ObjectiveTo explore the role and potential mechanism of circulating glutamate in enhancing insulin sensitivity by aerobic exercise. This research may provide a novel strategy for preventing metabolic diseases through precise exercise interventions. MethodsTo investigate the effects of elevated circulating glutamate on insulin sensitivity and its potential mechanisms, 18 male C57BL/6 mice aged 6 to 8 weeks were randomly divided into 3 groups: a control group (C), a group receiving 500 mg/kg glutamate supplementation (M), and a group receiving 1 000 mg/kg glutamate supplementation (H). The intervention lasted for 12 weeks, with treatments administered 6 d per week. Following the intervention, an insulin tolerance test (ITT) and a glucose tolerance test (GTT) were conducted. Circulating glutamate levels were measured using a commercial kit, and the activity of the skeletal muscle InsR/IRS1/PI3K/AKT signaling pathway was analyzed via Western blot. To further investigate the role of circulating glutamate in enhancing insulin sensitivity through aerobic exercise, 30 male C57BL/6 mice were randomly assigned to 3 groups: a control group (CS), an exercise intervention group (ES), and an exercise combined with glutamate supplementation group (EG). The ES group underwent treadmill-based aerobic exercise, while the EG group received glutamate supplementation at a dosage of 1 000 mg/kg in addition to aerobic exercise. The intervention lasted for 10 weeks, with sessions occurring 6 d per week, and the same procedures were followed afterward. To further elucidate the mechanism by which glutamate modulates the InsR/IRS1/PI3K/AKT signaling pathway, C2C12 myotubes were initially subjected to graded glutamate treatment (0, 0.5, 1, 3, 5, 10 mmol/L) to determine the optimal concentration for cellular intervention. Subsequently, the cells were divided into 3 groups: a control group (C), a glutamate intervention group (G), and a glutamate combined with MK801 (an NMDA receptor antagonist) intervention group (GK). The G group was treated with 5 mmol/L glutamate, while the GK group received 50 μmol/L MK801 in addition to 5 mmol/L glutamate. After 24 h of intervention, the activity of the InsR/IRS1/PI3K/AKT signaling pathway was analyzed using Western blot. ResultsCompared to the mice in group C, the circulating glutamate levels, the area under curve (AUC) of ITT, and the AUC of GTT in the mice of group H were significantly increased. Additionally, the expression levels of p-InsRβ, IRS1, p-AKT, and p-mTOR proteins in skeletal muscle were significantly downregulated. Compared to the mice in group CS, the circulating glutamate levels, the AUC of ITT, and the AUC of GTT in the mice of group ES were significantly reduced. Additionally, the expression levels of p-InsRβ, IRS1, p-AKT, and p-mTOR proteins in skeletal muscle of group ES mice were significantly upregulated. There were no significant changes observed in the mice of group EG. Compared to the cells in group 0 mmol/L, the expression levels of p-InsRβ, p-IRS1, p-PI3K, and p-AKT proteins in cells of group 5 mmol/L were significantly downregulated. Compared to the cells in group C, the expression levels of p-InsRβ, p-IRS1, p-PI3K, and p-AKT proteins in the cells of group G were significantly downregulated. No significant changes were observed in the cells of group GK. ConclusionLong-term aerobic exercise can improve insulin sensitivity by lowering circulating levels of glutamate. This effect may be associated with the upregulation of the InsR/IRS1/AKT signaling pathway activity in skeletal muscle. Furthermore, glutamate can weaken the activity of the InsR/IRS1/PI3K/AKT signaling pathway in skeletal muscle, potentially by binding to NMDAR expressed in skeletal muscle.

The angiogenic response is essential for the repair of ischemic brain tissue. Integrin α6 (Itga6) expression has been shown to increase under hypoxic conditions and is expressed exclusively in vascular structures; however, its role in post-ischemic angiogenesis remains poorly understood. In this study, we demonstrate that mice with endothelial cell-specific knockout of Itga6 exhibit reduced neovascularization, reduced pericyte coverage on microvessels, and accelerated breakdown of microvascular integrity in the peri-infarct area. In vitro, endothelial cells with ITGA6 knockdown display reduced proliferation, migration, and tube-formation. Mechanistically, we demonstrated that ITGA6 regulates post-stroke angiogenesis through the PI3K/Akt-eNOS-VEGFA axis. Importantly, the specific overexpression of Itga6 in endothelial cells significantly enhanced neovascularization and enhanced the integrity of microvessels, leading to improved functional recovery. Our results suggest that endothelial cell Itga6 plays a crucial role in key steps of post-stroke angiogenesis, and may represent a promising therapeutic target for promoting recovery after stroke.
Animals ; Nitric Oxide Synthase Type III/metabolism* ; Mice ; Proto-Oncogene Proteins c-akt/metabolism* ; Integrin alpha6/genetics* ; Endothelial Cells/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Stroke/pathology* ; Vascular Remodeling/physiology* ; Vascular Endothelial Growth Factor A/metabolism* ; Mice, Knockout ; Signal Transduction/physiology* ; Mice, Inbred C57BL ; Male ; Neovascularization, Physiologic/physiology*

