Background:Traditional Chinese medicine (TCM) formulations are increasingly used in combination with mesalazine to treat mild-to-moderate active ulcerative colitis (UC). However, direct comparisons between various TCM regimens are limited. Methods:We performed a frequentist network meta-analysis of 34 randomized controlled trials (n = 2,854) comparing oral mesalazine (1.0-4.0 g/day) alone versus mesalazine plus one of eight TCM formulations: Kangfuxin solution, Shaoyao decoction, Glycyrrhizae decoction, Scutellaria decoction (Huangqin granules), Baitouweng decoction (Pulsatilla; retention enema), Shenling Baizhu Powder, CurQD formula, or Fufangkushen capsules. Outcomes included clinical efficacy, adverse events, Mayo score, serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and intestinal Bifidobacteria, Lactobacilli, and Escherichia coli. Risk ratios (RRs) were calculated for dichotomous outcomes and mean differences (MDs) for continuous outcomes. Treatments were ranked using surface under the cumulative ranking curve (SUCRA). Results:Most TCM-mesalazine combinations improved clinical efficacy versus mesalazine alone. CurQD and Kangfuxin had the highest probabilities of being most effective for symptom improvement (SUCRA 96.7% and 72.7%, respectively); the direct CurQD-mesalazine comparison showed RR = 2.67 (95% CI 1.16-6.14). Adverse-event rates were similar across regimens, with lower incidence of adverse events. Mayo score reductions were greatest with Glycyrrhizae decoction (MD = -1.40), Baitouweng decoction via retention enema (MD = -1.09), and Kangfuxin solution (MD = -1.07). Scutellaria granules produced the largest IL-6 decrease (MD = -53.28 pg/mL) and ranked highest for TNF-α reduction, followed by Kangfuxin. For gut microbiota, Shaoyao decoction ranked highest for increasing Bifidobacteria, Glycyrrhizae decoction for increasing Lactobacilli, and Glycyrrhizae also reduced E. coli (MD = -1.93). Conclusion:Combining mesalazine with selected TCM formulations can enhance clinical response, reduce inflammatory cytokines, and beneficially modulate gut microbiota without increasing adverse events. CurQD or Kangfuxin may be prioritized for symptomatic improvement, Glycyrrhizae or Baitouweng for Mayo score reduction, Scutellaria for cytokine control, and Shaoyao or Glycyrrhizae for microbiota modulation. High-quality multicenter RCTs are warranted to confirm these comparative rankings.

Recurrence and metastasis are the main causes of death in ovarian cancer (OC). Long non-coding RNAs (lncRNAs) are considered as good prognostic models and potential therapeutic targets for cancer patients because of their easy detection and strong correlation. Our study identifies an OC-associated lncRNA with tumor progression and therapeutic implications. It's found that lncRNA AC093895.1 is highly expressed in OC tissues and correlated with poor prognosis. AC093895.1 has a potentiating effect during the progression and metastasis of ovarian cancer. The effects of AC093895.1 on ovarian cancer cells are miR-1253 dependent. Results showed that by interacting with tumor-suppressive gene miR-1253 as competing endogenous RNA (ceRNAs), AC093895.1 significantly upregulated the downstream gene SOX4 of AC093895.1/ miR-1253 axis, leading to tumor metastasis. In addition, chromatin immunoprecipitation (ChIP) results further confirmed that SOX4 could bind to the AC093895.1 promoter, forming a positive feedback loop SOX4/AC093895.1/miR-1253/SOX4. Therapeutic strategy to break the loop through AC093895.1 knockdown exhibited attenuated OC growth and metastasis in vivo both in SK-OV-3 subcutaneous model and pulmonary metastatic model. Our study unveiled the potentiating effects of SOX4/AC093895.1/miR-1253/SOX4 on ovarian cancer cell survival, migration, and invasion. AC093895.1 may be a promising patient prognostic biomarker and therapeutic candidate. Created with BioRender.com.

