BACKGROUND: Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. METHODS: Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. RESULTS: This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 ( COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. CONCLUSION P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.
Temozolomide ; Humans ; Glioblastoma/drug therapy* ; Animals ; Mice ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; YAP-Signaling Proteins ; Hydroxylation ; Dacarbazine/pharmacology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Collagen/biosynthesis* ; Collagen Type I/metabolism* ; Prolyl Hydroxylases/metabolism* ; Antineoplastic Agents, Alkylating/therapeutic use*

Grounded in the theory of "all marrows dominated by brain", this study explored the therapeutic mechanism of Zuogui Pills in modulating the oxytocin(OXT)/oxytocin receptor(OXTR) feed-forward loop in the treatment of postmenopausal osteoporosis(PMOP). A PMOP rat model was established using ovariectomy, and 70 Sprague-Dawley female rats were randomly divided into the following groups: sham operation group, model group, estradiol group(17β-estradiol, 0.05 mg·kg~(-1)·d~(-1)), Zuogui Pills low, medium, and high dose groups(0.2, 0.4, 0.8 g·kg~(-1)·d~(-1), respectively), and an antagonist group(atosiban 0.9 mg·kg~(-1)·d~(-1) + 17β-estradiol 0.05 mg·kg~(-1)·d~(-1) + Zuogui Pills 0.4 g·kg~(-1)·d~(-1)). After 12 weeks of model establishment, treatment was administered by gavage once daily for another 12 weeks, followed by sample collection. Enzyme-linked immunosorbent assay(ELISA) was used to measure serum levels of estrogen(E_2), OXT, tartrate-resistant acid phosphatase(TRACP-5b), and bone alkaline phosphatase(BALP). Histopathological changes in the left distal femur were observed through hematoxylin and eosin(HE) staining. Micro-computed tomography(micro-CT) was used to analyze the microstructure of the right distal femur. Western blot was employed to detect the expression levels of OXTR, small GTP-binding protein Ras, Raf1 proto-oncogene(Raf1), mitogen-activated protein kinase kinase 1/2(MEK1/2), and extracellular signal-regulated kinase 1/2(ERK1/2), and their phosphorylated forms in tibial tissues. Compared with the model group, the Zuogui Pills medium and high dose groups showed significantly increased levels of E_2, OXT, and BALP, with a notable decrease in TRACP-5b levels. Morphologically, the trabeculae in the left distal femur were more tightly arranged. The fibrous structure in the right distal femur was significantly improved in the Zuogui Pills high dose group. Additionally, the expression of OXTR, Ras, p-Raf1, p-MEK1/2, and p-ERK1/2 proteins in tibial tissues was significantly increased. The therapeutic effect of the Zuogui Pills high dose group was partially inhibited when an OXTR antagonist was administered. These findings suggest that Zuogui Pills can regulate the OXT/OXTR feed-forward loop, activate the phosphorylation of the downstream Ras/Raf1/MEK/ERK signaling pathway, and ultimately improve bone mineral density, thereby exerting therapeutic effects in PMOP.
Animals ; Rats, Sprague-Dawley ; Rats ; Female ; Drugs, Chinese Herbal/administration & dosage* ; Oxytocin/genetics* ; Receptors, Oxytocin/genetics* ; Humans ; Osteoporosis, Postmenopausal/genetics* ; Bone and Bones/drug effects* ; Brain/drug effects* ; Bone Marrow/drug effects*

