ObjectiveTo investigate the effect of solute carrier family 7 member 5 (SLC7A5) inhibitor JPH203 on renal fibrosis induced by unilateral ureteral obstruction in mice. MethodsSixteen SPF male C57BL/6 mice were randomly divided into the control group and the experimental group, with 8 mice in each group. The mouse model of renal fibrosis was established by unilateral ureteral obstruction. From the third day after surgery, the mice in the control group were intraperitoneally injected with phosphate-buffered saline (PBS) for 11 consecutive days, and the injection dose was 200 μL/d. Mice in the experimental group received intraperitoneal injection of JPH203 (50 mg/kg) every day for 11 days. On day 14, the mice were euthanized, then the kidney tissues were obtained. Hematoxylin and eosin (HE) staining was used to assess renal tissue damage, Masson staining was used to evaluate collagen fiber deposition in the extracellular matrix, and immunohistochemistry was used to detect the levels of fibroblast activation markers α-smooth muscle actin (α-SMA) and collagen type Ⅰ (COL-Ⅰ) in kidney tissues. Western blotting was further performed to measure the expression levels of SLC7A5 and transforming growth factor-β1 (TGF-β1), as well as the phosphorylation levels of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway-related molecules. Real-time quantitative PCR was used to verify changes in the mRNA levels of SLC7A5, α-SMA, and COL-Ⅰ in kidney tissues. ResultsCompared with the control group, the experimental group showed reduced destruction of renal tissue structure and a significantly lower pathological injury score (P<0.05). Additionally, collagen deposition in the extracellular matrix was decreased, and the percentage of collagen fiber area was significantly reduced (P<0.001) in the experimental group. The levels of fibroblast activation markers α-SMA and COL-Ⅰ were significantly lower in the experimental group (both P<0.001). The expression levels of SLC7A5 and TGF-β1 were also significantly decreased (P<0.001), and the phosphorylation levels of mTORC1 signaling pathway-related proteins 4E-BP1 and mTORC1 were significantly reduced (P<0.001). Real-time quantitative PCR confirmed that the mRNA levels of SLC7A5, α- SMA, and COL-Ⅰ in kidney tissues were significantly lower in the experimental group (P<0.001). ConclusionJPH203 may inhibit the progression of renal fibrosis in mice by suppressing SLC7A5 expression, regulating the mTORC1 signaling pathway, and altering fibroblast activation status.