ObjectiveTo observe the effect of electroacupuncture （EA） at “Zusanli” （ST36） on colonic mucosa injury， expression of nuclear factor κB （NF-κB）， and Aquaporin 8 （AQP8） in mice with transplanted colorectal cancer （CRC）， so as to explore its mechanisms underlying improvement of colonic mucosal injury.MethodsA colorectal cancer cell strain CT26 was subcutaneously injected into BALB/c mice to establish an animal model of transplanted CRC. When the tumor grew to 100–300 mm3， the mice were randomly divided into the tumor-bearing model， chemotherapy， and chemotherapy + EA groups， with 6 mice in each group. Another 6 normal BALB/c mice were used as the normal group. The mice of the chemotherapy group and the chemotherapy + EA group received intraperitoneal injection of 5-FU solution （50 mg/kg， 0.01 mL/g）， once daily for 5 days. For mice of the chemotherapy + EA group， EA （2 Hz， 1—2 mA） was applied to bilateral ST36 for 5 min immediately after chemotherapy. During the experiment， the mouse daily Disease Activity Index （DAI） score， was determined for assessing the disease severity. The tumor volume was measured once daily. At the end of the experiment， the mice were sacrificed to measure the tumor mass and colonic length. Histopathological changes of the colon tissue were observed after H.E. staining. The serum contents of diamine oxidase （DAO） and D-lactate （D-LA） were detected using ELISA for assessing the extent of colonic intestinal damage. The immunoactivity of colonic AQP8 was detected using immunohistochemistry， the immunofluorescence intensity of colonic NF-κB was detected using immunofluorescence staining for assessing the nuclear translocation status， and the expression levels of colonic NF-κB and AQP8 proteins were detected using Western blot.ResultsCompared with the normal group， the tumor-bearing model group hand no significant changes in the DAI score， contents of serum DAO and D-LA， immunoactivity， immunofluorescence intensity and protein expression levels of colonic NF-κB and AQP8 proteins. In comparison with the tumor-bearing model group， the DAI score in chemotherapy group， and serum DAO and D-LA contents， nuclear translocation and protein expression levels of NF-κB in the chemotherapy group were considerably increased （P<0.05）， while the colonic length， tumor volume， tumor mass， and the immunoactivity level of AQP8 were strikingly decreased （P<0.05）. Comparison between the chemotherapy and chemotherapy+EA groups showed that the DAI score， serum DAO and D-LA contents， nuclear translocation and protein expression levels of NF-κB in the chemotherapy + EA group were significantly lower than those in the chemotherapy group （P<0.05）， while the immunoactivity level of AQP8 in the chemotherapy+EA group were notably higher than those in the chemotherapy group （P<0.05）， and no significant differences were found between the chemotherapy and chemotherapy+EA groups in the levels of colonic length， tumor volume and mass. H.E. staining showed that the colonic tissue structure in the tumor-bearing group had no abnormal changes， and that in the chemotherapy group displayed pathological injury， including shortening and thickening of intestinal villi， destruction of glandular structure， increased shedding of goblet cells， infiltration of inflammatory cells， and enlargement of cell nuclei. Compared with the chemotherapy group， the colonic structure in the chemotherapy + EA group was improved， including increase in the villi length， and reduction in the disordered arrangement of the tissue cells and infiltration of inflammatory cells.ConclusionEA of ST36 can mitigate intestinal mucosal damage to maintain intestinal barrier function in mice with transplanted CRC， which may be related with its functions in inhibiting the excessive activation of the NF-κB signaling pathway， up-regulating the expression levels of AQP8 protein， and reducing DAO and D-LA release.

Background:Baicalein (BA) is a major bioactive flavonoid derived from Scutellaria baicalensis Georgi. Accumulating evidence has demonstrated that BA exhibits remarkable antitumor activity. However, the mechanisms underlying its effects in colorectal cancer (CRC) remain unclear. This study aimed to elucidate the potential therapeutic mechanisms of BA in CRC through an integrated approach using network pharmacology (NP), molecular docking, molecular dynamics simulations (MDS), and experimental validation. Methods:First, potential targets of BA and CRC were retrieved from public databases, and overlapping targets were identified. A protein-protein interaction (PPI) network was established, and candidate targets were analyzed using Gene Ontology (GO), Disease Ontology (DO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to identify signaling pathways through which BA may exert therapeutic effects in CRC. The stability of ligand-receptor binding was evaluated via molecular docking and MDS. Finally, the identified core targets and associated signaling pathways were validated through in vitro assays. Results:NP analysis identified 171 overlapping targets between CRC and BA, with EGFR, AKT1, MAPK3 (ERK1), BCL2, GSK3B, and SRC identified as the core nodes. Molecular docking and MDS revealed that BA forms stable interactions with the kinase domain of EGFR. Integrated enrichment analysis and in vitro experiments demonstrated that BA exerted anti-CRC effects primarily through EGFR-mediated MAPK and PI3K/AKT signaling pathways. Conclusions:BA inhibits CRC progression by inhibiting EGFR activation and modulating MAPK and PI3K/AKT signaling pathways. These findings provide a theoretical basis for developing BA as a natural therapeutic agent for CRC treatment.

