Sodium-glucose co-transporter protein 2 inhibitor(SGLT2i)has steadily demonstrated benefits in the treatment of type 2 diabetes complicated with cardiovascular diseases based on evidence-based medicine,but its precise mechanism is yet unknown.We identified type 2 diabetes patients with HFpEF by searching PubMed,Web of Science,China knowledge network(CNKI),and other databases.We then summarized the pathological mechanism of HFpEF caused by type 2 diabetes.At the same time,to link to evidence-based medical,we explored the future of SGLT2i in clinical application.

A case of spinal cord abscess caused by Nocardia cyriacigeorgica is reported. The patient is an elderly man with a history of nephritic syndrome who presented with aggravating lower back pain and then gradually developed urinary retention, weakness and numbness in both lower extremities. Operative intervention was performed, and postoperative pathological findings suggested spinal cord abscess formation. Metagenomic next-generation sequencing of the cerebrospinal fluid identified Nocardia cyriacigeorgica as the causative pathogen. Although appropriate antibiotics were prescribed, the patient died 3 months later.

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

The breakage pattern of unit particles during the production of oral solid dosage forms (OSD) is closely related to the quality of intermediate or final products. To accurately characterize the particles and study the evolution law of particle breakage, the Bonding model of the discrete element method (DEM) was used to investigate the breakage patterns of model parameters, particle shape and process conditions (loading mode and loading rate) on the dynamic breakage, force-time curve, breakage rate, maximum breakage size ratio and fracture strength of particles. The results showed that the particle breakage force was positively correlated with normal strength and bonded disk scale, negatively correlated with normal stiffness per unit area and tangential stiffness per unit area, and weakly correlated with tangential strength. The particle breakage rate was negatively correlated with the aspect ratio of the particles, and the maximum breakage size ratio was positively correlated with the aspect ratio of the particles; among the three loading modes, the breakage rate of compression breakage model was the largest, the breakage rate of shear breakage model was the second largest, and the breakage rate of wear breakage model was the smallest; the maximum breakage size ratio was positively correlated with the loading rate, the loading mode and the loading rate had no mutual influence on particle breakage rate, but had mutual influence on the maximum breakage size ratio. The research results will provide a theoretical basis for the shift of OSD from batch manufacturing to advanced manufacturing.

AIM:Bone morphogenetic protein 7(BMP7)reduces the expression of Yes-related protein 1(YAP1)by down-regulating Ajuba level and decreasing extracellular matrix(ECM)deposition.This study aimed to inves-tigate the influence of these factors on modifying the degree of renal fibrosis in rats with diabetic nephropathy.METH-ODS:Eighteen Sprague-Dawley(SD)rats were randomly divided into three groups:the normal control(NC)group,the diabetes mellitus(DM)group,and the DM group treated with BMP7 overexpressing adeno-associated virus(DM+rAAV-BMP7).Each group consisted of six rats.Diabetic kidney disease(DKD)was established in the DM and DM+rAAV-BMP7 groups by injecting 55 mg/kg streptozotocin(STZ)via the tail vein.NRK-52E cells were divided into three groups:the normal glucose(NG)group,the high glucose(HG)group,and the high glucose group treated with recombinant hu-man BMP7(HG+rhBMP7)group.Pathological changes in renal tissues were observed using hematoxylin and eosin(HE)and Sirius red staining.Immunohistochemical staining was performed to examine the expression sites of Ajuba and YAP1 in the renal cortex.Western blot analysis was conducted to determine the expression levels of BMP7,Ajuba,YAP1,colla-gen type Ⅲ(Col-Ⅲ),and fibronectin(FN)in the rat renal cortex and NRK-52E cells.RT-qPCR was used to measure the mRNA levels of Ajuba and YAP1 in the rat renal cortex.RESULTS:Biochemical indices revealed significantly ele-vated levels of blood glucose,serum creatinine,triglycerides,total cholesterol,and 24-hour urinary protein in the DM group compared to the NC group(P<0.05).In the DM+rAAV-BMP7 group,the levels of serum creatinine,24-hour uri-nary protein,triglycerides,and total cholesterol were lower than those in the DM group(P<0.05).Pathological staining demonstrated that the renal interstitium of the DM group exhibited inflammatory cell infiltration,fibrous tissue,collagen fi-ber deposition,disordered renal tubule arrangement,atrophy,and vacuolar degeneration,which were ameliorated in the DM+rAAV-BMP7 group.Immunohistochemistry revealed that Ajuba and YAP1 were mainly expressed in the cytoplasm and nucleus,with high expression in the cytoplasm of the DM group,which was significantly decreased in the DM+rAAV-BMP7 group.Western blot results indicated that the protein levels of FN,Col-Ⅲ,Ajuba,and YAP1 were up-regulated in the DM and the HG groups(P<0.05),but significantly down-regulated in the DM+rAAV-BMP7 group(P<0.05).RT-qP-CR results demonstrated that the mRNA levels of Ajuba and YAP1 were higher in the DM group and significantly lower in the DM+rAAV-BMP7 group(P<0.05).CONCLUSION:The overexpression of BMP7 can ameliorate renal fibrosis in rats with DKD.This effect is likely mediated by the down-regulation of Ajuba,reduction of YAP1 expression,and subse-quent inhibition of ECM deposition.