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.

Objective:To observe the clinical efficacy and safety of venetoclax(VEN)combined with azacitidine(AZA)in the treatment of adult acute myeloid leukemia(AML)patients who are unfit for intensive chemotherapy.Methods:The clinical data of 21 adult patients with unfit AML who were treated with VEN combined with AZA in the Second Hospital of Shanxi Medical University from January 2021 to May 2022 were collected,and the efficacy and safety were analyzed retrospectively.Results:After one course of treatment with VEN and AZA,16 out of 21 unfit AML patients reached complete remission(CR)/CR with incomplete hematologic recovery(CRi),2 patients reached partial remission(PR),the overall response rate(ORR)was 85.7％.Among the 16 patients with CR/CRi,13 achieved minimal residual disease(MRD)negativity.Among the 11 patients with adverse prognosis,8 achieved CR/CRi.By the deadline of follow-up,the median overall suivival(OS)of the entire cohort was not reached,with 1-year OS rate of 61.7％.The main adverse events of VEN combined with AZA were myelosuppression,gastrointestinal reactions and infections.There were 13 cases of leukopenia,7 cases of neutropenia,7 cases of anemia,4 cases of thrombocytopenia,and these hematologic adverse events were all grade 3-4.There were 11 cases with gastrointestinal reactions and 7 cases with infections.The above adverse events were controllable and tolerable.No tumor lysis syndrome or infection related death occurred.Conclusion:VEN combined with AZA can quickly achieve deep remission in adult patients with unfit AML,and it shows a good safety profile.

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

CAT3 is a promising anti-brain tumor agent that has significant anti-tumor activity on Daoy or U87MG orthotopic xenograft in nude mice. This study was carried out to investigate the metabolic profiles of CAT3 in mouse/dog/human blood and microsome as well as in humanized recombinant enzymes. All animal care and experimental procedures were reviewed and approved by the Animal Ethics Committee of Chinese Academy of Medical Sciences. Our findings showed that CAT3 could be hydrolyzed to active metabolite PF403 by carboxylesterase, butyrylcholinesterase and serine hydrolase in mouse/dog/ human blood. PF403 could be further metabolized to M1 oxidative dehydration product, M2 double oxidation dehydration product, M3 methylation oxidative dehydration product, M4 oxidation product and M5 demethylation product, which were mainly catalyzed by CYP1A2, 1A1, 2C9 and 3A4, and slightly by CYP2B6, 2C8, 2C19 and 2D6. Besides oxidative metabolism, PF403 also was transformed into glucuronylation metabolites GLU-PF403 by Phase II enzymes UGT1A1, 1A3 and 1A9. Taken together, the metabolism of CAT3 was a multiple enzyme catalytic reaction. These results could provide valuable information for potential enzyme-mediated DDI in clinic studies.

Breast cancer has the highest incidence rate among all women's malignant tumors worldwide.Surgery,radiotherapy and chemotherapy are three major treatments,while most patients showed adverse effects or complications during or after the treatment,including lymphedema,gastrointestinal reactions and leukopenia,which cause severe impact on patients' recovery and quality of life.Moxibustion has been used and certified to alleviate adverse effects of surgery or chemoradiotherapy for breast cancer.We have summarized literatures in recent years and suggest more systematic research in the future for the underlying mechanism.