Babao Dan (BBD), a traditional Chinese herbal compound, has demonstrated significant antitumor effects and is clinically used as an adjunctive therapy for various gastrointestinal malignancies. However, its underlying mechanisms of action remain poorly understood. This study aimed to investigate the effects of BBD on 5-fluorouracil (5-FU)-induced myelosuppression and T-lymphocyte subpopulation alterations, and to explore its mechanism in ameliorating cellular immune dysfunction caused by myelosuppression via the MAPK signaling pathway. The major constituents of BBD are fatty acids, triterpenoids, flavonoids, and alkaloids, along with other compounds. BBD significantly improved survival, reduced body weight loss, and mitigated the decline in splenic index in mice following 5-FU-induced chemotherapy. Additionally, it alleviated the reduction of peripheral blood cells, including leukocytes, neutrophils, and reticulocytes, and attenuated 5-FU-induced bone marrow hematopoiesis suppression. Furthermore, BBD restored the imbalance in the proportions of Th1 and Th2 cells within the spleens of 5-FU-induced mice. It also reversed the inhibition of CD25+ and CD69+ expression, the reduction in lymphocyte division generation, and the decreased expression of Ki67 and PCNA, thereby enhancing T-cell activation and proliferation in splenic cells. Moreover, BBD alleviated the G1 phase blockage in the bone marrow cell cycle and upregulated the expression of key proteins, including CDK2, CDK4, CDK6, Cyclin D1, Cyclin E1, p-Rb, p-c-Fos, p-c-Jun, p-ERK, p-NF-κB p65, and p-p38, in bone marrow cells. BBD may promote the expression of G1/S checkpoint-related proteins in myeloid cells by regulating the MAPK signaling pathway, thereby upregulating the phosphorylation level of Rb and facilitating the transition from the G1 phase to the S phase. This orderly cell cycle progression enhances cell proliferation and improves the hematopoietic function of myeloid cells after 5-FU chemotherapy. Consequently, BBD restores the ratio of peripheral T-cell subsets, corrects the imbalance of Th-cell subsets, and enhances the activation and proliferation functions of CD4+T cells and CD8+T cells, ultimately rectifying the dysregulated immune homeostasis of the organism.

Surgical resection is still the main means for clinical treatments of breast cancer, but the postoperative immunosuppressive microenvironment and neoangiogenesis of the residual tumors easily lead to tumor metastasis and recurrence, which will further endanger patients' lives. The combination of antiangiogenic therapy and immunotherapy may promote the mutually reinforced cycle of immune reprogramming and vascular normalization to avoid tumor metastasis and recurrence. Herein, we prepared polydopamine nanoparticles for improving tissue adhesion and enriching tumor-associated antigens. This nanoregulator together with regorafenib (REG) was further incorporated into a hydrogel developed from grafting adipic acid dihydrazide onto 2,2,6,6-tetramethylpiperidine-1-oxyl radical oxidized chitin and oxidized hyaluronic acid, which was injectable at the cavity after subcutaneous tumor surgery with good mechanical properties and degradability. The system showed long-term release of REG. After combining with anti-PD-L1, the hydrogel applied to the surgical wound exhibited a reduction in tumor metastasis and recurrence. This effect was achieved by suppressing angiogenesis and enhancing antitumor immunity, characterized by increased levels of effector T lymphocytes and activation of dendritic cells within tumors, spleens, and draining lymph nodes. The injectable hydrogel offers a promising strategy for postoperative management aimed at preventing tumor metastasis and recurrence.

Objective To observe the effect of electroacupuncture (EA) at u201CZusanliu201D (ST36) on colonic mucosa injury, expressions of nuclear factor u03BAB (NF-u03BAB), and Aquaporin 8 (AQP8) in 5-fluorouracil (5-FU)-treated mice with transplanted colorectal cancer (CRC), so as to explore its mechanisms underlying improvement of colonic mucosal injury. Methods A colorectal cancer cell strain CT26 was subcutaneously injected into BALB/c mice to establish an animal model of transplanted CRC. When the tumor grew to 100u2014300 mm3, the mice were randomly divided into the tumor-bearing model, chemotherapy, and chemotherapy+EA groups, with 6 mice in each group. Another 6 normal BALB/c mice were used as the normal group. The mice of the chemotherapy group and the chemotherapy+EA group received intraperitoneal injection of 5-FU solution (50 mg/kg, 0.01 mL/g), once daily for 5 d. For mice of the chemotherapy + EA group, EA (2 Hz, 1u20142 mA) was applied to bilateral ST36 for 5 min immediately after chemotherapy. During the experiment, the mouse daily Disease Activity Index (DAI) score was determined for assessing the disease severity. The tumor volume was measured once daily. At the end of the experiment, the mice were sacrificed to measure the tumor weight and colonic length. Histopathological changes of the colon tissue were observed after H.E. staining. The serum contents of diamine oxidase (DAO) and D-lactate (D-LA) were detected using ELISA. The immunoactivity of colonic AQP8 was detected using immunohistochemistry, the immunofluorescence intensity of colonic NF-u03BAB was detected using immunofluorescence staining for assessing the nuclear translocation status, and the protein expression levels of colonic NF-u03BAB and AQP8 were detected using Western blot. Results Compared with the normal group, the tumor-bearing model group had no significant changes in the DAI score, contents of serum DAO and D-LA, immunoactivity, immunofluorescence intensity and protein expression levels of colonic NF-u03BAB and AQP8. In comparison with the tumor-bearing model group, the DAI score in chemotherapy group, and serum DAO and D-LA contents, nuclear translocation and protein expression levels of NF-u03BAB in the chemotherapy group were considerably increased (Pu0026lt;0.05), while the colonic length, tumor volume, tumor weight, and the immunoactivity level of AQP8 were strikingly decreased (Pu0026lt;0.05). Comparison between the chemotherapy and chemotherapy+EA groups showed that the DAI score, serum DAO and D-LA contents, nuclear translocation and protein expression levels of NF-u03BAB in the chemotherapy+EA group were significantly lower than those in the chemotherapy group (Pu0026lt;0.05), while the immunoactivity level of AQP8 in the chemotherapy+EA group was notably higher than that in the chemotherapy group (Pu0026lt;0.05), and no significant differences were found between the chemotherapy and chemotherapy+EA groups in the levels of colonic length, tumor volume and mass. H. E. staining showed that the colonic tissue structure in the tumor-bearing group had no abnormal changes, and that in the chemotherapy group displayed pathological injury, including shortening and thickening of intestinal villi, destruction of glandular structure, increased shedding of goblet cells, infiltration of inflammatory cells, and enlargement of cell nuclei. Compared with the chemotherapy group, the colonic structure in the chemotherapy+EA group was improved, including increase in the villi length, and reduction in the disordered arrangement of the tissue cells and infiltration of inflammatory cells. Conclusion EA of ST36 can mitigate intestinal mucosal damage to maintain intestinal barrier function in 5-FU-treated mice with transplanted CRC, which may be related with its functions in inhibiting the excessive activation of the NF-u03BAB signaling pathway, up-regulating the expression levels of AQP8 protein, and reducing DAO and D-LA release.

