Diabetic cardiomyopathy is a distinct form of cardiomyopathy that can lead to heart failure, arrhythmias, cardiogenic shock, and sudden death. It has become a major cause of mortality in diabetic patients. The pathogenesis of diabetic cardiomyopathy is complex, involving increased oxidative stress, activation of inflammatory responses, disturbances in glucose and lipid metabolism, accumulation of advanced glycation end products (AGEs), abnormal autophagy and apoptosis, insulin resistance, and impaired intracellular Ca²⁺ homeostasis. Recent studies have shown that adenosine monophosphate-activated protein kinase (AMPK) plays a crucial protective role by lowering blood glucose levels, promoting lipolysis, inhibiting lipid synthesis, and exerting antioxidant, anti-inflammatory, anti-apoptotic, and anti-ferroptotic effects. It also enhances autophagy, thereby alleviating myocardial injury under hyperglycemic conditions. Consequently, AMPK is considered a key protective factor in diabetic cardiomyopathy. As part of diabetes prevention and treatment strategies, both pharmacological and exercise interventions have been shown to mitigate diabetic cardiomyopathy by modulating the AMPK signaling pathway. However, the precise regulatory mechanisms, optimal intervention strategies, and clinical translation require further investigation. This review summarizes the role of AMPK in the prevention and treatment of diabetic cardiomyopathy through drug and/or exercise interventions, aiming to provide a reference for the development and application of AMPK-targeted therapies. First, several classical AMPK activators (e.g., AICAR, A-769662, O-304, and metformin) have been shown to enhance autophagy and glucose uptake while inhibiting oxidative stress and inflammatory responses by increasing the phosphorylation of AMPK and its downstream target, mammalian target of rapamycin (mTOR), and/or by upregulating the gene expression of glucose transporters GLUT1 and GLUT4. Second, many antidiabetic agents (e.g., teneligliptin, liraglutide, exenatide, semaglutide, canagliflozin, dapagliflozin, and empagliflozin) can promote autophagy, reverse excessive apoptosis and autophagy, and alleviate oxidative stress and inflammation by enhancing AMPK phosphorylation and its downstream targets, such as mTOR, or by increasing the expression of silent information regulator 1 (SIRT1) and peroxisome proliferator-activated receptor‑α (PPAR‑α). Third, certain anti-anginal (e.g., trimetazidine, nicorandil), anti-asthmatic (e.g., farrerol), antibacterial (e.g., sodium houttuyfonate), and antibiotic (e.g., minocycline) agents have been shown to promote autophagy/mitophagy, mitochondrial biogenesis, and inhibit oxidative stress and lipid accumulation via AMPK phosphorylation and its downstream targets such as protein kinase B (PKB/AKT) and/or PPAR‑α. Fourth, natural compounds (e.g., dihydromyricetin, quercetin, resveratrol, berberine, platycodin D, asiaticoside, cinnamaldehyde, and icariin) can upregulate AMPK phosphorylation and downstream targets such as AKT, mTOR, and/or the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), thereby exerting anti-inflammatory, anti-apoptotic, anti-pyroptotic, antioxidant, and pro-autophagic effects. Fifth, moderate exercise (e.g., continuous or intermittent aerobic exercise, aerobic combined with resistance training, or high-intensity interval training) can activate AMPK and its downstream targets (e.g., acetyl-CoA carboxylase (ACC), GLUT4, PPARγ coactivator-1α (PGC-1α), PPAR-α, and forkhead box protein O3 (FOXO3)) to promote fatty acid oxidation and glucose uptake, and to inhibit oxidative stress and excessive mitochondrial fission. Finally, the combination of liraglutide and aerobic interval training has been shown to activate the AMPK/FOXO1 pathway, thereby reducing excessive myocardial fatty acid uptake and oxidation. This combination therapy offers superior improvement in cardiac dysfunction, myocardial hypertrophy, and fibrosis in diabetic conditions compared to liraglutide or exercise alone.

