Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) globally, representing a major global health burden with limited disease-modifying therapies. Podocyte injury serves as the core pathological hallmark of DN, and conventional treatments targeting metabolic disorders or hemodynamic abnormalities fail to reverse the progressive decline of renal function. Accumulating evidence over the past decade has established that high glucose-induced podocyte pyroptosis—a pro-inflammatory form of programmed cell death—is a key driving force in DN progression. Its core molecular mechanism hinges on the activation of the TXNIP-NLRP3 inflammasome axis. Under sustained hyperglycemic conditions, excessive reactive oxygen species (ROS) are generated via pathways including the polyol pathway, advanced glycation end products (AGEs) accumulation, and mitochondrial dysfunction. Concurrently, methylglyoxal (a glucose metabolite) mediates post-translational modification of thioredoxin-interacting protein (TXNIP). These events collectively trigger the dissociation of TXNIP from thioredoxin (TRX), a redox-regulating protein. The free TXNIP then translocates to the mitochondria, where it binds to The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) and promotes inflammasome assembly. This assembly activates cysteine-aspartic acid protease 1 (caspase-1), which cleaves Gasdermin D (GSDMD) to generate its N-terminal fragment (GSDMD-NT). GSDMD-NT oligomerizes to form membrane pores, leading to podocyte swelling, rupture, and the release of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). These cytokines amplify local inflammatory responses, induce mesangial cell proliferation, and accelerate extracellular matrix deposition, ultimately exacerbating glomerulosclerosis. MCC950, a highly selective NLRP3 inhibitor, exerts its therapeutic effects through a multi-layered mechanism: it binds to the NACHT domain (NAIP, CIITA, HET-E and TP1 domain) of NLRP3 with nanomolar affinity, forming hydrogen bonds with key residues (Lys-42 and Asp-166) within the ATP-hydrolysis pocket to block ATP hydrolysis, thereby locking NLRP3 in an inactive conformational state. Additionally, MCC950 interferes with the protein-protein interaction between TXNIP and NLRP3 and regulates mitochondrial homeostasis to reduce ROS production. Preclinical studies have demonstrated that MCC950 dose-dependently reduces proteinuria, restores the expression of podocyte-specific markers (nephrin and Wilms tumor 1 protein, WT1), and alleviates podocyte foot process fusion and glomerulosclerosis in both streptozotocin (STZ)-induced type 1 diabetic models (characterized by absolute insulin deficiency) and db/db type 2 diabetic models (driven by insulin resistance). However, discrepancies in therapeutic outcomes exist across different models—some studies report exacerbated renal inflammation and fibrosis in STZ-induced models—which may stem from differences in disease pathogenesis, intervention timing (early vs. mid-stage disease), and dosing duration. Despite its promising preclinical efficacy, MCC950 faces significant translational challenges, including low oral bioavailability, insufficient podocyte targeting, potential hepatotoxicity, and drug-drug interactions with statins (commonly prescribed to diabetic patients for cardiovascular risk management). Furthermore, off-target effects such as the inhibition of carbonic anhydrase 2 have been identified, raising concerns about its safety profile. Nevertheless, its unique mechanism of action—directly blocking podocyte pyroptosis by targeting the TXNIP-NLRP3 axis—endows it with substantial translational value. In the future, strategies to overcome these barriers are expected to advance its clinical application: targeted delivery via nanocarriers (e.g., PLGA-PEG nanoparticles or nephrin antibody-conjugated systems) to enhance renal accumulation and podocyte specificity; precise patient stratification based on biomarkers such as serum IL-18 and renal TXNIP/NLRP3 expression to identify “inflammatory-phenotype” DN patients most likely to benefit; and combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors—whose metabolic benefits synergize with MCC950’s anti-inflammatory effects. These approaches hold great potential to break through clinical translation bottlenecks, offering a novel, precise anti-inflammatory treatment option for DN and addressing an unmet clinical need for therapies targeting the inflammatory underpinnings of the disease.

Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) globally, representing a major global health burden with limited disease-modifying therapies. Podocyte injury serves as the core pathological hallmark of DN, and conventional treatments targeting metabolic disorders or hemodynamic abnormalities fail to reverse the progressive decline of renal function. Accumulating evidence over the past decade has established that high glucose-induced podocyte pyroptosis—a pro-inflammatory form of programmed cell death—is a key driving force in DN progression. Its core molecular mechanism hinges on the activation of the TXNIP-NLRP3 inflammasome axis. Under sustained hyperglycemic conditions, excessive reactive oxygen species (ROS) are generated via pathways including the polyol pathway, advanced glycation end products (AGEs) accumulation, and mitochondrial dysfunction. Concurrently, methylglyoxal (a glucose metabolite) mediates post-translational modification of thioredoxin-interacting protein (TXNIP). These events collectively trigger the dissociation of TXNIP from thioredoxin (TRX), a redox-regulating protein. The free TXNIP then translocates to the mitochondria, where it binds to The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) and promotes inflammasome assembly. This assembly activates cysteine-aspartic acid protease 1 (caspase-1), which cleaves Gasdermin D (GSDMD) to generate its N-terminal fragment (GSDMD-NT). GSDMD-NT oligomerizes to form membrane pores, leading to podocyte swelling, rupture, and the release of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). These cytokines amplify local inflammatory responses, induce mesangial cell proliferation, and accelerate extracellular matrix deposition, ultimately exacerbating glomerulosclerosis. MCC950, a highly selective NLRP3 inhibitor, exerts its therapeutic effects through a multi-layered mechanism: it binds to the NACHT domain (NAIP, CIITA, HET-E and TP1 domain) of NLRP3 with nanomolar affinity, forming hydrogen bonds with key residues (Lys-42 and Asp-166) within the ATP-hydrolysis pocket to block ATP hydrolysis, thereby locking NLRP3 in an inactive conformational state. Additionally, MCC950 interferes with the protein-protein interaction between TXNIP and NLRP3 and regulates mitochondrial homeostasis to reduce ROS production. Preclinical studies have demonstrated that MCC950 dose-dependently reduces proteinuria, restores the expression of podocyte-specific markers (nephrin and Wilms tumor 1 protein, WT1), and alleviates podocyte foot process fusion and glomerulosclerosis in both streptozotocin (STZ)-induced type 1 diabetic models (characterized by absolute insulin deficiency) and db/db type 2 diabetic models (driven by insulin resistance). However, discrepancies in therapeutic outcomes exist across different models—some studies report exacerbated renal inflammation and fibrosis in STZ-induced models—which may stem from differences in disease pathogenesis, intervention timing (early vs. mid-stage disease), and dosing duration. Despite its promising preclinical efficacy, MCC950 faces significant translational challenges, including low oral bioavailability, insufficient podocyte targeting, potential hepatotoxicity, and drug-drug interactions with statins (commonly prescribed to diabetic patients for cardiovascular risk management). Furthermore, off-target effects such as the inhibition of carbonic anhydrase 2 have been identified, raising concerns about its safety profile. Nevertheless, its unique mechanism of action—directly blocking podocyte pyroptosis by targeting the TXNIP-NLRP3 axis—endows it with substantial translational value. In the future, strategies to overcome these barriers are expected to advance its clinical application: targeted delivery via nanocarriers (e.g., PLGA-PEG nanoparticles or nephrin antibody-conjugated systems) to enhance renal accumulation and podocyte specificity; precise patient stratification based on biomarkers such as serum IL-18 and renal TXNIP/NLRP3 expression to identify “inflammatory-phenotype” DN patients most likely to benefit; and combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors—whose metabolic benefits synergize with MCC950’s anti-inflammatory effects. These approaches hold great potential to break through clinical translation bottlenecks, offering a novel, precise anti-inflammatory treatment option for DN and addressing an unmet clinical need for therapies targeting the inflammatory underpinnings of the disease.