OBJECTIVES:To observe the effect of electroacupuncture (EA) at "Zusanli" (ST36) on colonic mucosa injury, expressions of nuclear factor κB (NF-κB), and Aquaporin 8 (AQP8) in 5-fluorouracil (5-FU)-treated mice with transplanted colorectal cancer (CRC), so as to explore its mechanisms underlying improvement of colonic mucosal injury. METHODS:A colorectal cancer cell strain CT26 was subcutaneously injected into BALB/c mice to establish an animal model of transplanted CRC. When the tumor grew to 100-300 mm3, the mice were randomly divided into the tumor-bearing model, chemotherapy, and chemotherapy+EA groups, with 6 mice in each group. Another 6 normal BALB/c mice were used as the normal group. The mice of the chemotherapy group and the chemotherapy+EA group received intraperitoneal injection of 5-FU solution (50 mg/kg, 0.01 mL/g), once daily for 5 d. For mice of the chemotherapy + EA group, EA (2 Hz, 1-2 mA) was applied to bilateral ST36 for 5 min immediately after chemotherapy. During the experiment, the mouse daily Disease Activity Index (DAI) score was determined for assessing the disease severity. The tumor volume was measured once daily. At the end of the experiment, the mice were sacrificed to measure the tumor weight and colonic length. Histopathological changes of the colon tissue were observed after H.E. staining. The serum contents of diamine oxidase (DAO) and D-lactate (D-LA) were detected using ELISA. The immunoactivity of colonic AQP8 was detected using immunohistochemistry, the immunofluorescence intensity of colonic NF-κB was detected using immunofluorescence staining for assessing the nuclear translocation status, and the protein expression levels of colonic NF-κB and AQP8 were detected using Western blot. RESULTS:Compared with the normal group, the tumor-bearing model group had no significant changes in the DAI score, contents of serum DAO and D-LA, immunoactivity, immunofluorescence intensity and protein expression levels of colonic NF-κB and AQP8. In comparison with the tumor-bearing model group, the DAI score in chemotherapy group, and serum DAO and D-LA contents, nuclear translocation and protein expression levels of NF-κB in the chemotherapy group were considerably increased (P<0.05), while the colonic length, tumor volume, tumor weight, and the immunoactivity level of AQP8 were strikingly decreased (P<0.05). Comparison between the chemotherapy and chemotherapy+EA groups showed that the DAI score, serum DAO and D-LA contents, nuclear translocation and protein expression levels of NF-κB in the chemotherapy+EA group were significantly lower than those in the chemotherapy group (P<0.05), while the immunoactivity level of AQP8 in the chemotherapy+EA group was notably higher than that in the chemotherapy group (P<0.05), and no significant differences were found between the chemotherapy and chemotherapy+EA groups in the levels of colonic length, tumor volume and mass. H.E. staining showed that the colonic tissue structure in the tumor-bearing group had no abnormal changes, and that in the chemotherapy group displayed pathological injury, including shortening and thickening of intestinal villi, destruction of glandular structure, increased shedding of goblet cells, infiltration of inflammatory cells, and enlargement of cell nuclei. Compared with the chemotherapy group, the colonic structure in the chemotherapy+EA group was improved, including increase in the villi length, and reduction in the disordered arrangement of the tissue cells and infiltration of inflammatory cells. CONCLUSIONS:EA of ST36 can mitigate intestinal mucosal damage to maintain intestinal barrier function in 5-FU-treated mice with transplanted CRC, which may be related with its functions in inhibiting the excessive activation of the NF-κB signaling pathway, up-regulating the expression levels of AQP8 protein, and reducing DAO and D-LA release.