Aim To prepare tripterygium glycoside nanoparticles and probe into their therapeutic effect on collagen-induced arthritis ( CIA) rats. Methods Tripterygium glycosides polyglycoside nanoparticles were prepared by thin film dispersion method and their quality was assessed. The CIA model was established and drug intervention performed. The body weight, toe swelling degree and arthritis index were measured. The pathological changes of the organs, knee and ankle synovium were observed. The serum levels of kidney function and inflammatory cytokine expression were detected in rats. Results The prepared tripterygium wil-fordii polyglycoside nanoparticles were round particles with uniform distribution and stable properties under electron microscope. Compared with the model group, the swelling of the left and right toes of medication group significantly decreased (P < 0. 01), and the ar-thritis index markedly decreased ( P < 0. 01). Among them, the efficacy of the TG-NPs group was better than that of the TG group. Compared with the normal group, the indexes of heart, spleen, kidney and testis all significantly decreased (P <0. 05, P<0.01). TG-NPs group had a significantly reduced pathological ankle-joint injury in knee cartilage and increased apoptotic synovial cells. Compared with the model group, the serum levels of ALT and BUN and CRE in TG-NPs group were significantly lower (P < 0. 05 ), and IL-1β, TNF-α and IL-6 levels decreased significantly (P <0. 05). Conclusions TG-NPs have good therapeutic effect on CIA through induction of synovial cell apoptosis and decrease of the expression of inflammatory cytokines. By intravenous injection of blood circula-tion, slow and controlled release of drugs can be achieved, the first pass effect caused by oral drug can be avoided, the viscera toxicity can be reduced, which provides an experimental basis for the development of new nanoagents for the treatment of rheumatoid arthritis.

Obiective Alzheimer’s disease (AD) is a degenerative disease of the central nervous system (CNS) caused by a variety of risk factors. There are various pathological changes, but apoptosis of the neurological meridian cells is one of the most important pathological bases. Hyperlipidemia is a high-risk factor for the development of AD, which can lead to increased levels of oxidized low-density lipoprotein (ox-LDL) in brain tissues. PCSK9 is a protease closely related to lipid metabolism, but studies have shown that it may be related to the development of AD. LRP1 is abundantly expressed in neuronal cells, and it is an important transporter for the clearance of Aβ. There is now a large amount of literature confirming that PCSK9 can induce the degradation of LRP1. PI3K/AKT is an important signaling pathway in vivo, which plays an important role in apoptosis, and there is now a large amount of literature confirming that LRP1 activates the PI3K/AKT pathway, which has an anti-apoptotic effect. So can PCSK9 affect the PI3K/AKT pathway through LRP1 and thus regulate neuronal apoptosis? This deserves further investigation.The aim of this study was to explore the role of PCSK9 in mediating ox-LDL pro-apoptotic neuronal cell death and its mechanism, and then further elaborate the mechanism of hyperlipidemia leading to neurodegenerative diseases such as AD. MethodsFirstly, PC12 cells were treated with different concentrations of ox-LDL (0, 25, 50, 75 and 100 mg/L) for 24 h. Oil red O staining was used to detect lipid accumulation in PC12 cells, Hoechst33258 staining and flow cytometry to detect apoptosis in PC12 cells, ELISA to detect the content of Aβ secreted by PC12, Western blot to detect expression of SREBP2, PCSK9 and LRP1. Then PC12 cells were treated with 75 mg/L ox-LDL for different times (0, 6, 12, 24, 48 h), and Western blot were performed to detect the expression of SREBP2, PCSK9 and LRP1. Finally, after transfecting 100 nmol/L PCSK9 siRNA into PC12 cells for 48 h, PC12 cells were treated with 75 mg/L ox-LDL for 24 h, Hoechst33258 staining and flow cytometry to detect apoptosis rate of PC12 cells, and Western blot to detect PCSK9, LRP1, PI3K, AKT, P-PI3K , P-AKT, NF-κB, Bcl-2, Bax, Caspase-9 and Caspase-3 expression, and ELISA detected Aβ content secreted by PC12 cells. Resultsox-LDL increased lipid accumulation and promoted apoptosis and Aβ secretion in PC12 cells, as well as increasing the expression of SREBP2 and PCSK9 and decreasing the expression of LRP1 in PC12 cells. pCsk9 siRNA could be inhibited through the PI3K/AKT pathway and the NF-κB-Bcl-2/Bax-Caspase-9/3 pathway to inhibit ox-LDL-induced apoptosis in PC12 cells while increasing Aβ secretion in PC12 cells. Conclusionox-LDL plays a bidirectional regulatory role in ox-LDL-induced apoptosis of PC12 cells by inducing an increase in PCSK9 expression and a decrease in LRP1 expression in PC12 cells, which in turn affects different signaling pathways downstream.

