Sodium-dependent glucose transporter 2 inhibitors effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure

BACKGROUND Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have shown efficacy in reducing heart failure(HF)burden in a very heterogeneous groups of patients,raising doubts about some contemporary assumptions of their mechanism of action.We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy.Two groups of patients were included in the study:the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control.AIM To evaluate the outcomes regarding natriuretic peptide,oxidative stress,inflammation,blood pressure,heart rate,cardiac function,and body weight.METHODS The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain(GLS),N-terminal pro-brain natriuretic peptide,myeloperoxidase(MPO),high-sensitivity C-reactive protein(hsCRP),and systolic and diastolic blood pressure.To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up,a rise in stroke volume index,body mass index(BMI)decrease,and lack of heart rate increase,linear regression analysis was performed.RESULTS There was a greater reduction of MPO,hsCRP,GLS,and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up.Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI,while the predictor of stroke volume index increase was SGLT2i therapy itself.CONCLUSION SGLT2i affect body composition,reduce cardiac load,improve diastolic/systolic function,and attenuate the sympathetic response.Glycemic control contributes to the improvement of heart function,blood pressure control,oxidative stress,and reduction in inflammation.

Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus:A real-world experience

BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are a class of drugs with modest antidiabetic efficacy,weight loss effect,and cardiovascular benefits as proven by multiple randomised controlled trials(RCTs).However,real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse.AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data.METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs(dapagliflozin,canagliflozin,and empagliflozin)used for treating patients with type 2 diabetes mellitus.Data on the reduction of glycated hemoglobin(HbA1c),body weight,blood pressure(BP),urine albumin creatinine ratio(ACR),and adverse effects were recorded retrospectively.RESULTS Data from 467 patients with a median age of 64(14.8)years,294(62.96%)males and 375(80.5%)Caucasians were analysed.Median diabetes duration was 16.0(9.0)years,and the duration of SGLT-2i use was 3.6(2.1)years.SGLT-2i molecules used were dapagliflozin 10 mg(n=227;48.6%),canagliflozin 300 mg(n=160;34.3%),and empagliflozin 25 mg(n=80;17.1).Baseline median(interquartile range)HbA1c in mmol/mol were:dapagliflozin-78.0(25.3),canagliflozin-80.0(25.5),and empagliflozin-75.0(23.5)respectively.The respective median HbA1c reduction at 12 months and the latest review(just prior to the study)were:66.5(22.8)&69.0(24.0),67.0(16.3)&66.0(28.0),and 67.0(22.5)&66.5(25.8)respectively(P<0.001 for all comparisons from baseline).Significant improvements in body weight(in kilograms)from baseline to study end were noticed with dapagliflozin-101(29.5)to 92.2(25.6),and canagliflozin 100(28.3)to 95.3(27.5)only.Significant reductions in median systolic and diastolic BP,from 144(21)mmHg to 139(23)mmHg;(P=0.015),and from 82(16)mmHg to 78(19)mmHg;(P<0.001)respectively were also observed.A significant reduction of microalbuminuria was observed with canagliflozin only[ACR 14.6(42.6)at baseline to 8.9(23.7)at the study end;P=0.043].Adverse effects of SGLT-2i were as follows:genital thrush and urinary infection-20(8.8%)&17(7.5%)with dapagliflozin;9(5.6%)&5(3.13%)with canagliflozin;and 4(5%)&4(5%)with empagliflozin.Diabetic ketoacidosis was observed in 4(1.8%)with dapagliflozin and 1(0.63%)with canagliflozin.CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c,body weight,and better than those reported in RCTs,with low side effect profiles.A review of large-scale real-world data is needed to inform better clinical practice decision making.

Sodium-Glucose Cotransporter-2 Inhibitors: Who, When & How? Guidance for Use from a Multidisciplinary Practical Approach

Sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors) have transformed diabetes management by targeting renal glucose reabsorption. Designed initially as antidiabetic agents, their ability to lower blood glucose levels independently of insulin is well-documented. Beyond glycemic control, emerging research has unveiled their profound cardiorenal benefits. By inhibiting SGLT-2 protein, these drugs enhance glucose excretion in urine, reducing blood glucose levels. This mechanism has translated into significant cardiovascular and renal protection, establishing SGLT-2 inhibitors as pivotal in managing not only diabetes but also cardiovascular and renal diseases. Recent studies have illuminated the broader therapeutic potential of SGLT-2 inhibitors beyond diabetes. Evidence indicates their efficacy in managing heart failure, chronic kidney disease (CKD), and cardiovascular complications in individuals with or without diabetes. This expanded therapeutic landscape has catalyzed a paradigm shift in SGLT-2 inhibitor use, positioning them as key agents in the cardiorenal metabolic continuum. Moreover, their role in the secondary prevention of cardiovascular events and slowing CKD progression in T2DM patients has garnered considerable attention. This consensus-based review aims to offer practical guidance in an algorithmic approach to primary care healthcare professionals to optimize SGLT-2 inhibitors utilization and maximize their benefits. The review seeks to empower clinicians to effectively manage patients who may benefit from SGLT-2 inhibitor therapy by addressing common initiation barriers and optimizing treatment strategies. Additionally, it aims to raise awareness among primary care physicians regarding the multifaceted benefits of these medications and overcome clinical inertia in their adoption into routine clinical practice.

Sodium glucose cotransporter-2 inhibitors and heart disease:Current perspectives

Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are antidiabetic medications with remarkable cardiovascular(CV)benefits proven by multiple randomised controlled trials and real-world data.These drugs are also useful in the prevention of CV disease(CVD)in patients with diabetes mellitus(DM).Although DM as such is a huge risk factor for CVD,the CV benefits of SGLT-2i are not just because of antidiabetic effects.These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well.There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated.Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases.This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.

BET inhibitors potentiate melanoma ferroptosis and immunotherapy through AKR1C2 inhibition

Dear Editor,Ferroptosis,an iron-dependent form of cell death driven by overwhelming lipid peroxidation,represents a vulnerability in cancers,and therapeutic strategies to further potentiate ferroptosis hold great potential for melanoma treatment.

Effectiveness and mechanisms of sodium-dependent glucose transporter 2 inhibitors in type 2 diabetes and heart failure patients

We comment on an article by GrubićRotkvićet al published in the recent issue of the World Journal of Cardiology.We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent glucose transporter inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and their impact on comorbidities.SGLT2i inhibits SGLT2 in the proximal tubules of the kidneys,lowering blood glucose levels by inhibiting glucose reabsorption by the kidneys and causing excess glucose to be excreted in the urine.Previous studies have demonstrated a role of SGLT2i in cardiovascular function in patients with diabetes who take metformin but still have poor glycemic control.In addition,SGLT2i has been shown to be effective in anti-apoptosis,weight loss,and cardiovascular protection.Accordingly,it is feasible to treat patients with T2DM with cardiovascular or renal diseases using SGLT2i.

Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes:A systematic review with multiple network meta-regressions

BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.

In Silico Screening of Potential Inhibitors against dPLA2 from Named Chinese Herbs for Identification of Compounds with Antivenom Effects Due to Deinagkistrodon acutus Snake Bites

Phospholipase A2 (PLA2) is the key enzyme to the venom from Deinagkistrodon acutus which is one of the highly venomous snakes in China. In addition to being a catalyst for the hydrolysis of phospholipases A2 from snake venom, its well known that it possesses a broad spectrum of pharmacological activities, such as myotoxicity, neurotoxicity, cardiotoxicity, and hemolytic, anticoagulant and antiplatelet activities. However, snakebites are not efficiently treated by conventional serum therapy. Acute wounds can still cause poisoning and death. In order to find effective inhibitors of Deinagkistrodon venom acid phospholipase A2 (dPLA2), we obtained 385 compounds in 9 Chinese herbs from the TCMSP. These compounds were further performed to virtual screen using in silico tools like ADMET analysis, molecular docking and molecular dynamics (MD) simulation. After Pharmacokinetics analysis, we found 7 candidate compounds. Besides, analysis of small molecule interactions with dPLA2 confirmed that the amino acid residues HIS47 and GLY29 are key targets. Because they bind not only to the natural substrate phosphatidylcholine and compounds known for having inhibitory functions, but also for combining with potential antidote molecules in Chinese herbal medicine. This study is the first to report experience with virtual screening for possible inhibitor of dPLA2, such as the interaction spatial structure, binding energy and binding interaction analysis, these experiences not only provide reference for further experimental research, but also have a guideline for the study of drug molecular mechanism of action.

Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways:Experimental and clinical evidence

Mitochondrial dysfunction is a key driver of cardiovascular disease(CVD)in metabolic syndrome and diabetes.This dysfunction promotes the production of reactive oxygen species(ROS),which cause oxidative stress and inflammation.Angiotensin II,the main mediator of the renin-angiotensin-aldosterone system,also contributes to CVD by promoting ROS production.Reduced activity of sirtuins(SIRTs),a family of proteins that regulate cellular metabolism,also worsens oxidative stress.Reduction of energy production by mitochondria is a common feature of all metabolic disorders.High SIRT levels and 5’adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta,which promotes ketosis.Ketosis,in turn,increases autophagy and mitophagy,processes that clear cells of debris and protect against damage.Sodiumglucose cotransporter-2 inhibitors(SGLT2i),a class of drugs used to treat type 2 diabetes,have a beneficial effect on these mechanisms.Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events.SGLT2i also increase mitochondrial efficiency,reduce oxidative stress and inflammation,and strengthen tissues.These findings suggest that SGLT2i hold great potential for the treatment of CVD.Furthermore,they are proposed as anti-aging drugs;however,rigorous research is needed to validate these preliminary findings.

EGFR/ERK/MMP-2通路调控牙龈纤维化的初步研究

目的探讨表皮生长因子受体/细胞外信号调节激酶/基质金属蛋白酶-2(EGFR/ERK/MMP-2通路调控牙龈纤维化的作用机制。方法收集本院4例因畸形治疗的健康者和4例遗传性牙龈纤维瘤病(HGF)患者牙龈组织标本;苏木素-伊红(HE)染色检测牙龈组织的组织学变化情况;蛋白质免疫印迹检测牙龈组织中EGFR蛋白表达情况。体外培养人牙龈成纤维细胞(HGFs),并分为对照组、EGFR激动剂组、EGFR抑制剂组,EGFR激动剂组添加终浓度为10 ng/ml EGF,EGFR抑制剂组添加终浓度为10μmol/L AG1478,对照组添加10%胎牛血清的DMEM培养液培养细胞,处理48 h后,蛋白质免疫印迹检测细胞中EGFR、ERK1/2、p-ERK1/2、MMP-2蛋白水平;CCK-8法检测细胞增殖情况。结果HGF患者牙龈组织充满粗大的胶原纤维和成纤维细胞,血管偏少,结缔组织处出现轻微炎症。与健康者相比,HGF患者牙龈组织中EGFR蛋白水平升高(P<0.05)。在细胞实验中,与对照组相比,EGFR激动剂组细胞中EGFR、p-ERK1/2/ERK1/2、MMP-2蛋白水平及细胞增殖率升高(P<0.05),EGFR抑制剂组细胞中EGFR、p-ERK1/2/ERK1/2、MMP-2蛋白水平及细胞增殖率降低(P<0.05)。结论EGFR/ERK/MMP-2通路可能通过促进细胞增殖加强牙龈纤维化进程,抑制EGFR的表达从而缓解疾病。

血清CRP/Alb、MMP-2及MCP-1水平与结直肠癌患者腹腔镜根治术后吻合口瘘的关系及其预测价值分析

目的:探究血清C反应蛋白(CRP)/清蛋白(Alb)、基质金属蛋白酶-2(MMP-2)及单核细胞趋化蛋白-1(MCP-1)水平与结直肠癌患者腹腔镜根治术(LRS)后吻合口瘘的关系及其预测价值。方法:纳入2019年2月—2022年10月于我院接受LRS治疗后发生吻合口瘘的41例结直肠癌患者作为观察组。另取同期接受LRS治疗后未发生吻合口瘘的40例结直肠癌患者作为对照组。采用单因素及多因素Logistic回归分析影响结直肠癌患者LRS后吻合口瘘的因素,采用受试者工作特征(ROC)曲线分析各因子预测结直肠癌患者LRS后吻合口瘘的效能。结果:单因素分析发现,血清CRP/Alb、MMP-2及MCP-1水平与结直肠癌患者LRS后吻合口瘘有关(均P<0.05)。经多因素Logistic回归分析发现:血清CRP/Alb、MMP-2及MCP-1水平升高均是结直肠癌患者LRS后吻合口瘘的危险因素(均P<0.05)。经ROC曲线分析发现:血清CRP/Alb、MMP-2及MCP-1水平联合(Log P模型)预测结直肠癌患者LRS后吻合口瘘的效能优于上述三项指标单独预测,曲线下面积(AUC)(0.95CI)为0.863(0.783~0.920)。结论:血清CRP/Alb、MMP-2及MCP-1水平与结直肠癌患者LRS后吻合口瘘密切相关,可作为预测吻合口瘘的辅助指标,且CRP/Alb、MMP-2及MCP-1联合预测价值更高。