OBJECTIVES:To explore the therapeutic mechanism of Qingjie Fuzheng granules (QFG) for alleviating 5-fluorouracil (5-FU)-induced skeletal muscle atrophy. METHODS:Male BALB/c mice bearing subcutaneous colorectal cancer CT26 cell xenografts were randomized into control group, model group, and treatment group. The mice in model and treatment groups were given intraperitoneal 5-FU injections every 3 days and treated with daily gavage of saline and QFG for 21 days, respectively; the mice in the control group and normally fed mice were given only saline gavage. Gripping test and hanging test of the mice were performed before and after the treatment, and on day 21, tumor weight and gastrocnemius muscle weight were measured, and histopathology and cell apoptosis in the gastrocnemius muscle were examined with HE staining, transmission electron microscopy and TUNEL assay. ATP content in the muscle was measured, and protein expressions of AMPK, PGC-1α, Cyt c, AIF, Apaf-1, Smac, Bcl-2, Bax, cleaved caspase-3 and cleaved caspase-9 were determined with immunohistochemistry. RESULTS:The tumor-bearing mice in the control group showed significantly decreased gastrocnemius muscle weight and grip and suspension test scores. The gastrocnemius muscle showed ultrastructure injuries with lowered ATP content, obvious cell apoptosis, decreased expressions of AMPK, PGC-1 α, and Bcl-2, and increased expressions of Bax, Cyto C, AIF, Apaf-1, Smac, cleaved caspase-3 and cleaved caspase-9. These changes were obviously worsened in 5-FU-treated mice, while QFG treatment significantly increased gastrocnemius muscle weight and strength, ameliorated its ultrastructural injuries, reduced cell apoptosis, and reversed the abnormal protein expressions. CONCLUSIONS:QFG alleviates 5-FU-induced skeletal muscle fatigue in tumor-bearing mice by activating the AMPK/PGC-1α pathway and inhibiting mitochondria-dependent apoptosis in the gastrocnemius muscle.

Zhou et al. investigated demoralization syndrome (DS) among Chinese patients with colorectal cancer and identified cancer metastasis, anxiety, and depression as factors independently associated with greater DS severity. Their study provides valuable evidence for psychological screening and supportive care in this population. In this comment, we highlight two analytical considerations that may further strengthen the interpretation of their findings. First, although social support was associated with DS severity in univariate analysis, the loss of statistical significance after multivariable adjustment should not be interpreted as evidence of irrelevance; rather, social support may influence DS indirectly through anxiety, depression, or disease burden. Mediation or path analysis may therefore better reflect the underlying causal structure. Second, dichotomizing the continuous DS-II score into mild versus moderate-to-severe categories may reduce statistical power and obscure clinically meaningful variation. Analyzing the DS-II score as a continuous or ordinal outcome could provide a more informative assessment of the determinants of DS.

To investigate the protective effects and underlying mechanisms of Babao Dan (BBD) against doxorubicin (Dox)-induced cardiomyopathy (DIC). A zebrafish model of DIC alongside an in vitro model of cardiomyocyte injury induced by Dox was utilized to elucidate the protective effects of BBD against DIC. The zebrafish and cell models were divided into control, Dox, and BBD (low-, medium-, and high-dose) plus Dox treatment groups. Reactive oxygen species (ROS) and malondialdehyde (MDA) content were determined by commercial kits. Nrf2/GPX4 signaling activity was assessed by Western blot and RT-qPCR. A comprehensive network pharmacology analysis was conducted to explore the potential mechanisms of action of BBD on DIC. Compared with Dox group, BBD treatment significantly reduced ROS levels and decreased MDA content in zebrafish (P<0.01), indicating ameliorated oxidative stress, which contributed to a reduction in Dox-induced cardiac injury. Notably, BBD was found to inhibit cardiomyocyte ferroptosis by restoring mitochondrial function in vitro. Network pharmacology analysis identified 4 core network genes, including Nrf2, which is pivotal in linking oxidative stress with ferroptosis, along with 6 key active components of BBD. Molecular docking and dynamics simulations demonstrated that these active components exhibit a strong binding affinity with the identified core targets. BBD effectively activates the Nrf2/GPX4 signaling pathway, thereby inhibiting cardiomyocyte ferroptosis and mitigating DIC. These insights provide a theoretical foundation for the future exploration of BBD as a preventive and therapeutic agent against Dox-related cardiotoxicity.