Cancer stem cells (CSCs) represent a distinct subpopulation of cells characterized by self-renewal capacity, differentiation potential, and critical roles in driving tumor progression, therapeutic resistance, recurrence, and maintenance of the tumor microenvironment. Targeting CSCs has emerged as a pivotal direction in cancer research, offering novel strategies to overcome drug resistance and prevent metastasis and relapse. Lysosomes, traditionally recognized as central organelles for intracellular degradation and recycling, are indispensable for cellular homeostasis. Dysregulation of lysosomal function is intimately linked to various diseases, including cancer. In tumors, aberrant lysosomal activity can promote malignant progression through mechanisms such as altering metabolic pathways, enhancing lysosomal exocytosis, modulating drug resistance, and interfering with autophagy-lysosomal pathways. Recent studies have underscored the involvement of lysosomes in regulating CSC properties. This review synthesizes findings on lysosomal regulation of CSCs through the following aspects. (1) Lysosomes exert complex and critical bidirectional control over CSC stemness maintenance through three degradation pathways that are dependent on their degradative function. (i) The lysophagy pathway. This pathway exhibits dual roles. Activation can sustain CSC functions; for instance, in glioblastoma, hypoxia upregulates Gal-8 via the STAT3/HIF1α signaling axis to induce autophagy, supporting stem cell survival. In head and neck squamous cell carcinoma, degradation of GSK3β activates the Wnt pathway, enhancing stemness. Conversely, this pathway can suppress stemness by degrading stemness-related proteins such as BMI-1 and OCT4A, thereby impairing CSC self-renewal capacity. (ii) Mitophagy pathway. In non-small cell lung cancer stem cells, mitophagy-related mechanisms, such as the accumulation of mitochondrial DNA (mtDNA) activating the TLR9-Notch1-AMPK signaling axis, have been shown to promote CSC proliferation. (iii) Autophagosome-dependent lysosomal degradation pathway. This pathway directly regulates stemness-related proteins in a bidirectional manner. Enhanced degradative function can promote CSC properties, exemplified by the degradation of NUMB to activate Notch signaling. Conversely, attenuated degradative function can also enhance stemness by stabilizing oncoproteins (e.g., protecting Frizzled-1 from degradation to sustain Wnt signaling) or preventing the degradation of tumor suppressors (e.g., inhibiting Notch degradation). (2) Constituent proteins of lysosomes, including membrane proteins and luminal acid hydrolases, participate in regulating CSC stemness. Regarding membrane proteins, LAMP2A facilitates chaperone-mediated autophagy to maintain stemness in glioblastoma and ovarian cancer. V-ATPase, by maintaining an acidic luminal environment, promotes proliferation and drug resistance in glioma stem cells. Among hydrolases, cathepsins B and L are highly expressed in pancreatic and ovarian cancers and correlate with poor prognosis. Furthermore, targeting lysosomes to induce lysosomal membrane permeabilization (LMP) triggers lysosome-mediated cell death, presenting a potential therapeutic strategy for eradicating CSCs.(3) The acidic luminal environment, single-membrane structure, and the presence of transmembrane transporters (e.g., ABCA3) enable lysosomes to passively trap or actively uptake and sequester chemotherapeutic drugs. Subsequent drug extrusion via exocytosis confers drug resistance. In CSCs, this lysosome-mediated drug sequestration, often cooperating with autophagy, establishes multimodal drug resistance. Therefore, targeting lysosomal function represents a potential strategy to overcome therapy resistance. The central role of lysosomes in regulating CSC stemness and resistance positions them as highly promising therapeutic targets. Strategies aimed at disrupting lysosomal function to selectively eliminate CSCs include: inhibiting the lysosome-autophagy system using agents like IITZ or lovastatin; inducing lysosomal membrane permeabilization (LMP) with compounds such as hexamethylene amiloride to compromise membrane stability; and disrupting the acidic luminal environment using drugs like siramesine or the K/H transport compound 2. In conclusion, lysosomes critically regulate CSC stemness maintenance and drug resistance through degradative pathways, membrane protein functions, luminal hydrolase activities, and drug sequestration mechanisms. This redefines the lysosome from a traditional “waste disposal unit” to a “signal integration center” in CSCs. The duality and context-dependency of lysosomal function in CSCs offer novel insights into the heterogeneity observed across different tumors. Targeting lysosomal vulnerabilities—such as inducing LMP, disrupting acidity, or blocking autophagic flux—provides a strategy to bypass canonical CSC resistance mechanisms and directly trigger cell death. This establishes the lysosome as a key target to overcome CSC-mediated therapy resistance, paving the way for developing diverse candidate drugs and innovative combination therapies in oncology.

Objective:To investigate the completion rate of tumor evaluation at initial assessment and after neoadjuvant therapy for mid and low rectal cancer patients in the national multicenter real-world database.Methods:The prospective real-world study was conducted. The clinicopathological data of 1 074 patients who underwent surgical treatment for mid and low rectal cancer in 47 national medical institutions, including Peking Union Medical College Hospital et al, from May 12,2023 to May 11,2024 were collected. Observation indicators: (1) clinical characteristics of patients with mid and low rectal cancer; (2) initial colonoscopy and pathologic evaluation of tumors in patients with mid and low rectal cancer; (3) initial imaging evaluation of patients with mid and low rectal cancer; (4) imaging evaluation after neoadjuvant therapy for patients with mid and low rectal cancer. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M( Q1, Q3). Count data were described as absoluter numbers and/or percentages. Results:(1) Clinical characteristics of patients with mid and low rectal cancer. Of the 1 074 patients, there were 713 males and 361 females, aged 63(56,70)years. The body mass index of 1 074 patients was 24(21,26)kg/m 2.For American Society of Anesthesiologists classification, there were 147 cases of stage Ⅰ, 641 cases of stage Ⅱ, 157 cases of stage Ⅲ, 2 cases of stage Ⅳ, and there were 127 cases missing data. (2) Initial colonoscopy and pathologic evaluation of tumors in patients with mid and low rectal cancer. Of the 1 074 patients, there were 787 cases (73.28%) undergoing complete colonoscopy, and there were only 197 cases (18.34%) undergoing immunohistochemical evaluation of all four mismatch repair proteins. (3) Initial imaging evaluation of patients with mid and low rectal cancer. Of the 1 074 patients, there were 842(78.40%) patients completing magnetic resonance imaging (MRI) or ultrasound evaluation, and there were 914(85.10%) patients completing chest, abdomen, and pelvis enhanced computed tomography (CT) evaluation. In the 149 patients completing rectal ultrasound evaluation, there were 122 cases (81.88%) comple-ting T staging evaluation, and there were 81 cases (54.36%) completing N staging evaluation. In the 808 patients completing rectal MRI evaluation, there were 708 cases (87.62%) completing T staging evaluation, and there were 590 cases (73.02%) completing N staging evaluation. (4) Imaging evalua-tion after neoadjuvant therapy for patients with mid and low rectal cancer. Of the 388 patients with neoadjuvant therapy, there were 332 patients (85.57%) completing MRI or ultrasound evaluation, and there were 327 patients (84.28%) completing chest, abdomen, and pelvis enhanced CT evalua-tion. In the 70 patients completing rectal ultrasound evaluation, there were 65 cases (92.86%) com-pleting T staging evaluation, and there were 49 cases (70.00%) completing N staging evaluation. In the 327 patients completing rectal MRI evaluation, there were 246 cases (75.23%) completing T staging, and there were 228 cases (69.72%) completing N staging evaluation. Conclusion:The com-pletion rate of tumor imaging evaluation at initial assessment and after neoadjuvant therapy for mid and low rectal cancer patients on a national scale is relatively good.

