ABSTRACT
SUMMARY: The toxic effects of thioacetamide (TAA) and carbon tetrachloride on the human body are well recognized. In this study, we examined whether TAA intoxication can induce kidney leukocyte infiltration (measured as leukocyte common antigen CD45) associated with the augmentation of the reactive oxygen species (ROS)/tumor necrosis factor-alpha (TNF-α) axis, as well as biomarkers of kidney injury with and without metformin treatment. Rats were either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being sacrificed after 10 weeks (experimental group) or were pre-treated with metformin (200 mg/kg) daily for two weeks prior to TAA injections and continued receiving both agents until the end of the experiment, at week 10 (protective group). Using basic histology staining, immunohistochemistry methods, and blood chemistry analysis, we observed profound kidney tissue injury such as glomerular and tubular damage in the experimental group, which were substantially ameliorated by metformin. Metformin also significantly (p0.05) increase in kidney expression of CD45 positive immunostaining cells. In conclusion, we found that TAA induces kidney injury in association with the augmentation of ROS/TNF-α axis, independent of leukocyte infiltration, which is protected by metformin.
Son bien conocidosos los efectos tóxicos de la tioacetamida (TAA) y el tetracloruro de carbono en el cuerpo humano. En este estudio, examinamos si la intoxicación por TAA puede inducir la infiltración de leucocitos renales (medida como antígeno leucocitario común CD45) asociada con el aumento de las especies reactivas de oxígeno (ROS)/factor de necrosis tumoral-alfa (TNF-α), así como biomarcadores de daño renal con y sin tratamiento con metformina. A las ratas se les inyectó TAA (200 mg/kg; dos veces por semana durante 8 semanas) antes de sacrificarlas a las 10 semanas (grupo experimental) o se les pretrató con metformina (200 mg/kg) diariamente durante dos semanas antes de las inyecciones de TAA y continuaron recibiendo ambos agentes hasta el final del experimento, en la semana 10 (grupo protector). Usando tinción histológica básica, métodos de inmunohistoquímica y análisis químico de la sangre, observamos una lesión profunda del tejido renal, como daño glomerular y tubular en el grupo experimental, que mejoraron sustancialmente con la metformina. La metformina también inhibió significativamente (p0,05) en la expresión renal de células de inmunotinción positivas para CD45. En conclusión, encontramos que el TAA induce la lesión renal en asociación con el aumento del eje ROS/TNF-α, independientemente de la infiltración de leucocitos, que está protegida por metformina.
Subject(s)
Animals , Male , Rats , Thioacetamide/toxicity , Acute Kidney Injury/drug therapy , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Immunohistochemistry , Biomarkers , Tumor Necrosis Factor-alpha , Reactive Oxygen Species , Leukocyte Common Antigens , Acute Kidney Injury/chemically induced , InflammationABSTRACT
Background & objectives: Studies have shown that insulin resistance and hyperinsulinaemia play a major role in the pathogenesis of polycystic ovary syndrome (PCOS). Therefore, the use of insulin sensitizing drugs in the treatment of PCOS has attracted the attention of medicine and researchers. The aim of this study was to investigate the effects of sitaformin (sitagliptin/metformin) and metformin on the quality of oocyte and embryo in classic PCOS patients undergoing intracytoplasmic sperm injection (ICSI). Methods: Sixty patients of PCOS (25-35 yr) were randomly allocated into three groups (n=20, each group): a metformin-treated group (administered metformin 500 mg twice daily), a sitaformin-treated group (administered sitaformin 50/500 mg twice daily) and a placebo group. Participants in all the groups received the drug two months prior to the start of the ovulation cycle and treatment continued until the day of the oocyte aspiration. Results: Serum insulin and total testosterone levels decreaseed significantly after treatment in both the treatment groups as compared to the placebo (P<0.05). A significant decrease in the number of immature oocytes [MI + germinal vesicle (GV) stage] was observed in metformin and sitaformin groups as compared to the placebo. In addition, sitaformin group when compared to the metformin group showed a significant decrease in the number of immature oocytes (P<0.05). The number of mature and normal MII oocytes increased significantly in both the treatment groups compared to the placebo group (P<0.05). The number of mature and normal oocytes increased in sitaformin group in comparison to the metformin group, but the difference was not significant. There was a significant increase in the number of grade I embryos, fertilization and cleavage rates in the sitaformin group compared to the other groups (P<0.05). Interpretation & conclusions: This is the first study to compare the impact of sitaformin with metformin on oocyte and embryo quality in women with PCOS undergoing a gonadotropin-releasing hormone (GnRH) antagonist cycle. In conclusion, sitaformin can be more effective in decreasing immature oocytes and increasing the quality of embryos than the use of metformin.