BACKGROUND:Lung cancer remains a leading cause of cancer-related mortality worldwide, primarily due to late-stage diagnosis and resistance to conventional therapies. Recent studies have highlighted the potential of natural compounds in enhancing the efficacy and reducing the side effects of conventional cancer treatments. Baicalin, a bioactive compound from Scutellaria baicalensis, exhibits significant anticancer properties. OBJECTIVES:This study aimed to investigate the role of baicalin in modulating lung cancer cell behavior through the arachidonate 12-lipoxygenase (ALOX12)-mediated ferroptosis pathway. METHODS:We employed cyber pharmacology and molecular docking techniques to predict and validate the interaction between baicalin and ALOX12. In vitro experiments were conducted on A549 lung cancer cells to assess the effects of baicalin on cell proliferation, migration, and invasion. The expression levels of ALOX12, reactive oxygen species (ROS), and ferroptosis markers, such as Glutathione Peroxidase 4 (GPX4) and Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), were measured. RESULTS:Baicalin treatment significantly upregulated ALOX12 expression in lung cancer cells, and this upregulation was associated with a reduction in cell proliferation, migration, and invasion. Furthermore, baicalin-induced ferroptosis was characterized by increased ROS levels, iron accumulation, and elevated expression of GPX4 and ACSL4. These findings suggest that baicalin enhances ferroptosis through ALOX12 activation, synergistically inhibiting cancer cell growth. CONCLUSION:Baicalin significantly upregulated ALOX12 expression, promoted ferroptosis, and inhibited the proliferation and migration of A549 lung cancer cells. This finding provides evidence for the potential use of baicalin as a therapeutic agent for lung cancer and highlights the importance of ALOX12 in lung cancer treatment strategies.

Background: Janus-kinase (JAK) inhibitors are increasingly used across surgical practice for immune-mediated disorders, yet their gastrointestinal (GI) safety profiles remain incompletely defined. Upadacitinib (selective JAK-1) has been linked to severe mucosal complications, whereas ruxolitinib (JAK-1/2) appears better tolerated. Robust real-world comparisons are lacking. Methods: We performed a retrospective, observational pharmacovigilance study of the FDA Adverse Event Reporting System from 1 July 2019 to 31 December 2024. After deduplication, 58 548 upadacitinib and 28 968 ruxolitinib safety reports were retrieved. GI events were coded with MedDRA and grouped into inflammation, ulcer/perforation, bleeding, motility disorders, symptoms and other serious events. Multivariable logistic regression generated adjusted reporting odds ratios (aROR) for ruxolitinib versus upadacitinib, controlling for age, sex, comorbidities and concomitant NSAIDs; sensitivity analyses stratified by age and NSAID use. Results: Compared with upadacitinib, ruxolitinib showed higher reporting of GI motility disorders (803 events; aROR = 1.52, 95% CI 1.05–2.20) but markedly lower reporting of GI inflammation (641 events; aROR = 0.14, 0.07–0.29) and ulcer/perforation (229 events; aROR = 0.27, 0.10–0.68). Upadacitinib-related inflammation was dominated by ulcerative colitis (40.8 %) and Crohn’s disease (28.2 %), while 20.8 % of ulcer/perforation events were frank intestinal perforations. Median onset occurred within the first treatment year for both agents (8 months for upadacitinib ulcers/perforations; 6.5 months for ruxolitinib motility disorders). Age-stratified analyses confirmed an excess of upadacitinib-associated inflammation in adults and children, whereas ruxolitinib-related symptoms were concentrated in patients > 65 years. NSAID co-administration magnified upadacitinib-associated ulcers/perforations but had little effect on ruxolitinib patterns. Conclusions: In real-world practice, upadacitinib carries a substantially higher signal for severe inflammatory and ulcerative GI injury, whereas ruxolitinib is mainly associated with non-serious motility disturbances. Upadacitinib carries a higher signal for severe inflammatory and ulcerative GI injury, whereas ruxolitinib is mainly associated with non-serious motility disturbances. These associations are hypothesis‑generating rather than causal and warrant validation through prospective studies and mechanistic investigations.

Cancer cachexia, a debilitating syndrome characterized by muscle wasting and systemic inflammation, remains a major unmet clinical need. Qingxie Fuzheng Granules (QFG), a traditional Chinese medicine formulation, have shown promise in cancer therapy, but their role in cachexia management is unclear. Here, we investigated the anti-cachectic effects of QFG in a murine model of colon adenocarcinoma-induced cachexia. 16S rRNA sequencing revealed gut dysbiosis in cachectic mice, with increased Enterobacteriaceae and decreased Lactobacillus. QFG treatment restored microbial balance, reduced pro-inflammatory cytokines TNF-α, IL-6, and enhanced intestinal barrier integrity by upregulating tight junction proteins ZO-1, Occludin, Calprotectin. Mechanistically, QFG rebalanced Th17/Treg cell ratios and suppressed IL-6/NF-κB signaling, a key driver of muscle atrophy. Combining QFG with glutamine (Gln) further amplified these effects, suggesting synergistic therapeutic potential. Our findings demonstrate that QFG ameliorates cancer cachexia through microbiota modulation and IL-6/NF-κB inhibition, providing a novel multi-targeted approach for cachexia treatment.