Colorectal cancer(CRC) is one of the most common malignant tumors worldwide, primarily originating from recurrent inflammatory bowel disease(IBD). Therefore, blocking the inflammation-cancer transformation in the colon has become a focus in the early prevention and treatment of CRC. The inflammation-cancer transformation in the colon involves multiple types of cells and complex pathological processes, including inflammatory responses and tumorigenesis. In this complex pathological process, immune cells(including non-specific and specific immune cells) and non-immune cells(such as tumor cells and fibroblasts) interact with each other, collectively promoting the progression of the disease. In traditional Chinese medicine(TCM), inflammation-cancer transformation in the colon belongs to the categories of dysentery and diarrhea, with the main pathogenesis being cold and heat in complexity. This paper first elaborates on the complex molecular mechanisms involved in the inflammation-cancer transformation process in the colon from the perspectives of inflammation, cancer, and their mutual influences. Subsequently, by comparing the pathogenic characteristics and clinical manifestations between inflammation-cancer transformation and the TCM pathogenesis of cold and heat in complexity, this paper explores the intrinsic connections between the two. Furthermore, based on the correlation between inflammation-cancer transformation in the colon and the TCM pathogenesis, this paper delves into the importance of the interaction between inflammation and cancer. Finally, it summarizes and discusses the clinical and basic research progress in the TCM intervention in the inflammation-cancer transformation process, providing a theoretical basis and treatment strategy for the treatment of CRC with integrated traditional Chinese and Western medicine.
Humans ; Colon/pathology* ; Integrative Medicine ; Animals ; Cold Temperature ; Cell Transformation, Neoplastic/drug effects* ; Medicine, Chinese Traditional ; Hot Temperature ; Inflammation ; Drugs, Chinese Herbal/therapeutic use* ; Colonic Neoplasms/drug therapy*

The Masquelet technique, also known as the induced membrane technique, is a surgical technique for repairing large bone defects based on the use of a membrane generated by a foreign body reaction for bone grafting. This technique is not only simple to perform, with few complications and quick recovery, but also has excellent clinical results. To better understand the mechanisms by which this technique promotes bone defect repair and the factors that require special attention in practice, we examined and summarized the relevant research advances in this technique by searching, reading, and analysing the literature. Literature show that the Masquelet technique may promote the repair of bone defects through the physical septum and molecular barrier, vascular network, enrichment of mesenchymal stem cells, and high expression of bone-related growth factors, and the repair process is affected by the properties of spacers, the timing of bone graft, mechanical environment, intramembrane filling materials, artificial membrane, and pharmaceutical/biological agents/physical stimulation.
Humans ; Bone Transplantation/methods* ; Membranes, Artificial ; Bone Regeneration ; Animals