The bumpy road of purinergic inhibitors to clinical application in immune-mediated diseases

Purinergic signaling plays important roles throughout the body in the regulation of organ functions during and following the disruption of homeostasis.This is also reflected by the widespread expression of two families of purinergic receptors(P1 and P2)with numerous subtypes.In the last few decades,there has been increasing evidence that purinergic signaling plays an important role in the regulation of immune functions.Mainly,signals mediated by P2 receptors have been shown to contribute to immune system-mediated pathologies.Thus,interference with P2 receptors may be a promising strategy for the modulation of immune responses.Although only a few clinical studies have been conducted in isolated entities with limited success,preclinical work suggests that the use of P2 receptor inhibitors may bear some promise in various autoimmune diseases.Despite the association of P2 receptors with several disorders from this field,the use of P2 receptor antagonists in clinical therapy is still very scarce.In this narrative review,we briefly review the involvement of the purinergic system in immunological responses and clinical studies on the effect of purinergic inhibition on autoimmune processes.We then open the aperture a bit and show some preclinical studies demonstrating a potential effect of purinergic blockade on autoimmune events.Using suramin,a non-specific purinergic inhibitor,as an example,we further show that off-target effects could be responsible for observed effects in immunological settings,which may have interesting implications.Overall,we believe that it is worthwhile to further investigate this hitherto underexplored area.

High-throughput computational screening and in vitro evaluation identifies 5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione(C3),as a novel EGFR—HER2 dual inhibitor in gastric tumors

Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations.Hence,dual inhibition strategies are recommended to increase potency and reduce cytotoxicity.In this study,we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities.Diversity-based High-throughput Virtual Screening(D-HTVS)was used to screen the whole ChemBridge small molecular library against EGFR and HER2.The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes.EGFR/HER2 kinase enzymes,KATOIII,and Snu-5 cells were used for in vitro validations.The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules,identified compound C3(5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione)to have a good affinity for both EGFR and HER2.The predicted compound,C3,was promising with better binding energy,good binding pose,and optimum interactions with the EGFR and HER2 residues.C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM,respectively.The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM,respectively.Based on these findings,we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase,and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects,though testing in higher models with pharmacokinetic approach is required.

Long noncoding RNAs HAND2-AS1 ultrasound microbubbles suppress hepatocellular carcinoma progression by regulating the miR-873-5p/tissue inhibitor of matrix metalloproteinase-2 axis

BACKGROUND Increasing data indicated that long noncoding RNAs(lncRNAs)were directly or indirectly involved in the occurrence and development of tumors,including hepatocellular carcinoma(HCC).Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues,but its role in HCC progression is unclear.Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes.AIM To study the role of ultrasound microbubbles(UTMBs)mediated HAND2-AS1 in the progression of HCC,in order to provide a new reference for the treatment of HCC.METHODS In vitro,we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs,and detected cell proliferation,apoptosis,invasion and epithelial-mesenchymal transition(EMT)by cell counting kit-8 assay,flow cytometry,Transwell invasion assay and Western blotting,respectively.In addition,we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior.Next,the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2(TIMP2)overexpression vector,and we detected cell proliferation,apoptosis,invasion and EMT.In vivo,we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability.RESULTS We found that UTMBs carrying HAND2-AS1 restricted cell proliferation,invasion,and EMT,encouraged apoptosis,and HAND2-AS1 silencing eliminated the effect of UTMBs.Additionally,miR-873-5p targets the gene HAND2-AS1,which also targets the 3’UTR of TIMP2.And miR-873-5p mimic counteracted the impact of HAND2-AS1.Further,miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs.We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase(MMP)2/MMP9.In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice.CONCLUSION LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.