Objective:Osteosarcoma is the most common malignant bone tumor in children and adolescents,characterized by a high potential for proliferation and metastasis.Patients with osteosarcoma who have distant metastases generally have a poor prognosis.Challenges in treatment include incomplete resection of tumor and chemotherapy resistance,with no effective cure currently available.Recent studies suggest that β-1,4-N-acetyl-galactosaminyltransferase 1(B4GALNT1)plays a role in the progression of various malignant tumors.However,the function of B4GALNT1 in osteosarcoma cells has not been reported.This study aims to investigate the expression of B4GALNT1 in osteosarcoma tissues compared to normal tissues and to explore its effects on the proliferation,migration,and invasion of osteosarcoma cells,thereby providing new theoretical foundations and directions for the treatment of osteosarcoma patients. Methods:Tumor tissues and corresponding normal tissue samples were collected from 16 osteosarcoma patients who underwent tumor resection at the Second Xiangya Hospital of Central South University.The patients'ages ranged from 8 to 17 years(median age 12 years).The expression of B4GALNT1 mRNA in osteosarcoma tissues,corresponding normal tissues,3 osteosarcoma cell lines(MG63,Saos-2,and U2OS),and human fetal osteoblastic cells(hFOB)was detected using real-time reverse transcription PCR(real-time RT-PCR).The effects of B4GALNT1 knockdown on the proliferation of osteosarcoma cells Saos-2 and U2OS were analyzed using cell counting kit-8(CCK-8)assays and colony formation assays.The effects of B4GALNT1 knockdown on the migration and invasion abilities of Saos-2 and U2OS cells were evaluated using Transwell migration and invasion assays.Western blotting analysis was performed to assess the impact of B4GALNT1 knockdown on the expression of epithelial-mesenchymal transition(EMT)and invasion-related proteins in Saos-2 and U2OS cells. Results:Real-time RT-PCR results showed that B4GALNT1 mRNA expression levels were significantly higher in osteosarcoma tissues and the 3 osteosarcoma cell lines compared to normal tissues and hFOB cells(all P＜0.0 1).CCK-8 and colony formation assays indicated that B4GALNT1 knockdown significantly reduced the proliferation rate of osteosarcoma cells compared to the control group(all P＜0.05).Transwell migration and invasion assays demonstrated that B4GALNT1 knockdown significantly decreased the number of migrating and invading osteosarcoma cells(all P＜0.01).Western blotting analysis revealed that B4GALNT1 knockdown inhibited the expression of N-cadherin,Snail,Vimentin,and matrix metalloproteinase 9(MMP9)compared to the control group(all P＜0.01). Conclusion:B4GALNT1 is upregulated in osteosarcoma tissues and cell lines,and its knockdown suppresses the malignant phenotype of osteosarcoma cells.B4GALNT1 may function as an oncogene in the proliferation and metastasis of osteosarcoma cells.

Objective To investigate the effect and mechanism of endothelin-1(ET-1)on atrial fibrosis in Atrial fibrillation(AF)rats.Methods Fourteen adult male SD rats were randomly divided into normal control(NC)group and Atrial fibrillation(AF)group.The rat model of Atrial fibrillation was established by injecting 0.1 ml/100g CaCl2-Ach mixture into the tail vein once a day for one week.The control group was injected with the same dose of normal saline.An electrocardiogram of normal or atrial fibrillation was recorded on the first day and the eighth day in each group,and echocardiography was used to monitor atrial size and cardiac function.The fibrosis of atrial was observed using Masson and HE staining.The expression of endothelin-1(ET-1),collagen-I(Col-I),transforming growth factor-β(TGF-β)and the store operated calcium channel(SOCC)protein Orai1,stromal in-teraction molecule 1(STIM1)in atrial tissue were detected by Western blot.HL-1 cells were cultured and treated with gradient concentration of ET-1 for 24 hours.Western blot was used to observe changes in the expression of TGF-β,Orai1 and STIM1 proteins in ET-1/SOCC/TGF-β signaling pathway of HL-1 cells.Small interfering RNA(siRNA)transfection method was used to knock down the expression of Orai1 in HL-1 cells,then the cells were treated with appropriate concentrations of ET-1 for 24 hours,and the expression of TGF-β protein in HL-1 cells was detected by Western blot.Results Compared with the control group,echocardiography showed a significant in-crease in left atrial diameter(LAD)of the heart in atrial fibrillation rats(P<0.05).The HE and Masson staining results showed significant fibrosis in the myocardial tissue of AF group rats(P<0.05),and the Western blot re-sults indicated the expression of ET-1,Orai1,STIM1,TGF-β and COL-Ⅰ in the myocardial tissue of AF group significantly increased compared to the NC group(P<0.05).After ET-1 treatment of HL-1 cells,the protein ex-pression of Orai1,STIM1and TGF-β increased(P<0.05),while knocking down Orai1 in HL-1 cells,ET-1 treat-ment no longer caused the expression of TGF-β a significant upregulation.Conclusion AF caused by atrial fibril-lation results in a significant increase in ET-1 expression in atrial tissue,and ET-1/SOCC/TGF-β signal pathway promotes atrial fibrillation and fibrosis.