Objective:To observe the clinical effect of acupuncture for persistent allergic rhinitis (PAR).Methods:A total of 154 PAR patients were randomized into a treatment group and a control group,78 cases in the treatment group received acupuncture at meridian points,while 76 cases in the control group received acupuncture at non-meridian points.The treatment was done every other day,3 times a week for a total 4 weeks.The total nasal symptom score (TNSS),the total non-nasal symptom score (TNNSS) and the rhinoconjunctivitis quality of life questionnaire (RQLQ) were measured before the treatment and after 2 weeks and 4 weeks of treatment,as well as 1 month and 3 months after the treatment to compare the clinical effect between the two groups.Results:After 4 weeks of treatment,the total effective rate in the treatment group was 92.3％,versus 76.3％ in the control group,showing a statistically significant difference (P＜0.05).Intra-group comparisons of TNSS,TNNSS and RQLQ scores after 4 weeks of treatment showed statistically significant differences (all P＜0.05).Between-group comparisons of TNSS,TNNSS and RQLQ score after 4 weeks of treatment and in follow-up visits showed statistically significant differences (all P＜0.05).Conclusion:Acupuncture is effective for PAR,and acupuncture at meridian points can produce a better effect than acupuncture at non-meridian points.

Objective To analyze the chemical components of the ethanol-soluble portion of Liuwei Dihuang Decoction,and to explore its mechanism in kidney-Yin deficiency of mice.Methods Bioactive components were analyzed by HPLC,the method was used at Hypersile C1s column(4.6 mm × 250 mm,5 μm),the mobile phase consisted of methanol-water (27 ∶ 73),the detective wavelength was 236 nm,the flow rate was 1.0 mL · min-1,the column temperature was 25 ℃.The mice were divided randomly into three groups (n =10):blank group,model group,experimental group.The mice were gavaged with oral administration of corresponding medicines (9.75 g · kg-1)for nine weeks.At time 6 d after administration,in addition to that the normal group was given distilled water,the other groups were gavaged with hydrocortisone injection per day according to 50 mg · kg-1 body weight for 4 d to establish the kidney Yin deficiency mice model.The contents of cyclic adenosine monophosphate (cAMP),cyclic guanosine monophosphate (cGMP) were determined by ELISA and the follicle-stimulating hormone (FSH),estradiol (E2),testosterone (T) were determined by radioimmunoassay after administration.Results The linear range of morroniside,sweroside,paeoniflorin and loganin were 0.24-2.40 μg (r=0.999 6),0.14-1.38 μg(r =0.999 1),0.12-1.20 μg(r =0.999 1),0.24-2.40 μg(r =0.999 4) respectively.The recovery and relative standard deviation of them were (100.22 ± 1.80) ％,(100.83 ± 1.94) ％,(102.40 ± 1.47) ％,(101.40 ± 1.50) ％,and RSD were 1.80％,1.92％,1.44％,1.50％.The average content of morroniside,sweroside,paeoniflorin and loganin in Liuwei Dihuang Decoction water extract-alcohol soluble parts were calculate in terms of material were 0.20％,0.02％,0.06％,0.13％.The plasma level of cAMP in model group and experimental group were (8.20 ±0.63),(6.90 ±0.15) nmol · L-1 with significant different (P ＜0.01).The serum contents of FSH,E2,T in model group and experimental group were(0.54 ±0.10),(0.88 ±0.04)mU · mL-1;(13.93 ± 0.29),(15.48 ± 0.43) pg · mL-1;(2.23 ± 0.14),(5.63 ± 0.48) ng · mL-1 with significant different (P ＜ 0.01).Conclusion It is found that ethanol-soluble portion might be one of the bioactive component of Liuwei Dihaung Decoction to improve kidney Yin deficiency,and it mainly contains loganin,morroniside,sweroside and paeoniflorin.Its function mechanism of tonifying kidney may be related to the regulation of cAMP content and the levels of hormones in the HPG axis.

Objective To evaluate the safety and tolerability of continu-ous intravenous infusion of innovative calcium sensitizer piperphent-onamin ( PPTA) at a loading dose and a maintenance dose in healthy vol-unteers.Methods A randomized, open, single-center, phase I clini-cal trial in 11 healthy male and female subjects was conducted.Each subject was intravenously administered with a single loading dose of 0.1 mg· kg -1 for 20 min, and then a maintenance dose of 0.9 mg· kg -1 for 24 h.Safety and tolerance of PPTA were assessed by vital sign , dynamic electrocardiogram monitoring , physical examination , laboratory tests and eye exams, according to which adverse events ( AEs) were identified and recorded.The safety and tolerability were evaluated.Results Vital signs of all subjects were stable , and no QTc interval prolongation was observed during the trial.A total of 13 AEs were reported in 6 subjects , among which 9 AEs were the reflections of the effects of PPTA and all AEs were all relieved without treatment.Conclusion The regimen of in-travenous PPTA loading dose for 20 min and then a maintenance dose for 24 h is safe and tolerable.