OBJECTIVE: To examine the effectiveness of Chinese medicine (CM) Lianhua Qingwen Granule (LHQW) and Jingyin Gubiao Prescription (JYGB) in asymptomatic or mild patients with Omicron infection in the shelter hospital. METHODS: This single-center retrospective cohort study was conducted in the largest shelter hospital in Shanghai, China, from April 10, 2022 to May 30, 2022. A total of 56,244 asymptomatic and mild Omicron cases were included and divided into 4 groups, i.e., non-administration group (23,702 cases), LHQW group (11,576 cases), JYGB group (12,112 cases), and dual combination of LHQW and JYGB group (8,854 cases). The length of stay (LOS) in the hospital was used to assess the effectiveness of LHQW and JYGB treatment on Omicron infection. RESULTS: Patients aged 41-60 years, with nadir threshold cycle (C_T) value of N gene <25, or those fully vaccinated preferred to receive CM therapy. Before or after propensity score matching (PSM), the multiple linear regression showed that LHQW and JYGB treatment were independent influence factors of LOS (both P<0.001). After PSM, there were significant differences in LOS between the LHQW/JYGB combination and the other groups (P<0.01). The results of factorial design ANOVA proved that the LHQW/JYGB combination therapy synergistically shortened LOS (P=0.032). CONCLUSIONS Patients with a nadir C_T value <25 were more likely to accept CM. The LHQW/JYGB combination therapy could shorten the LOS of Omicron-infected individuals in an isolated environment.
Humans ; Drugs, Chinese Herbal/therapeutic use* ; Male ; Female ; Middle Aged ; Adult ; China/epidemiology* ; Hospitalization ; COVID-19 Drug Treatment ; COVID-19/epidemiology* ; SARS-CoV-2 ; Retrospective Studies ; Treatment Outcome ; Length of Stay ; Young Adult ; Aged

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in regulating the necroptosis and apoptosis in cerebral ischemia-reperfusion (I/R) injury. However, the regulation of RIPK1 kinase activity after cerebral I/R injury remains largely unknown. In this study, we found the downregulation of protein arginine methyltransferase 1 (PRMT1) was induced by cerebral I/R injury, which negatively correlated with the activation of RIPK1. Mechanistically, we proved that PRMT1 directly interacted with RIPK1 and catalyzed its asymmetric dimethylarginine, which then blocked RIPK1 homodimerization and suppressed its kinase activity. Moreover, pharmacological inhibition or genetic ablation of PRMT1 aggravated I/R injury by promoting RIPK1-mediated necroptosis and apoptosis, while PRMT1 overexpression protected against I/R injury by suppressing RIPK1 activation. Our findings revealed the molecular regulation of RIPK1 activation and demonstrated PRMT1 would be a potential therapeutic target for the treatment of ischemic stroke.

OBJECTIVES: To investigate the therapeutic effect of the natural compound niranthin on Crohn's disease-like colitis in mice and explore the underlying molecular mechanisms. METHODS: In a mouse model of colitis induced by 2,4,6-trinitro-benzenesulfonic acid (TNBS), the therapeutic effect of niranthin was evaluated by observing the changes in body weight, disease activity index (DAI), and colon length of the mice. The levels of inflammatory cytokines (IL-6, IL-1β, TNF-α, IL-17A and IL-10) in the intestinal mucosal tissue were detected using ELISA and quantitative real-time PCR (qRT-PCR). TUNEL staining and Western blotting were used to assess intestinal epithelial cell apoptosis and the expressions of Bcl-2 and Bax. The expression levels of tight junction proteins (ZO-1 and claudin-1) and the activation of the p38/JNK signaling pathway were investigated using Western blotting, and diprovocim intervention experiments were conducted to explore the molecular regulatory mechanism of niranthin. RESULTS: Niranthin treatment significantly increased body weight of TNBS-treated mice, lowered the DAI and histological inflammation scores, and increased colon length of the mice. The niranthin-treated mouse models showed obviously reduced protein and mRNA levels of IL-6, IL-1β, IL-17A, and TNF-α and upregulated expression of IL-10 in the colon tissue. TUNEL staining and Western blotting demonstrated that niranthin significantly inhibited intestinal epithelial cell apoptosis and activated the anti-apoptotic pathway in the mouse models. Niranthin treatment obviously upregulated the expression levels of ZO-1 and claudin-1 and downregulated the phosphorylation levels of p38 and JNK in the colon tissues of the mice. Diprovocim intervention obviously attenuated the inactivation of the p38/JNK signaling pathway induced by niranthin in the mouse models. CONCLUSIONS Niranthin ameliorates TNBS-induced Crohn's disease-like colitis in mice by inhibiting intestinal epithelial cell apoptosis and protecting the integrity of the intestinal barrier via regulating the activation of the p38/JNK signaling pathway.
Animals ; Apoptosis/drug effects* ; Mice ; Intestinal Mucosa/drug effects* ; Crohn Disease/drug therapy* ; MAP Kinase Signaling System/drug effects* ; Epithelial Cells/drug effects* ; Disease Models, Animal ; Signal Transduction/drug effects* ; p38 Mitogen-Activated Protein Kinases/metabolism* ; Male