ABSTRACT
Studies have demonstrated high prevalence of mortality in coronavirus disease (COVID-19) patients with type 2 diabetes mellitus; however, the effects of antidiabetic pharmacotherapy on COVID-19 complications need further exploration. The aim of the study was to explore the association of metformin use and mortality in COVID-19 patients. A literature search was conducted using the databases Medline (via PubMed) and Cochrane Central Register of Controlled Trials until February 09, 2021. Nine studies were included in the meta-analysis, including 12,684 COVID-19 patients. The meta-analysis suggested 37% lower risk of mortality in patients receiving metformin (risk ratio: 0.63; 95% confidence interval: 0.50–0.78; p?<?0.001). However, no significant difference in hospitalization days between the two groups (p?=?0.197) was observed. The analysis revealed significantly lower risk of having obesity (p?<?0.001), hypertension (p?<?0.001), heart failure (p?<?0.001), and cerebrovascular disease (p?=?0.015) in the group receiving metformin. The analysis also demonstrated significantly lower risk of using anticoagulants (p?=?0.015), diuretics (p?<?0.001), and antiplatelets (p?=?0.010) in patients receiving metformin. Our findings suggest that metformin use decreases mortality in COVID-19 patients. However, randomized studies demonstrating the consequences of metformin use are needed to understand the magnitude of the beneficial effects of metformin
ABSTRACT
SUMMARY OBJECTIVE: The primary objective of this study was to explore the impact of metformin and metformin/gliptin combination therapy on the serum concentrations of vitamin B12, ferritin, and folic acid in individuals diagnosed with type 2 diabetes. METHODS: This study included 118 patients, classified into two groups: 59 patients using only metformin and 59 patients using a combination of metformin/gliptin. Among the latter group, 35 patients used vildagliptin/metformin, and 24 used sitagliptin/metformin. The study recorded the demographic data such as the age and gender of the patients, as well as their initial and 1-year follow-up blood parameters. RESULTS: Folic acid decreased significantly in the metformin group but not in the metformin/gliptin group. Vitamin B12 and ferritin decreased significantly in both groups. The decrease in vitamin B12 and ferritin was not significantly different between the two groups. The decrease in fasting plasma glucose was more significant in the metformin/gliptin group than in the metformin group. CONCLUSION: After 1 year, both groups taking metformin and metformin/gliptin showed low serum ferritin and vitamin B12 levels. Therefore, vitamin B12 levels in patients using these drugs should be closely monitored. Ferritin levels can be used to indicate whether glycemic control has been achieved.
ABSTRACT
Objective:To explore the roles and mechanisms of metformin in the improvement of cognitive dysfunction induced by chronic cerebral hypoperfusion in rats.Methods:Total 82 SD male rats (SPF grade) aged 3-4 months were randomly divided into four groups: sham operation control group (Con group, n=15), sham operation with metformin treatment group (Met group, n=20), 2-vessel occlusion group (2VO group, n=22), and 2-vessel occlusion with metformin administration group (2VO+ Met group, n=25). The chronic cerebral hypoperfusion model was established by bilateral common carotid artery ligation, and the carotid arteries of rats in Con group and Met group were only separated without ligation.After 2VO operation, rats in 2VO+ Met group and Met group were given metformin solution in drinking water at a dose of 100 mg/kg per day for 4 weeks.After 4-week continuous intervention with metformin, Morris water maze was performed to test the spatial cognitive function of the rats, in vivo electrophysiological technology was used to detect the long-term potential of the rats, and enzyme-linked immunosorbent assay(ELISA) was used to detect the concentrations of inflammatory factor tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6) in the hippocampus.The density of dendritic spines of hippocampal neurons was observed by Golgi staining, and the synaptic structure of hippocampal neurons, especially the vesicle density, was observed by transmission electron microscopy.SPSS 16.0 software was used for statistical analysis.Repetitive measurement ANOVA was used for the escape latency data of 7 days repeated learning training in water maze.One-way ANOVA was used for the comparison of other data among multiple groups, and Dunnett's t test was used for further pairwise comparison. Results:Morris water maze results showed that during 7 days of learning training, the time and group interaction for escape latency was not significant in the 4 groups of rats ( F=0.93, P>0.05), but the time main effect ( F=25.90, P<0.05) and group main effect ( F=13.20, P<0.05) were significant.Morris water maze test showed that from the 3rd to 7th day, the escape latencies in 2VO group were significantly longer than those in Con group and 2VO+ Met group(all P<0.05). The short-term memory of rats was detected after 1 day of rest.The results showed