Objective To analyze the implementation of MPOWER tobacco control policies in different regions and populations in China,as well as the impact of perceptions of tobacco control policies on individual smoking behavior and quit intentions,to promote the fairness of policy implementation and protection for vulnerable groups.Methods A multivariable regression model was constructed utilizing raw data from the China Adult Tobacco Survey to analyze disparities in perceived MPOWER policy implementation among various social demographics and its impact on smoking behavior and quitting intentions.Results Regarding protection from tobacco smoke(P),local economic level,urban-rural divide were significantly correlated with awareness of comprehensive smoking bans.For offering help to quit smoking(O),local tobacco industry revenue and individual age were associated with the doctor's advice for quitting.As to the warning about the harm of tobacco(W),economic level,geography and urban-rural disparity were correlated with the visibility of health warnings.About the tobacco advertising,promotion and sponsorship(E),geography was related to the exposure to tobacco advertisements,local tobacco industry revenue was associated with the tobacco promotion.For tobacco taxes(R),education level and age were significantly correlated with tobacco affordability.People who perceived comprehensive smoking bans(OR=0.69,95%CI:0.59-0.81)was associated with less smoking behavior,while people perceiving tobacco promotional activities(OR=2.51,95%CI:2.00-3.17)were more likely to smoke.Additionally,people who perceived comprehensive smoking bans(OR=1.70,95%CI:1.25-2.31)and health warning(OR=2.09,95%CI:1.48-3.01)had higher intention to quit smoking.Conclusion In economically disadvantaged regions and among specific socially vulnerable groups(such as low-income individuals,rural residents,and the elderly)in China,the perception of tobacco control policy implementation is relatively low,the perception of tobacco control policies can influence smoking behavior and quitting intentions.Legislative and enforcement efforts should be increased targeting these groups with lower perceptions of the policies to enhance the fairness of tobacco control measures.

Objective:To investigate the completion rate of tumor evaluation at initial assessment and after neoadjuvant therapy for mid and low rectal cancer patients in the national multicenter real-world database.Methods:The prospective real-world study was conducted. The clinicopathological data of 1 074 patients who underwent surgical treatment for mid and low rectal cancer in 47 national medical institutions, including Peking Union Medical College Hospital et al, from May 12,2023 to May 11,2024 were collected. Observation indicators: (1) clinical characteristics of patients with mid and low rectal cancer; (2) initial colonoscopy and pathologic evaluation of tumors in patients with mid and low rectal cancer; (3) initial imaging evaluation of patients with mid and low rectal cancer; (4) imaging evaluation after neoadjuvant therapy for patients with mid and low rectal cancer. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M( Q1, Q3). Count data were described as absoluter numbers and/or percentages. Results:(1) Clinical characteristics of patients with mid and low rectal cancer. Of the 1 074 patients, there were 713 males and 361 females, aged 63(56,70)years. The body mass index of 1 074 patients was 24(21,26)kg/m 2.For American Society of Anesthesiologists classification, there were 147 cases of stage Ⅰ, 641 cases of stage Ⅱ, 157 cases of stage Ⅲ, 2 cases of stage Ⅳ, and there were 127 cases missing data. (2) Initial colonoscopy and pathologic evaluation of tumors in patients with mid and low rectal cancer. Of the 1 074 patients, there were 787 cases (73.28%) undergoing complete colonoscopy, and there were only 197 cases (18.34%) undergoing immunohistochemical evaluation of all four mismatch repair proteins. (3) Initial imaging evaluation of patients with mid and low rectal cancer. Of the 1 074 patients, there were 842(78.40%) patients completing magnetic resonance imaging (MRI) or ultrasound evaluation, and there were 914(85.10%) patients completing chest, abdomen, and pelvis enhanced computed tomography (CT) evaluation. In the 149 patients completing rectal ultrasound evaluation, there were 122 cases (81.88%) comple-ting T staging evaluation, and there were 81 cases (54.36%) completing N staging evaluation. In the 808 patients completing rectal MRI evaluation, there were 708 cases (87.62%) completing T staging evaluation, and there were 590 cases (73.02%) completing N staging evaluation. (4) Imaging evalua-tion after neoadjuvant therapy for patients with mid and low rectal cancer. Of the 388 patients with neoadjuvant therapy, there were 332 patients (85.57%) completing MRI or ultrasound evaluation, and there were 327 patients (84.28%) completing chest, abdomen, and pelvis enhanced CT evalua-tion. In the 70 patients completing rectal ultrasound evaluation, there were 65 cases (92.86%) com-pleting T staging evaluation, and there were 49 cases (70.00%) completing N staging evaluation. In the 327 patients completing rectal MRI evaluation, there were 246 cases (75.23%) completing T staging, and there were 228 cases (69.72%) completing N staging evaluation. Conclusion:The com-pletion rate of tumor imaging evaluation at initial assessment and after neoadjuvant therapy for mid and low rectal cancer patients on a national scale is relatively good.

