating IR and diabetes. Full article

Previous studies conducted by our research groups have demonstrated that the HGF/c-Met signaling pathway promotes the proliferation and migration of MSCs in the antlers of Tarim red deer. However, the role and mechanism of this gene in the osteogenic differentiation of antler MSCs remain unclear. In this study, we used antler MSCs as experimental materials. CRISPR/Cas9 technology was employed to knock out the HGF gene, and lentivirus-mediated overexpression of the HGF gene was constructed in antler MSCs. Subsequently, antler MSCs were induced to undergo osteogenic differentiation in vitro. Alizarin Red staining was employed to identify calcium nodules, while the expression levels of various osteogenic differentiation marker genes were assessed using immunohistochemistry, RT-qPCR, and Western blotting techniques. The findings indicated that the HGF gene facilitates the osteogenic differentiation of antler MSCs. Analysis of genes associated with the PI3K/Akt and MEK/ERK signaling pathways demonstrated that in antler MSCs with HGF gene knockout, the expression levels of PI3K/Akt and MEK/ERK pathway genes were significantly downregulated on days 7 and 14 of osteogenic differentiation (p < 0.05). In contrast, antler MSCs with HGF gene overexpression exhibited a significant upregulation of the PI3K/Akt and MEK/ERK signaling pathways on days 4 and 6 of osteogenic differentiation (p < 0.01). These findings suggest that the HGF gene in antlers enhances the osteogenic differentiation of MSCs by activating the PI3K/Akt and MEK/ERK pathways. Full article

MRGPRX2 (Mas-related G protein-coupled receptor member X2) is implicated in mast cell (MC)-driven disorders due to its ability to bind diverse ligands, which may be G-protein-biased or balanced, with the latter activating both G-proteins and the β-arrestin pathway. Icatibant, a peptide drug, produces injection-site reactions in most patients and is used experimentally to probe MRGPRX2 function in skin tests. While reported to be G-protein-biased, it is unknown how skin MCs respond to icatibant, although these are the primary target cells during therapy. We therefore compared responses to icatibant with those induced by the balanced agonist substance P (SP) in skin MCs. Degranulation and desensitization were assessed via β-hexosaminidase release, receptor internalization by flow cytometry, and downstream signaling by immunoblotting. Skin MCs degranulated in response to SP and icatibant, relying on Gi proteins and calcium channels; Gq and PI3K (Phosphoinositide 3-kinase) contributed more strongly to exocytosis following icatibant, while JNK (c-Jun n-terminal kinase) was more relevant for SP. Both agonists activated ERK, PI3K/AKT, and (weakly) p38. Surprisingly, and in contrast to the LAD2 (Laboratory of Allergic Diseases 2 mast cell line) MC line, icatibant was at least as potent as SP in eliciting MRGPRX2 internalization and (cross-)desensitization in skin MCs. These findings suggest that icatibant functions differently in primary versus transformed MCs, acting as a fully balanced ligand in the former by triggering not only degranulation but also receptor internalization and desensitization. Therefore, not only the ligand but also the MRGPRX2-expressing cell plays a decisive role in whether a ligand is balanced or biased. These findings are relevant to our understanding of icatibant’s clinical effects on edema and itch. Full article

Recent years have provided numerous reports on the mechanisms of action of psychiatric medications (antidepressants, antipsychotics, mood stabilizers, and antidementia drugs) that directly inhibit the growth of cancer cells, as well as on their indirect effects on the psyche and immune system, and their supportive effects on chemotherapeutic agents. The mechanisms of the anticancer activity of psychiatric drugs include inhibition of dopamine and N-methyl-D-aspartate receptors that work via signaling pathways (PI3K/AKT/mTOR/NF-κB, ERK, Wnt/ß-catenin, and bcl2), metabolic pathways (ornithine decarboxylase, intracellular cholesterol transport, lysosomal enzymes, and glycolysis), autophagy, Ca²⁺-dependent signaling cascades, and various other proteins (actin-related protein complex, sirtuin 1, p21, p53, etc.). The anticancer potential of psychiatric drugs seems to be extremely broad, and the most extensive anticancer literature has been reported on antidepressants (fluoxetine, amitriptyline, imipramine, mirtazapine, and St John’s Wort) and antipsychotics (chlorpromazine, pimozide, thioridazine, and trifluoperazine). Among mood stabilizers, lithium and valproates have the largest body of literature. Among antidementia drugs, memantine has documented anticancer effects, while there is limited evidence for galantamine. Of the new psychiatric substances, the antipsychotic drug brexpiprazole and the antidepressant vortioxetine have a very interesting body of literature regarding glioblastoma, based on in vitro and in vivo animal survival studies. Their use in brain tumors and metastases is particularly compelling, as these substances readily cross the blood–brain barrier (BBB). Moreover, the synergistic effect of psychiatric drugs with traditional cancer treatment seems to be extremely important in the fight against chemo- and radio-resistance of tumors. Although there are some studies describing the possible carcinogenic effects of psychiatric drugs in animals, the anticancer effect seems to be extremely significant, especially in combination treatment with radio/chemotherapy. The emerging evidence supporting the anticancer properties of psychiatric drugs presents an exciting frontier in oncology. The anticancer properties of psychiatric drugs may prove particularly useful in the period between chemotherapy and radiotherapy sessions to maintain the tumor-inhibitory effect. While further research is necessary to elucidate the mechanisms, clinical implications, dose-dependence of the effect, and clear guidelines for the use of psychiatric medications in cancer therapy, the potential for these commonly prescribed medications to contribute to cancer treatment enhances their value in the management of patients facing the dual challenges of mental health and cancer. Full article