Sodium-glucose Cotransporter-2 Inhibitors induced euglycemic diabetic ketoacidosis:A meta summary of case reports

BACKGROUND Sodium-glucose cotransporter-2 inhibitors(SGLT2i)are commonly prescribed to manage patients with diabetes mellitus.These agents may rarely lead to the development of euglycemic diabetic ketoacidosis(EDKA),which may complicate the disease course of these patients.AIM To analyze the demographic profile,predisposing factors,symptomology,clinical interventions and outcomes of patients presenting with EDKA secondary to SGLT2i use by reviewing the published case reports and series.METHODS We performed a systematic search of PubMed,Science Direct,Google Scholar and Reference Citation Analysis databases using the terms“canagliflozin”OR“empagliflozin”OR“dapagliflozin”OR“SGLT2 inhibitors”OR“Sodium-glucose cotransporter-2”AND“euglycemia”OR“euglycemic diabetic ketoacidosis”OR“metabolic acidosis”.The inclusion criteria were:(1)Case reports or case series with individual patient details;and(2)Reported EDKA secondary to SGLT2i.Furthermore,the data were filtered from the literature published in the English language and on adults(>18 years).We excluded:(1)Conference abstracts;and(2)Case reports or series which did not have individual biochemical data.All the case reports and case series were evaluated.The data extracted included patient demographics,clinical symptomatology,clinical interventions,intensive care unit course,need for organ support and outcomes.RESULTS Overall,108 case reports and 17 cases series with 169 unique patients that met all the inclusion criteria were included.The majority of patients were females(54.4%,n=92),and the commonly reported symptoms were gastrointestinal(nausea/vomiting 65.1%,abdominal pain 37.3%)and respiratory(breathlessness 30.8%).One hundred and forty-nine(88.2%)patients had underlying type II diabetes,and the most commonly involved SGLT-2 inhibitor reported was empagliflozin(46.8%).A triggering factor was reported in most patients(78.7%),the commonest being acute severe infection(37.9%),which included patients with sepsis,coronavirus disease 2019,other viral illnesses,and acute pancreatitis.61.5%were reported to require intensive unit care,but only a minority of patients required organ support in the form of invasive mechanical ventilation(13%),vasopressors(6.5%)or renal replacement therapy(5.9%).The overall mortality rate was only 2.4%.CONCLUSION Patients on SGLT2i may rarely develop EDKA,especially in the presence of certain predisposing factors,including severe acute infections and following major surgery.The signs and symptoms of EDKA may be similar to that of DKA but with normal blood sugar levels,which may make the diagnosis challenging.Outcomes of EDKA are good if recognized early and corrective actions are taken.Hence,physicians managing such patients must be aware of this potential complication and must educate their patients accordingly to ensure early diagnosis and management.

LuminalB型乳腺癌原发灶和同侧腋窝淋巴结转移灶中CD147和MMP-2的表达差异及其临床意义

研究细胞外基质金属蛋白酶诱导因子(CD147)和基质金属蛋白酶-2(MMP-2)在luminal B型乳腺癌原发灶和同侧腋窝淋巴结转移灶中的表达差异及其临床意义,探讨CD147及MMP-2在该分型乳腺癌的表达与预后的关系。方法 提取luminal B型的乳腺癌数据,分别对CD147及MMP2进行单基因分析。选取了2013年06月至2018年01月在贵州医科大学附属医院乳腺外科的67名接受手术治疗的女性luminai B型乳腺癌患者。检测其中原发灶与淋巴结转移灶的雌激素受体(ER)、孕酮受体(PR)、人表皮生长因子受体2(HER-2)、Ki-67、CD147和MMP-2的表达。电话随访调查其生存情况。结果 1相关性分析结果表明,MMP-2在淋巴结转移灶中的表达差异与临床分期有关(p<0.05),但与年龄、家族遗传史和肿瘤大小无关(p>0.05);CD147和MMP-2在原发灶和腋窝淋巴结中的表达被分为四个亚组进行分析,CD147和MMP-2的OS(overall survival)总体差异具有统计学意义(p<0.05)。