Objective To analyze the implementation of MPOWER tobacco control policies in different regions and populations in China,as well as the impact of perceptions of tobacco control policies on individual smoking behavior and quit intentions,to promote the fairness of policy implementation and protection for vulnerable groups.Methods A multivariable regression model was constructed utilizing raw data from the China Adult Tobacco Survey to analyze disparities in perceived MPOWER policy implementation among various social demographics and its impact on smoking behavior and quitting intentions.Results Regarding protection from tobacco smoke(P),local economic level,urban-rural divide were significantly correlated with awareness of comprehensive smoking bans.For offering help to quit smoking(O),local tobacco industry revenue and individual age were associated with the doctor's advice for quitting.As to the warning about the harm of tobacco(W),economic level,geography and urban-rural disparity were correlated with the visibility of health warnings.About the tobacco advertising,promotion and sponsorship(E),geography was related to the exposure to tobacco advertisements,local tobacco industry revenue was associated with the tobacco promotion.For tobacco taxes(R),education level and age were significantly correlated with tobacco affordability.People who perceived comprehensive smoking bans(OR=0.69,95%CI:0.59-0.81)was associated with less smoking behavior,while people perceiving tobacco promotional activities(OR=2.51,95%CI:2.00-3.17)were more likely to smoke.Additionally,people who perceived comprehensive smoking bans(OR=1.70,95%CI:1.25-2.31)and health warning(OR=2.09,95%CI:1.48-3.01)had higher intention to quit smoking.Conclusion In economically disadvantaged regions and among specific socially vulnerable groups(such as low-income individuals,rural residents,and the elderly)in China,the perception of tobacco control policy implementation is relatively low,the perception of tobacco control policies can influence smoking behavior and quitting intentions.Legislative and enforcement efforts should be increased targeting these groups with lower perceptions of the policies to enhance the fairness of tobacco control measures.

Aim To investigate the role and underlying mechanisms of transient receptor potential cation chan-nel 6(TRPC6)in epileptogenesis using a kainic acid(KA)-induced mouse model.Methods C57BL/6 and TRPC6-KO(KO)mice were divided into two groups and implanted with cannulas for microinjection of KA(0.03 g·L-1,5 μL)into the lateral ventricle to establish the acute epilepsy model group,with saline injection serving as the control group.The Racine score was used to record the uninterrupted seizure grade of mice within two hours after KA administration.Immunohistochemistry was used to detect neuronal loss and tissue damage in the hippocampus brain region of mice.Immunofluorescence staining,Western blot and qPCR were used to detect the expressions of TRPC6,NLRP3,ASC,Caspase-1,p62,Atg7,Atg5,Beclin-1,LC3b-Ⅱ/LC3b-Ⅰ.in the hippocampus.Results KA induced significant neuronal loss and tissue damage in the hippocampal CA3 brain region of epilep-sy mice,while the expression levels of TRPC6,NL-RP3,ASC and Caspase-1 and other proteins in the hippocampus brain area of epilepsy mice increased,and the protein expression of autophagy-related proteins Atg7,Atg5,Beclin-1,LC3b-Ⅱ/LC3b-Ⅰ increased,while the expression of p62 protein decreased.TRPC6 knockout exacerbated KA-induced epileptogenesis,neuronal injury,inflammatory response and autophagy activation.Conclusion TRPC6 is involved in KA-in-duced epileptigenesis,and the mechanism may be re-lated to the activation of NLRP3 inflammasome-autoph-agy signaling caused by TRPC6 deletion.