Objective: The aim is to study the synergistic effects of Qingjie Fuzheng Granule(QFG) and 5-fluorouracil(5-FU) on colorectal cancer and elucidate its mechanism. Materials and Methods: Chou-Talalay was used to calculate the combination index of QFG and 5-FU; the synergistic anti-cancer ability of QFG and 5-FU that targets phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT) signaling pathway was studied in human colorectal cells and its xenograft mice. Results: QFG and 5-FU synergistically inhibited the growth of HCT-8 cells. QFG combined with 5-FU inhibited proliferation, migration and invasion, as well as promoted apoptosis through regulating related proteins in HCT-8 cells and in mice.Furthermore, QFG and 5-FU down-regulated 5-FU metabolism-related enzymes such as thymidylate synthase and dihydropyrimidine dehydrogenase.In addition, it blocked PI3K/AKT signaling pathway and alleviated cancer-related functions(proliferation, migration, and invasion) through this pathway. Conclusions: QFG combined with 5-FU exerts synergistic anti-cancer effects though blocking the PI3K/AKT signaling pathway.

Objective To investigate the protective mechanisms of Qingjie Fuzheng Granules(QFG)against intestinal muco-sal injury induced by docetaxel and cyclophosphamide combination chemotherapy in breast cancer.Methods A total of 32 female BALB/c mice were selected and inoculated with 4T1 breast cancer cells to establish subcutaneous tumor models,with tumor vol-umes ranging from 50 to 100 mm3.The mice were randomly divided into control group,Qingjie Fuzheng Granules group(QFG group),chemotherapy group(TC group),and chemotherapy+Qingjie Fuzheng granules group(TC+QFG group)by Excel software,with eight mice in each group.The control group received sterile normal saline gavage once daily and intraperitoneal injections of sterile saline once weekly.The QFG group was given Qingjie Fuzheng Granules at 1 g/kg by gavage once daily,along with weekly intraperitoneal injections of sterile normal saline.The TC group received weekly intraperitoneal injections of docetaxel(15 mg/kg)and cyclophosphamide(20 mg/kg),along with daily intragastric sterile normal saline.The TC+QFG group received intraperitoneal docetaxel and cyclophosphamide once weekly and 1 g/kg of Qingjie Fuzheng Granules by gavage once daily,with a 0.5-hour inter-val between gavage and injection.The intervention lasted for four weeks in all groups.After intervention,the mice were assessed for body weight,diarrhea,and tumor volume growth.Hematoxylin and eosin(HE)staining was used to evaluate morphological changes in the ileal mucosa.Enzyme-linked immunosorbent assay(ELISA)was used to measure serum contents of diamine oxidase(DAO),D-lactic acid(D-LA),tumor necrosis factor-alpha(TNF-α),interleukin-1 beta(IL-1β),IL-6,IL-2,IL-4,IL-10,gamma interferon(IFN-γ),and secretory immunoglobulin A(sIgA).The TUNEL staining method was used to detect apoptosis in ileal mucosal cells.Immunohistochemistry was used to assess the expression of IgA+cells and tight junction proteins(ZO-1,Occludin)in the ileal mucosa.Western blot was used to determine the expression levels of TLR4,NF-κB,and p-NF-κB proteins in the ileal mucosa.Results(1)Body weight,diarrhea score,and tumor volume:compared with the TC group,body weight in the TC+QFG group increased sig-nificantly at day 27 of intervention(P＜0.05),along with significantly decreased diarrhea scores at 1st and 8th day of intervention(P＜0.05).No statistically significant differences in body weight and diarrhea scores were observed at other times(P＞0.05).Compared with the control group,the tumor volume in the TC+QFG group decreased significantly on day 13 of intervention and all subsequent time points(P＜0.05).(2)Histopathological changes in ileal tissue:compared with the TC group,the TC+QFG group showed signifi-cant improvements in intestinal mucosal structure,including reduced epithelial edema,increased villus height,better organized villi arrangement,shallower crypt depth,and decreased inflammatory cell infiltration.After intervention,the villus height and villus/crypt ratio increased significantly(P＜0.05),while crypt depth significantly decreased in the TC+QFG group(P＜0.05).(3)Expression levels of ZO-1 and Occludin proteins in ileal mucosal tissue:compared with the TC group,the expression levels of ZO-1 and Occlu-din proteins in the ileal mucosal tissue of the TC+QFG group increased significantly after intervention(P＜0.05).(4)Serum levels of DAO and D-LA:compared with the TC group,serum levels of DAO and D-LA in the TC+QFG group decreased significantly after intervention(P＜0.05).(5)Serum levels of TNF-α,IL-1β,IL-6,IL-2,IL-4,IL-10,and IFN-γ:compared with the TC group,serum levels of IL-1β,TNF-α,IL-6,and IFN-γ in the TC+QFG group decreased significantly after intervention(P＜0.05),while the levels of IL-2,IL-4,and IL-10 increased significantly(P＜0.05).(6)Apoptosis in ileal mucosal tissue:compared with the TC group,nuclear yellowing and positive staining rate in the TC+QFG group decreased significantly after intervention(P＜0.05).(7)Serum sIgA levels and the number of IgA+cells in ileal mucosal tissue:compared with the TC group,the serum sIgA contents and number of IgA+cells in ileal mucosal tissue in the TC+QFG group increased significantly after intervention(P＜0.05).(8)Expression levels of TLR4/NF-κB pathway-related proteins in the ileal mucosal tissue:compared with the TC group,the expression levels of TLR4 and p-NF-κB proteins in the ileal mucosal tissue of the TC+QFG group decreased significantly after intervention(P＜0.05).Conclusion QFG demonstrates a protective effect against intestinal mucosal damage induced by chemotherapy in breast cancer,potentially through modulation of the TLR4/NF-κB signaling pathway,which may inhibit inflammatory responses,reduce intestinal epithelial cell apop-tosis,and enhance both epithelial and immune barrier functions of the intestinal mucosa.