OBJECTIVE To study the correlation between SLCO1B1 （521T＞C and 388A＞G） gene polymorphisms and the efficacy and safety of rosuvastatin. METHODS Retrieved from PubMed， Embase， Cochrane Library， PharmGKB， CNKI database and Wanfang database， the studies about the effects of 521T＞C and 388A＞G gene polymorphisms on the efficacy and safety of rosuvastatin were collected during the inception to Dec. 2023. The included data were analyzed by using RevMan 5.3 software. RESULTS A total of 16 studies were included. The results of meta-analysis showed that 521T＞C gene polymorphism was significantly correlated with the efficacy of rosuvastatin. In the dominant gene model， compared with TT genotype， CC+TC genotype significantly improved the efficacy of rosuvastatin in raising high-density lipoprotein cholesterol （HDL-C） [MD＝2.38， 95%CI（0.61，4.16）， P＝0.009 0]. In the homozygous gene model， compared with TT genotype， CC genotype significantly improved the efficacy of rosuvastatin in reducing total cholesterol [MD＝－7.50，95%CI（－13.05， －1.95）， P＝0.008 0]. In heterozygous gene model， compared with TT genotype， TC genotype significantly improved rosuvastatin in reducing low-density lipoprotein cholesterol （LDL-C） [MD＝－5.14， 95%CI（－9.74， －0.53）， P＝0.03] and increasing HDL-C [MD＝5.67， 95%CI 232102311200） （2.61， 8.73）， P＝0.000 3]. 388A＞G gene polymorphism was also significantly correlated with the efficacy of rosuvastatin. In dominant or homozygous gene models， compared with AA E-mail：dushuzhang911@163.com genotype， GG+AG genotype [MD＝－6.88， 95%CI （－7.46，－6.30），P＜0.000 1] or GG genotype [MD＝－9.23， 95%CI（－9.41， 9.04）， P＜0.000 1] significantly improved the efficacy of rosuvastatin in lowering LDL-C. In the heterozygous gene model， compared with AA genotype， AG genotype significantly improved the efficacy of rosuvastatin in lowering LDL-C [MD＝－3.00， 95%CI（－3.19， －2.82）， P＜0.000 1]， total cholesterol [MD＝－5.80， 95%CI（－6.00， －5.59）， P＜0.000 1] and triglyceride [MD＝－11.79， 95%CI（－19.57， －4.02）， P＝0.003 0]. In the recessive gene model， compared with AA+AG genotype， GG genotype significantly improved the therapeutic efficacy of rosuvastatin in reducing LDL-C[MD＝－4.31， 95%CI（－8.47， －0.14）， P＝0.040 0] and elevating HDL-C [MD＝4.49， 95%CI （2.20， 6.77）， P＝0.000 1]. Under 4 gene models， there was a significant correlation between 521T＞C gene polymorphism and rosuvastatin-related ADR probability （P＜0.05）， but no significant correlation was found in 388A＞G gene polymorphism （P＞0.05）. CONCLUSIONS The polymorphism of 521T＞C gene is significantly related to the efficacy and safety of rosuvastatin in lowering lipid， and the C allele may be one of the factors leading to the increase of rosuvastatin in lipid-lowering efficacy and ADR. 388A＞ G gene polymorphism is significantly associated with the lipid-lowering efficacy of rosuvastatin， but not with its safety.