Objective To investigate the effect of hedysarum polysacchcaide(HPS)on nuclear transcription factor-κB(NF-κB)/IκB kinase β(IKKβ)signaling pathway in cardiac tissue of db/db mice with diabetic cardiomyopathy(DCM).Methods Altogether 60 7-week-old male db/db mice were randomly divided into model group,control group and experimental-H,-M,-L groups,with 12 mice in each group.In addition,12 db/m mice of the same week age were selected as the normal group.Normal group and model group were given 0.9％NaCl by intragastric administration.Experimental-L,-M,-H groups were given 50,100 and 200 mg·kg-1 HPS suspension by intragastriction,respectively.Control group was given 4 mg·kg-1 rosiglitazone suspension by intragastric administration.Six groups of rats were given the drug once a day for 8 weeks.The contents of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)in myocardial tissue were detected by enzyme-linked immunosorbent assay.The mRNA expression levels of NF-κB and IKKβ in myocardial tissue were detected by real-time fluorescence quantitative polymerase chain reaction.The correlation between the expression of NF-κB protein and the content of TNF-α and IL-6 was analyzed.Results The contents of IL-6 in myocardial tissue of normal,model,control and experimental-H groups were(1.24±0.54),(7.72±0.24),(2.90±0.50)and(2.78±0.56)ng·L-1;the contents of TNF-α were(1.96±0.52),(5.25±0.72),(2.84±0.86)and(2.82±0.58)ng·L-1;the mRNA expression levels of NF-κB were I.00±0.00,3.35±0.81,2.05±0.44 and 1.67±0.22;the mRNA expression levels of IKKβ were 1.00±0.00,2.92±0.07,1.51±0.07 and 1.41±0.08,respectively.Compared with the model group,the above indexes of the control and experimental-H groups were statistically significant(P＜0.01,P＜0.05).The expression of NF-κB protein was positively correlated with the content of IL-6 and TNF-α,and the correlation coefficients were 0.866 and 0.740(all P＜0.01).Conclusion HPS can alleviate the damage of myocardial pathology in mice,reduce myocardial collagen deposition and fibrosis,its mechanism may be through regulating the expression of NF-κB/IKKβ signaling pathway to play a role in inhibiting the inflammatory reaction.

Liposome was used as carrier to carry triptolide and ginsenoside Rg3 in the treatment of pancreatic cancer tumor mice. The effects of liposome on the levels of CD4⁺ and CD8⁺ microenvironmental immune factors of pancreatic cancer tumor were investigated, and the tumor inhibitory effect and safety were evaluated. In this study, Pan02 cells were used to construct a tumor-bearing C57BL/6 mouse model. After 14 days of treatment, the changes in tumor volume and body weight of tumor-bearing mice were observed. The results showed that the high and low doses of liposome had significant therapeutic effect on tumor volume in the model group (P < 0.01), and the tumor inhibition rate of high doses of liposome was significantly increased compared with triptolide group (P < 0.05). Immunohistochemistry showed that compared with the model group, the tumor inhibition rate of liposome was significantly increased. The high-dose liposome group can up-regulate the ratio of immune factor CD4⁺/CD8⁺, inhibit the expression of tumor proliferation factor and promote the expression of tumor apoptosis factor, and has a high safety after pathological hematoxylin and eosin staining of liver, spleen, lung and kidney and serum factor detection. Animal welfare and experimental procedures are in accordance with the regulations of the Experimental Animal Ethics Committee of Henan University of Chinese Medicine (approval No.: DWLL202103173). This study provides a new idea for the exploration of immunotherapy for pancreatic cancer.