Ammonia is a common toxic pollutant in aquaculture environments that poses significant threats to the health, growth, and survival of aquatic organisms. This study investigates the physiological and molecular responses of triploid Crassostrea gigas to ammonia exposure, focusing on the activation and regulation of oxidative stress and immune-related pathways. By integrating histological observations, biochemical assays, and transcriptomic analysis, we systematically revealed the oxidative stress and immune regulatory mechanisms in the hepatopancreas of triploid C. gigas under ammonia exposure. Results showed significant tissue damage in the hepatopancreas, disrupted activities of key antioxidant enzymes including SOD, CAT, and GSH-Px, along with elevated MDA levels, indicating oxidative damage to cellular membrane lipids. Transcriptomic data further indicated significant activation of the glutathione metabolism pathway, with antioxidant genes such as GPX5 and GPX7 displaying a dynamic pattern of initial upregulation followed by downregulation, suggesting their critical roles in modulating oxidative stress responses and maintaining cellular homeostasis. Immunologically, ammonia exposure significantly activated lysosomal and phagosomal pathways, as well as multiple signaling cascades including FOXO, mTOR, and PI3K-Akt. Several key immune regulatory genes exhibited dynamic expression changes, reflecting coordinated regulation of apoptosis, autophagy, and energy metabolism to maintain immune defense and cellular homeostasis. Notably, dynamic expression of the GADD45 gene family in the FOXO signaling pathway underscores the important role of triploid C. gigas in mounting stress responses and adaptive immune regulation under ammonia toxicity. This study provides in-depth molecular insights into the integrated response mechanisms of triploid oysters to ammonia exposure, offering a molecular foundation for understanding bivalve adaptation to ammonia and revealing novel perspectives on molluscan ammonia tolerance. Full article

Repeated UV exposure, air pollution, and toxins promote skin oxidative stress. ROS destroy macromolecules, changing cellular mechanisms and signaling cascades. Inflammation and injury to skin cells degrade function and accelerate aging, causing wrinkles, firmness loss, and dermatological disorders. Gymnema inodorum (GI) contains phytochemical antioxidants such polyphenols and triterpenoids that lower ROS and strengthen skin. GI extracts (GIEs) have never been examined for their effects on dermal skin fibroblasts’ oxidative stress and intracellular cytoprotective mechanisms. In this study, GIEs were prepared as a water extract (GIE0) and ethanol extracts with concentrations ranging from 20% to 95% v/v (GIE20, GIE40, GIE60, GIE80, and GIE95). These extracts were assessed for phytochemical content, antioxidant capacity, and free radical scavenging efficacy. The results were compared to a commercially available native Gymnema extract (NGE) obtained from Gymnema sylvestre. During principal component analysis (PCA), the most effective extracts were identified and subsequently evaluated for their ability to mitigate oxidative stress in fibroblasts. Cytoprotective effects of GIE and NGE against H₂O₂-induced human dermal fibroblast injury were investigated by cell viability, intracellular ROS production, and signaling pathways. GIE0, GIE80, GIE95, and NGE were the best antioxidants. By preserving ROS balance and redox homeostasis, GIE and NGE reduce fibroblast inflammation and oxidative stress-induced damage. Decreased ROS levels reduce MAPK/AP-1/NF-κB and PI3K/AKT/NF-κB signaling pathways, diminishing inflammatory cytokines. In conclusion, GIE and NGE have antioxidant and anti-inflammatory capabilities that can reduce H₂O₂-induced fibroblast oxidative stress and damage, thereby preventing skin aging and targeting cancer-associated fibroblasts. Full article