OBJECTIVE To screen and quantitatively analyze differential quality markers （Q-Marker） in Zingiber officinale mixed and triturated with Schisandra chinensis （ZMTS） before and after processing. METHODS HPLC fingerprints of before processing [Z. officinale complicated with S. chinensis （ZWS）] and after processing （ZMTS） （10 batches each） were established. The differences of Q-Markers before and after processing were screened by the chemical pattern recognition method and Q-Marker “five principles”， and the contents were determined. RESULTS A total of 14 common peaks were identified in the fingerprints of ZWS， 22 common peaks were identified in the fingerprints of ZMTS， and 8 components were identified. Differential Q-Marker were screened by chemical pattern recognition and Q-Marker “five principles”， i. e. 6-gingerol， schisandrol A schisandrol B， 8-gingerol， 10-gingerol， schisandrin A， schisandrin B， schizandrin C. The average contents of the 8 differential Q-Markers in ZMTS were 229.46， 244.48， 39.96， 44.12， 61.17， 47.82， 100.11 and 9.70 μg/g， respectively. The average contents of the 4 differential Q-Markers （6-gingerol， schisandrol A， schisandrol B， 8-gingerol） in ZWS were 112.58， 19.01， 26.74 and 5.98 μg/g， respectively. CONCLUSIONS In this study， the differential Q-Markers before and after ZMTS processing are screened. The contents of the Q-Markers in ZMTS after processing are higher than those before processing.

Objective This study aimed to compare the current Essen rabies post-exposure immunization schedule(0-3-7-14-28)in China and the simple 4-dose schedule(0-3-7-14)newly recommended by the World Health Organization in terms of their safety,efficacy,and protection. Methods Mice were vaccinated according to different immunization schedules,and blood was collected for detection of rabies virus neutralizing antibodies(RVNAs)on days 14,21,28,35,and 120 after the first immunization.Additionally,different groups of mice were injected with lethal doses of the CVS-11 virus on day 0,subjected to different rabies immunization schedules,and assessed for morbidity and death status.In a clinical trial,185 rabies-exposed individuals were selected for post-exposure vaccination according to the Essen schedule,and blood was collected for RVNAs detection on days 28 and 42 after the first immunization. Results A statistically significant difference in RVNAs between mice in the Essen and 0-3-7-14 schedule groups was observed on the 35th day(P<0.05).The groups 0-3-7-14,0-3-7-21,and 0-3-7-28 showed no statistically significant difference(P>0.05)in RVNAs levels at any time point.The post-exposure immune protective test showed that the survival rate of mice in the control group was 20%,whereas that in the immunization groups was 40%.In the clinical trial,the RVNAs positive conversion rates on days 28(14 days after 4 doses)and 42(14 days after 5 doses)were both 100%,and no significant difference in RVNAs levels was observed(P>0.05). Conclusion The simple 4-dose schedule can produce sufficient RVNAs levels,with no significant effect of a delayed fourth vaccine dose(14-28 d)on the immunization potential.

Objective:By analyzing the relationship between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong,it explores the path of coordinated development between traditional Chinese medicine and western medicine in traditional Chinese medicine hospitals,providing references for the high-quality development of county-level traditional Chinese medicine hospitals.Methods:The efficiency of traditional Chinese medicine services and comprehensive medical services in county-level traditional Chinese medicine hospitals in Shandong Province from 2019 to 2022 was analyzed by Data Envelopment Analysis(DEA),and the correlation was analyzed by Spearman correlation coefficient.Results:The efficiency of traditional Chinese medicine services in county-level traditional Chinese medicine hospitals in Shandong Province is lower than that of comprehensive medical services,and the scale return coefficient of traditional Chinese medicine category indicators is better than that of comprehensive category indicators.There is a positive correlation between the efficiency of traditional Chinese medicine services and the efficiency of comprehensive medical services.Conclusion:Traditional Chinese medicine hospitals should appropriately expand their investment in traditional Chinese medicine resources.Adhere to the hospital management model of traditional Chinese medicine services as the main focus,and build a coordinated development path between traditional Chinese and western medicine from both the supply and demand sides.