Knee osteoarthritis has become one of the common diseases of the elderly,total knee arthroplasty(TKA)is the most effective treatment for end-stage knee osteoarthritis at present.In TKA,the effective restoration of the lower extremity alignment is one of the key factors for the success of the operation,which greatly affects the postoperative clinical effect and prosthesis survival rate of patients.Mechanical alignment is a TKA alignment method which is first proposed,recognized and widely used in TKA.In recent years,with the in-depth research on the lower limb alignment and the rapid development of com-puter technology,the alignment technology in TKA has realized the transformation from"unified"to"individualized",two-di-mensional to three-dimensional.New alignment methods,such as adjusted mechanical alignment,anatomic alignment,kine-matic alignment,inverse kinematic alignment,restricted kinematic alignment and functional alignment have been proposed to provide surgeons with more choices.However,there is no conclusion on which alignment method is the best choice.This paper summarizes the current research status,advantages and disadvantages of various alignment methods in TKA,and aims to pro-vide some reference for the selection of alignment methods in TKA.

To investigate the recent prevalence and molecular epidemiological characteristics of por-cine diarrhea viruses in Sichuan Province,this study used fluorescence quantitative PCR to detect porcine diarrhea samples from multiple regions in Sichuan Province from 2021 to 2023.RT-PCR was used to identify the genotypes of PEDV,PoRVA,PDCoV,and PTV,and their genetic variabil-ity,evolutionary characteristics,and recombination events were analyzed.The results showed that PEDV,PoRVA,PDCoV,and PTV were still prevalent in Sichuan region,with overall positive rates of 14.2％(40/281),13.2％(37/281),15.6％(44/281),and 12.5％(35/281),respectively.PEDV mixed infection with other pathogens was the most common.This study obtained a total of six strains of G2b PEDV,three strains of G3 PDCoV,three strains of G9P[13]PoRVA,one strain of G3P[13]PoRVA,three strains of Type 5 PTV,and one strain of Type 9 PTV.Compared to the seven vaccine strains including CV777,DR13,KPEDV-9,Chinju99,KNU-0801,AJ1102,and LW/L,the 6 PEDV strains showed multiple amino acid mutation sites in the COE region and S1D epitope region.Among them,the strains PSCLZ01 and PSCMY04 formed a separate branch in the phylogenetic tree.The three PDCoV strains have a closer genetic evolution distance to the previ-ously prevalent strains in Sichuan,but they also have 6-48 amino acid mutations compared to them.The four PoRVA strains have 104-108 amino acid variations in the VP4 gene compared to the early vaccine strain LLR,and they have 25 common amino acid variations in the VP7 gene.From the phylogenetic tree,the VP7 gene of RSCMY01/G3P[13]belongs to the same branch as the Heilongjiang strain LNCY,but its VP4 gene clusters with the Sichuan strain SCYA-C7,indica-ting that this PoRVA strain may have undergone genetic reassortment during inter-provincial transmission between different genotypes.It is worth noting that in the detected samples of PTV-5 and PTV-9,other diarrheal viruses tested negative,indicating that these two genotypes of PTV may be important pathogens causing porcine diarrhea.Additionally,the S gene of PEDV PSCLZ01 strain and PDCoV PCSCMY02 strain have undergone recombination events,and their parental strains come from different regions,both domestic and international.These findings reveal the main types of porcine diarrheal viruses,as well as their genetic diversity and variations in Sichuan Province in recent years.This study enriches the molecular epidemiological data of porcine diarrhe-al pathogens in the region and provides an important theoretical basis for the prevention,control,and purification of porcine diarrhea in the local area.