ObjectiveMagnetoencephalography (MEG), a non-invasive neuroimaging technique, meticulously captures the magnetic fields emanating from brain electrical activity. Compared with MEG based on superconducting quantum interference devices (SQUID), MEG based on optically pump magnetometer (OPM) has the advantages of higher sensitivity, better spatial resolution and lower cost. However, most of the current studies are clinical studies, and there is a lack of animal studies on MEG based on OPM technology. Pain, a multifaceted sensory and emotional phenomenon, induces intricate alterations in brain activity, exhibiting notable sex differences. Despite clinical revelations of pain-related neuronal activity through MEG, specific properties remain elusive, and comprehensive laboratory studies on pain-associated brain activity alterations are lacking. The aim of this study was to investigate the effects of inflammatory pain (induced by Complete Freund’s Adjuvant (CFA)) on brain activity in a rat model using the MEG technique, to analysis changes in brain activity during pain perception, and to explore sex differences in pain-related MEG signaling. MethodsThis study utilized adult male and female Sprague-Dawley rats. Inflammatory pain was induced via intraplantar injection of CFA (100 μl, 50% in saline) in the left hind paw, with control groups receiving saline. Pain behavior was assessed using von Frey filaments at baseline and 1 h post-injection. For MEG recording, anesthetized rats had an OPM positioned on their head within a magnetic shield, undergoing two 15-minute sessions: a 5-minute baseline followed by a 10-minute mechanical stimulation phase. Data analysis included artifact removal and time-frequency analysis of spontaneous brain activity using accumulated spectrograms, generating spectrograms focused on the 4-30 Hz frequency range. ResultsMEG recordings in anesthetized rats during resting states and hind paw mechanical stimulation were compared, before and after saline/CFA injections. Mechanical stimulation elevated alpha activity in both male and female rats pre- and post-saline/CFA injections. Saline/CFA injections augmented average power in both sexes compared to pre-injection states. Remarkably, female rats exhibited higher average spectral power 1 h after CFA injection than after saline injection during resting states. Furthermore, despite comparable pain thresholds measured by classical pain behavioral tests post-CFA treatment, female rats displayed higher average power than males in the resting state after CFA injection. ConclusionThese results imply an enhanced perception of inflammatory pain in female rats compared to their male counterparts. Our study exhibits sex differences in alpha activities following CFA injection, highlighting heightened brain alpha activity in female rats during acute inflammatory pain in the resting state. Our study provides a method for OPM-based MEG recordings to be used to study brain activity in anaesthetized animals. In addition, the findings of this study contribute to a deeper understanding of pain-related neural activity and pain sex differences.

Objective To summarize the changing prevalence of carbapenem resistance in Enterobacterales based on the data of CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021 for improving antimicrobial treatment in clinical practice.Methods Antimicrobial susceptibility testing was performed using a commercial automated susceptibility testing system according to the unified CHINET protocol.The results were interpreted according to the breakpoints of the Clinical & Laboratory Standards Institute(CLSI)M100 31st ed in 2021.Results Over the seven-year period(2015-2021),the overall prevalence of carbapenem-resistant Enterobacterales(CRE)was 9.43％(62 342/661 235).The prevalence of CRE strains in Klebsiella pneumoniae,Citrobacter freundii,and Enterobacter cloacae was 22.38％,9.73％,and 8.47％,respectively.The prevalence of CRE strains in Escherichia coli was 1.99％.A few CRE strains were also identified in Salmonella and Shigella.The CRE strains were mainly isolated from respiratory specimens(44.23±2.80)％,followed by blood(20.88±3.40)％and urine(18.40±3.45)％.Intensive care units(ICUs)were the major source of the CRE strains(27.43±5.20)％.CRE strains were resistant to all the β-lactam antibiotics tested and most non-β-lactam antimicrobial agents.The CRE strains were relatively susceptible to tigecycline and polymyxins with low resistance rates.Conclusions The prevalence of CRE strains was increasing from 2015 to 2021.CRE strains were highly resistant to most of the antibacterial drugs used in clinical practice.Clinicians should prescribe antimicrobial agents rationally.Hospitals should strengthen antibiotic stewardship in key clinical settings such as ICUs,and take effective infection control measures to curb CRE outbreak and epidemic in hospitals.