ETHNOPHARMACOLOGICAL RELEVANCE:Qingjie Fuzheng Granules (QFG), a herbal formula, has been employed as an adjuvant therapy for colitis-associated colorectal cancer (CAC), yet the underlying mechanisms by which QFG operates remain unclear. AIMS OF THE STUDY:The aim of this study is to investigate whether the potential mechanism of QFG against CAC is associated with macrophage polarization. MATERIALS AND METHODS:Non-targeted metabolomics and molecular docking assessed potential compounds of QFG to interact with targets associated with macrophage polarization. A model of AOM/DSS-induced CAC mice was established to analyze the effects of QFG on macrophage polarization using flow cytometry and immunohistochemical staining. In vitro experiments involved models of Ana-1 macrophages, either induced by varying QFG concentrations or with MD2 knockdown, to analyze M1-like phenotype. Meanwhile, M2-like macrophages models induced by IL-4 or culture supernatant of CT26 cells were utilized to assess the effects of QFG on M2-like macrophages. Finally, the mRNA expression of M1-like phenotype related to TLR4 pathways and the protein expression in IL-4R-mediated pathways were analyzed using RT-qPCR and Western blot, respectively. RESULTS:Molecular docking confirmed the presence of binding sites between the ingredients of QFG and IL-4R or TLR4/MD2 receptor complex. QFG could induce a shift in macrophages towards an M1-like phenotype while inhibiting an M2-like phenotype in the colon with CAC mice and Ana-1 macrophages. QFG resulted in the upregulation of iNOS, IL-6, IL-1β, and TNF-α mRNA expression, which could be counteracted by TAK242, SR11302, INH14, PDTC, and LY294002, or by the knockdown of MD2. Meanwhile, QFG inhibited IL-4R-induced phosphorylation of STAT 6 and Akt. CONCLUSION:Various monomer components within QFG can bind to MD2 or IL-4R, respectively, thereby inducing macrophages towards an M1-like phenotype through TLR4-mediated NF-κB, MAPK, and PI3K/Akt pathway activation, or inhibiting macrophages towards an M2-like phenotype via IL-4R-mediated JAKs pathway inhibition, ultimately exerting an inhibitory effect on the occurrence and development of CAC.

Objective: Multidrug resistance (MDR) is one main cause of chemotherapy failure. Baicalin is an important active ingredient with anticancer potential in many Chinese herbal medicines. In order to understand the function of baicalin reversing MDR in hepatocellular carcinoma (HCC) and the molecular mechanisms that underlie it, the current study was designed. Methods: Bel-7402 and Bel-7402/5-FU cells were cultured, and MTT assay was applied to detect cell viability and the cross-resistance of Bel-7402/5-FU cells. The pump function, apoptosis, and autophagy were detected by flow cytometry. The related proteins were detected by Western blot assay. The PI3K agonist (740Y-P) was used to verify whether baicalin overcomes the drug resistance of HCC cells by blocking the PI3K/AKT pathway. Results: The findings showed that Bel-7402/5-FU cells were cross-resistant to different chemotherapeutic drugs. Baicalin inhibited cell viability in both Bel-7402/5-FU and Bel-7402 ​cells, and baicalin increased sensitivity of Bel-7402/5-FU cells to 5-FU in time- and dose-dependent manners. Baicalin increased the accumulation of doxorubicin and rhodamine-123 in Bel-7402/5-FU cells and inhibited the protein expression of ABCG2, ABCB1, and ABCC1, associated with pump function. In addition, baicalin induced apoptosis of Bel-7402/5-FU cells via up-regulating Bax expression. Furthermore, baicalin increased autophagy through regulating LC3-Ⅱ, p62, and Beclin-1. Baicalin reversed drug resistance in Bel-7402/5-FU cells by inhibiting the PI3K/AKT pathway, which promoted autophagy and apoptosis to restore chemosensitivity. Conclusion: Baicalin increased accumulation of chemotherapy drugs and induced apoptosis and autophagy in Bel-7402/5-FU cells by inhibiting the PI3K/AKT signaling pathway, that may be the important mechanism by which baicalin reverses the MDR of HCC.