Alzheimer’s disease (AD) and major depressive disorder (MDD) are prevalent central nervous system (CNS) disorders that share overlapping symptoms but differ in underlying molecular mechanisms. Distinguishing these mechanisms is essential for developing targeted diagnostic and therapeutic strategies. In this study, we integrated multi-tissue transcriptomic datasets from brain and peripheral samples to identify differentially expressed microRNAs (miRNAs) in AD and MDD. Functional enrichment analyses (KEGG, GO) revealed that dysregulated miRNAs in AD were associated with MAPK, PI3K–Akt, Ras, and PD-1/PD-L1 signaling, pathways linked to synaptic plasticity, neuroinflammation, and immune regulation. In contrast, MDD-associated miRNAs showed enrichment in Hippo signaling and ubiquitin-mediated proteolysis, implicating altered neurogenesis and protein homeostasis. Network analysis highlighted key disease- and tissue-specific miRNAs, notably hsa-miR-1202 and hsa-miR-24-3p, with potential roles in neuronal survival and molecular network regulation. These findings suggest that miRNAs may serve as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring in both disorders. While therapeutic targeting of miRNAs offers promise, challenges such as blood–brain barrier penetration and tissue-specific delivery remain. This integrative approach provides a translational framework for advancing miRNA-based strategies in CNS disease research. Full article

This study investigated the molecular mechanisms by which phthalates induce depression, utilizing network toxicology and molecular docking techniques. By integrating the TargetNet, GeneCards, and PharmMapper databases, 658 potential target genes of phthalates were identified. Additionally, 5433 depression-related targets were retrieved from the GeneCards and OMIM databases. Comparative analysis revealed 360 common targets implicated in both phthalate action and depression. A Protein-Protein Interaction (PPI) network was constructed using the STRING database. Subsequently, the CytoHubba plugin (employing the MCC algorithm) within Cytoscape was used to screen the network, identifying the top 20 hub genes. These core genes include AKT1, CASP3, TNF, TP53, BCL2, and IL6, among others. Validation on the GEO dataset (GSE23848) revealed that the expression of multiple core genes was significantly upregulated in patients with depression (p < 0.05). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that phthalates mainly regulate biological processes such as extracellular stimulus response, lipopolysaccharide metabolism, and chemical synaptic transmission. Depression is mediated by the AGE-RAGE signaling pathway (a complication of diabetes), lipids and atherosclerosis, Endocrine resistance, and the PI3K-Akt signaling pathway. Molecular docking confirmed that phthalates have strong binding activity with key targets (CASP3, TNF, TP53, BCL2, IL6). These findings present a novel paradigm for evaluating the health risks posed by environmental pollutants. Full article

Type II diabetes mellitus (T2DM) is characterized by chronic glycolipid metabolic dysregulation. This study aimed to investigate the effects and mechanisms of Artemisia integrifolia Linn. (LH) as a functional food in a T2DM rat model. The UPLC-Q-TOF-MS/MS technique was used to identify the components of LH. T2DM was induced in rats via a high-fat/high-sugar diet combined with streptozotocin (STZ, 35 mg/kg, i.p.). The rats were subsequently treated with LH (90 mg/kg, 180 mg/kg) for 15 days. A total of 66 compounds were identified in both positive and negative ions. LH treatment resulted in an increase in body weight while reducing FBG levels. It also improved insulin resistance, blood lipid levels, liver pathology, function, and lipid accumulation. Furthermore, 18 metabolites and 5 metabolic pathways were identified in the liver. Mechanistically, LH may improve T2DM through modulation of the S1P and PI3K/AKT signaling pathway. Caffeic acid, coumarin, trifolin, and apigetrin were identified as the likely active components. In conclusion, LH may mitigate glycolipid metabolism disorders in T2DM rats by modulating metabolic profiling, S1P, and the PI3K/AKT signaling pathway, supporting its potential as a functional food. Full article