From the natural-philosophical model of medicine in ancient Greece to the modern bio-psycho-social par-adigm,the evolution of medical models has always been shaped by philosophy.In classical antiquity,medicine and philosophy were closely intertwined;the natural-philosophical model,exemplified by Hippocrates,emphasized the human body as an integrated whole.During the Renaissance,the rise of experimental science challenged traditional philosophical systems and pushed medicine toward empirical investigation.In the late twentieth century,the bio-psycho-social model emerged to address the limitations of the purely biomedical approach.In the twenty-first centu-ry,the advent of artificial intelligence is driving a new transformation in medicine and continually prompting reflec-tion on the future direction of medical models and their underlying philosophical significance.

Objective To investigate the effects of peripheral blood neutrophil infiltration on the polarization regulation of cerebral resident microglia under a permanent ischemic stroke model.Methods Fifty-eight C57BL/6 mice were divided into two groups.One group was sham group,and the other group of mice was subjected to permanent middle cerebral artery occlusion surgery.Mice were euthanized 48 hours,7 days,14 days,and 30 days after surgery for tissue collection.Western blotting was used to detect expression levels of M1 microglia markers CD 16,M2 microglia marker arginase 1(Arg1),inflammatory cytokine interleukin-1 β(IL-1β),and neutrophil marker myeloperoxidase(MPO)in brain tissue.Immunofluorescence histochemical staining was used to assess neutrophil infiltration and M2 microglial distribution around the infarct area in brain sections.In vitro,purified neutrophils were co-cultured with BV2 microglial cells.After lipopolysaccharide stimulation,the phagocytosis of neutrophils by BV2 cells was observed,and the expression levels of CD16 and Arg1 proteins in BV2 cells were detected.Results Western blotting showed that the levels of CD16(P＜0.05),IL-1β(P＜0.001),and MPO(P＜0.05)in brain tissue increased significantly 48 hours and 7 days after surgery,then decreased,with MPO expression returning to normal levels 30 days after surgery.Immunofluorescence showed a significant increase of MPO-positive cells around the infarct area of the mouse cerebral cortex 48 hours after surgery(P＜0.001),followed by a decrease(P＜0.05).The number of ionized calcium binding adapter molecule 1(Iba1)and MPO double-positive cells gradually increased after surgery,and reached their peak at 14 days(P＜0.05).Iba1 and Arg1 double-positive cells also increased significantly 7 days(P＜0.05)and 14 days(P＜0.01)after surgery.In vitro,co-culture experiments showed that after BV2 phagocytosing neutrophils,CD 16(P＜0.05)significantly decreased and Arg1 significantly upregulated(P＜0.05).Conclusion In a permanent ischemic stroke model,microglia transition from M1 to M2 type after phagocytosing neutrophils,and the injured brain area changes from pro-inflammatory state to anti-inflammatory state.

Aim To investigate the role and underlying mechanisms of transient receptor potential cation chan-nel 6(TRPC6)in epileptogenesis using a kainic acid(KA)-induced mouse model.Methods C57BL/6 and TRPC6-KO(KO)mice were divided into two groups and implanted with cannulas for microinjection of KA(0.03 g·L-1,5 μL)into the lateral ventricle to establish the acute epilepsy model group,with saline injection serving as the control group.The Racine score was used to record the uninterrupted seizure grade of mice within two hours after KA administration.Immunohistochemistry was used to detect neuronal loss and tissue damage in the hippocampus brain region of mice.Immunofluorescence staining,Western blot and qPCR were used to detect the expressions of TRPC6,NLRP3,ASC,Caspase-1,p62,Atg7,Atg5,Beclin-1,LC3b-Ⅱ/LC3b-Ⅰ.in the hippocampus.Results KA induced significant neuronal loss and tissue damage in the hippocampal CA3 brain region of epilep-sy mice,while the expression levels of TRPC6,NL-RP3,ASC and Caspase-1 and other proteins in the hippocampus brain area of epilepsy mice increased,and the protein expression of autophagy-related proteins Atg7,Atg5,Beclin-1,LC3b-Ⅱ/LC3b-Ⅰ increased,while the expression of p62 protein decreased.TRPC6 knockout exacerbated KA-induced epileptogenesis,neuronal injury,inflammatory response and autophagy activation.Conclusion TRPC6 is involved in KA-in-duced epileptigenesis,and the mechanism may be re-lated to the activation of NLRP3 inflammasome-autoph-agy signaling caused by TRPC6 deletion.