that the escape latency in 2VO group was significantly longer than that in Con group and 2VO + Met group( P<0.01). The retention time and crossing times in the platform area of 2VO rats were less than those in Con group and 2VO + Met group ( P<0.01). Electrophysiological results showed that the relative field excitatory postsynaptic potential slope of 2VO group (1.29±0.09) was significantly lower than that in Con group (2.07±0.09) and 2VO + Met group (1.69±0.08)( P<0.01). ELISA results showed that TNF-α level in hippocampal tissue of 2VO group was significantly higher than that in Con group and 2VO+ Met group; IL-1β and IL-6 levels in hippocampal tissue of 2VO group were significantly higher than those in Con group and 2VO + Met group.Density of dendritic spines in hippocampal neurons of 2VO group was significantly lower than that in Con group and 2VO+ Met group.The density and proportion of immature dendritic spines in hippocampal neurons of 2VO group were significantly higher than those in Con group and 2VO + Met group.Synaptic vesicle density of neurons in CA1 area of hippocampus in 2VO group ((230.29±19.44) vescicles/μm 2) was significantly lower than that in the Con group ((414.52±13.17) vescicles/μm 2) and 2VO+ Met group ((313.19±12.42) vescicles/μm 2). Conclusion:Metformin can reduce neuroinflammation of hippocampus with chronic cerebral hypoperfusion and improve synaptic plasticity and cognitive dysfunction.It may have potential application value in the treatment of vascular cognitive dysfunction.
ABSTRACT
Objective:To investigate the clinical effect of dapagliflozin combined with metformin on type 2 diabetes mellitus (T2DM).Methods:A total of 100 patients with T2DM who received treatment in The Second People's Hospital of Hefei from June 2019 to May 2021 were included in this study. They were randomly divided into a control group ( n = 50) and an experimental group ( n = 50). The control group was treated with metformin, and the experimental group was treated with dagglitazin combined with metformin. All patients were treated for 3 months. Blood glucose index, blood lipid level, and the incidence of adverse reactions were compared between the two groups. Results:After treatment, fasting blood glucose, 2-hour post-prandial blood glucose, and glycosylated hemoglobin in the experimental group were (5.56 ± 0.37) mmol/L, (8.32 ± 0.23) mmol/L, and (6.17 ± 0.26)% respectively, which were significantly lower than (6.96 ± 0.48) mmol/L, (9.58 ± 0.39) mmol/L, and (7.27 ± 0.26)% respectively in the control group ( t = 3.59, 6.92, 5.03, all P < 0.05). The total cholesterol and triglyceride in the experimental group were (3.58 ± 0.53) mmol/L and (1.25±0.26) mmol/L, respectively, which were significantly lower than (4.94 ± 0.58) mmol/L and (1.93 ± 0.18) mmol/L in the control group ( t = 3.16, 4.25, both P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Conclusion:Dapagliflozin combined with metformin can effectively control blood glucose and blood lipid in T2DM patients without increasing adverse reactions.
ABSTRACT
Objective:To investigate the clinical efficacy of liraglutide combined with metformin in the treatment of type 2 diabetes mellitus in overweight or obese patients.Methods:The clinical data of 120 overweight or obese patients with type 2 diabetes mellitus admitted to Bayannur Hospital from January 2020 to June 2021 was retrospectively analyzed. They were divided into study and control groups ( n = 60/group) according to different treatments. The study group was treated with liraglutide combined with metformin, and the control group was treated with metformin alone. All patients were treated for 12 weeks. Clinical efficacy was compared between the two groups. Results:After treatment, body mass, body mass index, fasting blood glucose, 2-hour postprandial blood glucose, glycated hemoglobin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, visceral fat area, and insulin resistance index in the study group were (71.51 ± 10.12) kg, (25.98 ± 2.63) kg/m 2, (6.09 ± 0.99) mmol/L, (9.08 ± 2.39) mmol/L, (6.75 ± 1.13)%, (4.43 ± 0.88) mmol/L, (1.76 ± 0.68) mmol/L, (2.29 ± 0.90) mmol/L, (108.21 ± 26.46) cm 2 and (3.57 ± 1.45), respectively, which were significantly lower than (75.57 ± 7.11) kg, (27.91 ± 2.46) kg/m 2, (7.02 ± 0.95) mmol/L, (11.26 ± 2.86) mmol/L, (7.28 ± 1.04)%, (5.24 ± 1.11) mmol/L, (2.19 ± 0.70) mmol/L, (2.86 ± 0.97) mmol/L, (118.32 ± 28.63) cm 2, and (4.28 ± 2.07) respectively in the control group ( t = 2.54, 4.15, 5.23, 4.53, 2.66, 4.45, 3.43, 3.39, 2.01, 2.19, all P < 0.05). High-density lipoprotein cholesterol in the study group was significantly higher than that in the control group [(1.55 ± 0.28) mmol/L vs. (1.20 ± 0.32) mmol/L, t = -6.38, P < 0.05]. The grade of nonalcoholic fatty liver disease in the study group was significantly superior to that in the control group ( Z =-2.16, P < 0.05). Conclusion:Liraglutide combined with metformin can effectively improve blood glucose and lipid levels, and reduce insulin resistance, body weight, visceral adipose tissue and liver hepatocellular fatty deposits in overweight or obese patients with type 2 diabetes mellitus.