Objective To characterize the changing species distribution and antibiotic resistance profiles of respiratory isolates in hospitals participating in the CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021.Methods Commercial automated antimicrobial susceptibility testing systems and disk diffusion method were used to test the susceptibility of respiratory bacterial isolates to antimicrobial agents following the standardized technical protocol established by the CHINET program.Results A total of 589 746 respiratory isolates were collected from 2015 to 2021.Overall,82.6％of the isolates were Gram-negative bacteria and 17.4％were Gram-positive bacteria.The bacterial isolates from outpatients and inpatients accounted for(6.0±0.9)％and(94.0±0.1)％,respectively.The top microorganisms were Klebsiella spp.,Acinetobacter spp.,Pseudomonas aeruginosa,Staphylococcus aureus,Haemophilus spp.,Stenotrophomonas maltophilia,Escherichia coli,and Streptococcus pneumoniae.Each microorganism was isolated from significantly more males than from females(P＜0.05).The overall prevalence of methicillin-resistant S.aureus(MRSA)was 39.9％.The prevalence of penicillin-resistant S.pneumoniae was 1.4％.The prevalence of extended-spectrum β-lactamase(ESBL)-producing E.coli and K.pneumoniae was 67.8％and 41.3％,respectively.The overall prevalence of carbapenem-resistant E.coli,K.pneumoniae,Enterobacter cloacae,Pseudomonas aeruginosa,and Acinetobacter baumannii was 3.7％,20.8％,9.4％,29.8％,and 73.3％,respectively.The prevalence of β-lactamase was 96.1％in Moraxella catarrhalis and 60.0％in Haemophilus influenzae.The H.influenzae isolates from children(＜18 years)showed significantly higher resistance rates to β-lactam antibiotics than the isolates from adults(P＜0.05).Conclusions Gram-negative bacteria are still predominant in respiratory isolates associated with serious antibiotic resistance.Antimicrobial resistance surveillance should be strengthened in clinical practice to support accurate etiological diagnosis and appropriate antimicrobial therapy based on antimicrobial susceptibility testing results.

Aim To investigate the regulatory mecha-nisms of donepezil on the expression and enzymatic ac-tivity of cytochrome P450 3A4(CYP3A4),elucidate the synergistic impact of hypoxia on CYP3A4 function,and reveal its potential association with drug-induced cardiotoxicity,particularly QT interval prolongation.Methods Western blot,co-immunoprecipitation,and gene knockdown techniques were employed to evaluate the effects of donepezil and hypoxia on CYP3A4 pro-tein expression.CYP3A4 enzymatic activity was as-sessed using an in vitro incubation system with rat liver microsomes combined with high-performance liquid chromatography(HPLC),and the half-maximal inhib-itory concentration(IC50)was determined.Results Donepezil(10 μmol·L-1)and hypoxia reduced CYP3A4 protein expression to 31.75％and 45.90％of the control levels,respectively.Both interventions activated the gp78-mediated ubiquitin-proteasome path-way,significantly increasing CYP3A4 ubiquitination levels by 2.1-fold compared to the control group,thereby promoting proteasomal degradation.Donepezil inhibited CYP3A4 enzyme activity with an IC50 of 83.4μmol·L-1,and hypoxia synergistically enhanced this inhibitory effect,reducing the IC50 to 20.79 μmol·L-1.Conclusion Donepezil downregulates CYP3A4 function through dual mechanisms involving ubiquitin-mediated proteasomal degradation and direct enzymatic inhibition.Hypoxia potentiates this effect,leading to impaired metabolism of CYP3A4 substrate drugs,ele-vated plasma drug concentrations(1.6-2.3-fold in-crease compared to normal metabolic conditions),and an increased risk of QT interval prolongation and other forms of cardiotoxicity.

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.

With the rapid development of competitive sports, the incidence of anterior cruciate ligament (ACL) injury is on the rise. Such injuries may shorten athletes′ career and lead to other long-term adverse consequences. Although athletes generally recover well after ACL reconstruction, many still struggle to return to their pre-injury performance levels. Advances in the understanding of ACL anatomy and injury mechanisms, along with the evolution of surgical techniques and rehabilitation methods, have provided more individualized and tailored options for athletes following ACL injuries. However, there is currently no consensus in China regarding surgical and rehabilitation strategies for competitive athletes aiming to return to sports after ACL injuries. To this end, the Sports Medicine Committee of the Chinese Research Hospital Association and the Editorial Board of the Chinese Journal of Trauma jointly formulated the Expert consensus on surgical treatment and rehabilitation for competitive sports athletes returning to sports after anterior cruciate ligament injury ( version 2025), and presented 14 recommendations covering surgical indications, preoperative rehabilitation, surgical timing, surgical strategies and postoperative rehabilitation strategies, aiming to improve the surgical treatment and rehabilitation system for ACL injuries in competitive athletes and facilitate their return to high-level sports performance after injury.