唾液CA-Ⅵ、MMP-2、CCL28与儿童龋病严重程度关系及预测龋病复发价值

目的:探讨唾液碳酸酐酶Ⅵ(Carbonic anhydraseⅥ,CA-Ⅵ)、基质金属蛋白酶-2(Matrix metalloproteinase2,MMP-2)、CC趋化因子配体28(CC chemokine ligand 28,CCL28)水平在判断儿童龋病病情及预测龋病复发中的应用效果。方法:选取2019年4月至2022年4月我院收治且均完成1 y随访的86例龋病者为研究对象。根据龋失补指数(decay missing fill index,DMFT)将患者分为低龋组(39例,DMFT=1~4)和高龋组(47例,DMFT≥5)。根据治疗后1 y复发情况将患者分为复发(24例)和未复发(62例)。比较低龋组和高龋组入院时唾液CA-Ⅵ、MMP-2、CCL28水平及与DMFT的相关性;比较复发、未复发患者唾液CA-Ⅵ、MMP-2、CCL28水平。分析CA-Ⅵ、MMP-2、CCL28水平对龋病复发的危险度。分析CA-Ⅵ、MMP-2、CCL28水平预测龋病复发的价值。结果:入院时高龋组唾液CA-Ⅵ水平低于低龋组,与DMFT呈负相关;高龋组唾液MMP-2、CCL28水平高于低龋组,与DMFT呈正相关(P<0.05)。入院时、治疗后1 m时复发者唾液CA-Ⅵ水平均明显低于未复发者,MMP2、CCL28水平均明显高于未复发者(P<0.05)。CA-Ⅵ、MMP-2、CCL28水平联合预测龋病复发AUC为0.808,最佳敏感度、特异度分别为91.67%、77.42%。结论:唾液CA-VI、MMP-2、CCL28水平的变化对儿童龋病病情判断提供参考依据,对预后评估具有重要意义。

CD147、MMP-2在胃癌组织中的表达及临床意义

目的 研究胃癌组织中CD147、MMP-2的表达,并分析其与胃癌病理特征的关系.方法 制备组织芯片,采用免疫组织化学法和原位杂交技术分别检测CD147、MMP-2在170例胃癌组织和30例正常胃黏膜组织中的表达情况.结果 CD147、MMP-2蛋白在胃癌组织的阳性表达率为72.9%和77.1%;CD147、MMP-2 mRNA在胃癌组织中阳性表达率为68.8%和74.7%,均明显高于在正常胃黏膜组织(P<0.05).CD147、MMP-2蛋白和CD147、MMP-2 mRNA与胃癌分化程度无关,但与肿瘤浸润程度、淋巴结转移、临床分期有关(P<0.05).胃癌组织中CD147、MMP-2蛋白和CD147、MMP-2 mRNA的阳性表达,分别具有显著正相关性(P<0.05).结论 检测胃癌组织中CD147、MMP-2的表达,可预估胃癌的浸润和转移,对抗肿瘤综合治疗和预后评估具有重要意义.

原发性高血压患者血清sST2、MMP-3和Gal-3水平及其与左心室重塑的相关性研究

探讨原发性高血压患者血清可溶性ST2(sST2)、基质金属蛋白酶(MMP-3)及半乳糖凝集素-3(Gal-3)水平及其与左心室重塑的相关性。选择2019年11月—2021年12月在桂林市人民医院接受治疗的136例原发性高血压患者为研究对象,评估患者左心室质量指数(LVMI)。将136例原发性高血压患者分为伴左心室肥厚与不伴左心室肥厚,其中伴左心室肥厚52例,纳入观察组;不伴左心室肥厚84例,纳入对照组。重点分析患者血清sST2、MMP-3和Gal-3水平,以及血清sST2、MMP-3和Gal-3水平与左心室重塑的相关性。结果显示,观察组血清sST2、MMP-3和Gal-3水平均高于对照组,差异有统计学意义(P<0.05)。研究发现,原发性高血压患者血清sST2、MMP-3和Gal-3水平与左心室重塑有关,血清sST2、MMP-3和Gal-3水平过表达会增加LVMI的风险,检测各项指标水平有助于为临床准确诊断左心室重塑提供重要参考和指导价值。

dbSCI:A manually curated database of SARS-CoV-2 inhibitors for COVID-19

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the pathogen of the ongoing coronavirus disease 2019(COVID-19)global pandemic.Here,by centralizing published cell-based experiments,clinical trials,and virtual drug screening data from the NCBI PubMed database,we developed a database of SARS-CoV-2 inhibitors for COVID-19,dbSCI,which includes 234 SARS-CoV-2 inhibitors collected from publications based on cell-based experiments,81 drugs of COVID-19 in clinical trials and 1305 potential SARS-CoV-2 inhibitors from bioinformatics analyses.dbSCI provides four major functions:(1)search the drug target or its inhibitor for SARS-CoV-2,(2)browse target/inhibitor information collected from cell experiments,clinical trials,and virtual drug screenings,(3)download,and(4)submit data.Each entry in dbSCI contains 18 types of information,including inhibitor/drug name,targeting protein,mechanism of inhibition,experimental technique,experimental sample type,and reference information.In summary,dbSCI provides a relatively comprehensive,credible repository for inhibitors/drugs against SARS-CoV-2 and their potential targeting mechanisms and it will be valuable for further studies to control COVID-19.