Objective:To investigate the efficacy and safety of ixazomib combined with thalidomide and dexamethasone in the treatment of multiple myeloma(MM).Methods:The clinical data of 60 MM patients admitted to our center from January 2019 to June 2022 were analyzed retrospectively,including 43 newly diagnosed patients and 17 patients with recurrence and progression.All patients were treated with ixazomib combined with thalidomide and dexamethasone,and completed 2 to 7 treatment cycles.Results:The overall response rate(ORR)of all patients was 98.3％.Among them,53 patients completed 4 treatment cycles,and the ORR was 86.8％.Seventeen patients completed the whole treatment cycle,with curative effect reaching 88.2％achieving very good partial response and above,and 52.9％achieving complete response and above.Albumin and β2-microglobulin of all patients had been improved rapidly after treatment.The deadline was August 31,2022.The median follow-up time was 14(3-24)months,and overall survival(OS)rate was 86.67％.The OS rate of patients with recurrence and progression was significantly lower than that of newly diagnosed patients(P＜0.05).The most common adverse reaction of hematology was lymphopenia(53.3％),followed by anemia(33.3％).The most common non-hematological adverse reaction was fatigue(68.33％),followed by peripheral neuropathy(31.67％).Conclusion:Ixazomib combined with thalidomide and dexamethasone is effective in the treatment of MM,with good short-term efficacy,survival and safety.However,its long-term efficacy needs further observation.

Aim To establish a gait analysis system based on DeepLabCut(DLC)algorithm for evaluating motor function in aged mice.Methods Based on DLC algorithm in deep learning technology,treadmill device and fully closed design were used in the system,including software and hardware.This system was applied to evaluate gait characteristics of mice due to aging un-der different movement modes.Correlation analysis was used to explore the effects of body weight and body length on gait indica-tors.Results This system realized the synchronous analysis of three-dimensional gait(lateral and ventral plane)of mice at specific gait speed,and automatically quantified 47 gait indica-tors.Using this system,it was found that during walking(15 cm·s-1),the standard deviation of body turning angle decreased,forelimb sway duration,standard deviation of knee angle,mean outward angles of left and right hind paw increased in 8 and 15 month-old mice,compared with 2-month-old mice.However,15-month-old mice showed decreased walking frequency,and in-creased stride width,total duration of double support,and knee extension and contraction distance.In addition,at trot(20 cm·s-1),15-month-old mice were unable to walk steadily,and 8-month-old mice had increased total duration of double support and mean outward angles of left hind paw,compared with 2-month-old mice.Correlation analysis revealed that indicators like walking frequency,stride width,forelimb sway duration,total duration of double support,standard deviation of knee an-gle,knee extension and contraction distance,were not affected by changes in body weight and body length.Conclusions The gait analysis system based on DLC algorithm can achieve a more sensitive,accurate and comprehensive evaluation of the gait of aged mice,distinguishing the gait characteristics of aged mice to maintain gait stability,and selecting behavioral indicators that better reflect the gait changes of aged mice.It provides a meth-odological basis for more effective assessment of efficacy and side effects of drugs for anti-aging and anti-decline of motor coordina-tion in the future.

Traditionally,the brain was considered as an immune-privileged organ.However,the re-discoveries of meningeal lymphatic vessels have revolutionized our understanding,revealing direct physical and functional connections between the central nervous system and the peripheral immunity.Meningeal lymphatic vessels play a crucial role in draining cerebro-spinal fluid,clearing metabolic waste from the brain,eliciting immune surveillance and maintaining immune homeostasis within the brain.They are implicated in the pathogenesis and progression of multiple central nervous system diseases.This review mainly focuses on the anatomical structure and physiological functions of meningeal lymphatic vessels,with brief introduction to their role in neurological diseases.We summarize recent research advances in meningeal lymphatic vessels,and provide insights for further research and clinical applications.