Saline–alkaline water resources are globally widespread, and their rational development offers significant potential to alleviate freshwater scarcity. Saline–alkaline water aquaculture farming not only affects fish growth and survival but also impairs reproductive and developmental functions. Largemouth bass (Micropterus salmoides), an economically important fish, has demonstrated excellent high tolerance to such environments, in order to investigate the effects of alkaline water aquaculture environments on its growth performance, sex hormone levels, gonadal development, and molecular adaptation mechanisms. In this study, largemouth bass were chronically exposed to freshwater (0.55 mmol/L), low alkalinity (10 mmol/L), or high alkalinity (25 mmol/L) and cultured for 80 days. Alkalinity exposure more severely impacted the growth rate of females. High alkalinity significantly increased the hepatosomatic index and decreased the gonadosomatic index in both sexes; moreover, it induced oxidative stress in both sexes, evidenced by reduced superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAOC) levels and elevated malondialdehyde (MDA) content. Furthermore, the levels of sex hormones Serum estradiol (E2), 11-ketotestosterone (11-KT), and testosterone were significantly reduced, accompanied by either an elevated ratio of primary oocytes and follicular atresia, or by reduced spermatogenesis. Apoptotic signals appeared in gonadal interstitial cells, with upregulated expression of genes P53, Bax, Casp3, and Casp8. Ultrastructural damage included fewer mitochondria and cristae blurring, further indicating tissue damage causing dysfunction. Transcriptome results showed that oxidative stress damage and energy metabolism imbalance caused by carbonate alkalinity were key to the delayed gonadal development, which was mainly manifested in enrichment of the ECM–receptor interaction and PI3K-Akt signaling pathways in females exposed to low alkalinity, and the GnRH secretion and chemokine signaling pathways in males. Glycosphingolipid biosynthesis and Ferroptosis pathway were enriched in females exposed to high alkalinity, and the Cortisol synthesis and secretion pathway were enriched in males. Overall, high-alkalinity exposure significantly delayed gonadal development in both sexes of largemouth bass, leading to reproductive impairment. Full article

Background: Clear cell renal cell carcinoma with rhabdoid features (ccRCC-R) is a highly aggressive variant of renal cell carcinoma that carries a poor prognosis and limited treatment options. Methods: To better define the clinicopathologic and molecular landscape of ccRCC-R, we conducted an integrated clinicopathologic and molecular study of 17 tumors of ccRCC-R, utilizing comprehensive histomorphologic evaluation, immunohistochemistry, and targeted next-generation sequencing (NGS). Results: Histologically, all tumors demonstrated classic clear cell renal cell carcinoma morphology with focal to extensive rhabdoid differentiation, characterized by eccentrically located nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and paranuclear intracytoplasmic inclusion. Architectural alterations, including solid/sheet-like, alveolar/trabecular, and pseudopapillary growth patterns, were frequently observed. Immunohistochemically, tumors commonly exhibited loss of PAX8 and Claudin4 expression, preserved cytokeratin AE1/AE3 staining, and diffuse membranous CAIX expression. Frequent loss of SMARCA2 with retained SMARCA4 supported aberrations in chromatin remodeling. Unsupervised hierarchical clustering based on pathway-specific somatic mutations identified four distinct molecular subgroups defined by recurrent alterations in (1) DNA damage repair (DDR) genes, (2) chromatin remodeling genes, (3) PI3K/AKT/mTOR signaling components, and (4) MAPK pathway genes. Clinicopathologic correlation revealed that each subgroup was associated with unique biological characteristics and suggested distinct therapeutic vulnerabilities. Conclusions: Our findings underscore the molecular heterogeneity of ccRCC-R and support the utility of pathway-based stratification for guiding precision oncology approaches and biomarker-informed clinical trial design. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)—a bioactive glycoside from Morus alba L.—present promising alternatives. This study investigated MsA’s neuroprotective potential using scopolamine-induced AD-like mice and N2a/APP695swe cells. In vivo, MsA significantly ameliorated cognitive deficits and neuronal loss, concurrently enhancing cholinergic neurotransmission through increased acetylcholine levels and inhibited acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) activities. MsA also upregulated neurotrophic factors (BDNF, CREB) in critical brain regions. In vitro, MsA restored cholinergic function, mitigated oxidative stress, and crucially reduced amyloid-β (Aβ) production by dual regulation of APP processing: promoting the non-amyloidogenic pathway via ADAM10 upregulation and inhibiting the amyloidogenic pathway via suppression of BACE1 and γ-secretase components. Mechanistically, these multi-target benefits were mediated by MsA’s activation of the PI3K/AKT pathway, which triggered downstream inhibitory phosphorylation of GSK3β—directly reduced tau hyperphosphorylation—and activation of CREB/BDNF signaling. Collectively, our findings demonstrate that MsA confers comprehensive neuroprotection against AD pathology by simultaneously targeting cholinergic dysfunction, oxidative stress, Aβ accumulation, tau phosphorylation, and impaired neurotrophic signaling, highlighting its strong therapeutic candidacy. Full article