Berberine is an antipyretic and detoxicating drug commonly used in clinical practice,and it is currently used for the routine treatment of gastrointestinal diseases such as bacterial gastroenteritis and diarrhea.However,several recent studies have shown that berberine can exert a therapeutic effect on the diseases such as autoimmune hepatitis,viral hepatitis,nonalcoholic fatty liver disease,and liver cancer by regulating the AMPK and TGF-β pathways and altering the composition of intestinal flora.This provides new drugs for the treatment of these diseases,expands the potential indications of berberine,and provides clues for the follow-up research and development of similar drugs.This article summarizes the therapeutic effect and mechanism of berberine on various liver diseases,in order to provide a reference for effective clinical application.

Objective To observe and analyze the influence of the improved ultra-low temperature storage box on the quality of fresh frozen plasma(FFP).Methods A total of 80 qualified whole blood samples(400 mL,O type not includ-ed)collected from July to November in 2023 were selected,and were divided into 4 groups,with 20 samples in each group.Group A:quick-frozen in a traditional low temperature box for 1 hour and then stored in a-30℃cold storage;Group B:quick-frozen in the flat freezer for 1 hour and then stored in a-30℃cold storage;Group C:quick-frozen in a newly im-proved ultra-low temperature storage box for 1 hour and stored in a-30℃cold storage;Group D:quick-frozen in a new im-proved ultra-low temperature storage box for 12 hours and stored in a-30℃cold storage.The contents of FⅧand fibrinogen(Fg)in four groups were detected.Results The contents of FⅧin group B,C and D were significantly higher than those in group A,with statistical difference(P＜0.05),but with no statistical difference among gourp B,C and D(P＞0.05),and no statistical difference in the contents of Fg was found among the four groups(P＞0.05).Conclusion The improved ultra-low temperature storage box is superior to the traditional low temperature box in preparing FFP,and there is no obvious difference between the improved ultra-low temperature storage box and the flat-plate quick freezer.However,the improved ultra-low temperature storage box can make the process of preparing FFP more flexible and improve the efficiency of compo-nent preparation.

Objective To study the common basis and association between sickness behaviour and occurrence of classical symptoms of kidney yang deficiency of rats with adriamycin nephropathy.Methods The SD rats were given adriamycin by tail-vein injection for 2 times(4.0 and 3.5 mg·kg-1,one week apart)to construct the model of nephrotic syndrome with Chinese medicine symptom of kidney yang deficiency.After successful modeling,the model rats were randomly divided into adriamycin group(ADR group),corticosterone group(CORT group)and hydrocortisone group(HYD group),with 12 rats per group;another 12 normal rats were taken as normal group.In the HYD group,25 mg·kg-1·d-1 HYD was administered for 14 d to establish kidney yang deficiency model with simple hypothalamus-pituitary-adrenal cortex(HPA)axis inhibition.CORT group was adding 25 μg·mL-1 corticosterone to the water for 6 weeks,and the others drinking water supplied.The levels of urinary 17-hydroxy steroid were measured by enzyme linked immunosorbent assay.Glucocorticoid receptor(GR)and nuclear factor-kappa B(NF-κB)protein expression levels in kidney and hypothalamus were detected by Western blotting.Results In the normal,ADR,CORT and HYD groups,the urinary 17-hydroxysteroid levels were(19.14±1.94),(10.07±1.62),(20.30±1.55)and(14.23±2.37)μg·L-1;the relative expression levels of GR protein in hypothalamic were 0.63±0.05,0.11±0.05,0.85±0.08 and 0.35±0.06;the relative expression levels of NF-κB protein in hypothalamic were 0.06±0.03,0.96±0.03,0.59±0.01 and 0.23±0.04;the relative expression levels of GR protein in kidney tissue were 0.94±0.06,0.06±0.02,0.40±0.02 and 0.09±0.08;the relative expression levels of NF-κB protein in kidney tissue were 0.07±0.05,0.81±0.12,0.72±0.07 and 0.49±0.08,respectively.Compared with the ADR and HYD groups,the above indexes in the normal group were statistically significant(P＜0.05,P＜0.01).And compared with the ADR group,the relative expression levels of NF-κB protein in renal tissue with CORT group were not statistically significant(P＞0.05),but the other indexes in CORT group were statistically significant(all P＜0.01).Conclusion HPA axis dysfunction with GR damaged and activated inflammatory levels are the common basis for the combination of typical symptoms of kidney yang deficiency and sickness behaviour which characterised by"deficiency and cold syndrome".