ABSTRACT
The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed inde-pendently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endo-thelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.
ABSTRACT
Objective:To explore the effects of metformin on levels of peripheral blood regulatory T cells (Treg)/Th17 cells and related cytokines in patients with type 2 diabetes mellitus (T2DM) and influenza A.Methods:A total of 108 patients with T2DM and influenza A treated in Zhejiang Veteran Hospital were prospectively enrolled between April 2021 to April 2022. According to different medication methods, they were divided into observation group (54 cases, oseltamivir + metformin) and control group (54 cases, oseltamivir + gliclazide). The average usage time and dosage of oseltamivir, concentration of blood lactate and blood gas level, counts of Th17 and Treg cells, and levels of related cytokines in the two groups were compared before and after treatment.Results:The average usage time and dosage of oseltamivir, and concentration of blood lactate were higher in observation group than control group: (8.94 ± 0.88) d vs. (7.23 ± 0.79) d, (1.32 ± 0.15) g vs. (1.08 ± 0.11) g, (1.83 ± 0.43) mmol/L vs. (1.61 ± 0.32) mmol/L, P<0.05. The differences in pH, partial pressure of arterial oxygen (PaO 2) and partial pressure of arterial carbon dioxide (PaCO 2) between the two groups had no statistically significant before and after treatment ( P>0.05). After treatment, the differences in count of Treg cells, interleukin-10 (IL-10), interleukin-4 (IL-4), CD 3+, CD 4+ and CD 4+/CD 8+ between the observation group and the control group were statistically significant: (35.48 ± 5.64)% vs. (42.53 ± 6.17)%, (30.49 ± 4.72) ng/L vs. (35.64 ± 5.08) ng/L, (32.15 ± 3.06) ng/L vs. (35.33 ± 3.12) ng/L, (61.39 ± 3.28) % vs. (66.27 ± 3.05)%, (34.12 ± 1.93)% vs. (36.59 ± 2.61)%, 1.26 ± 0.34 vs. 1.52 ± 0.41, P<0.05. After treatment, the count of Th17 cells, Th17/Treg, interleukin-17 (IL-17) and γ-interferon (IFN-γ) in the observation group were higher than those in the control group:(8.69 ± 1.42)% vs. (7.94 ± 2.03)%, 0.24 ± 0.06 vs. 0.19 ± 0.05, (17.67 ± 3.11) ng/L vs. (12.18 ± 3.42) ng/L, (287.48 ± 45.12) ng/L vs. (254.27 ± 41.09) ng/L, P<0.05. During treatment, the difference in incidences of adverse reactions between the two groups had no statistically significant ( P>0.05). Conclusions:Oseltamivir combined with metformin can recover the balance of Th17/Treg cells in patients with T2DM and influenza A to a certain extent. Clinically, level of blood lactate should be monitored.
ABSTRACT
Objective:To investigate the effect of liraglutide combined with metformin on overweight and obese patients with type 2 diabetes mellitus (T2DM) after short-term intensive insulin pump therapy.Methods:A total of 80 overweight and obese patients with T2DM admitted to Ningguo People′s Hospital from November 2018 to December 2020 were selected as the research subjects. After 1 week of intensive insulin pump therapy, they were divided into two groups according to the random number table method. The observation group received liraglutide combined with metformin therapy, the control group received metformin combined with sitagliptin therapy, both for 16 weeks. The blood glucose, blood lipids, body weight and other indicators were compared between the two groups after treatment. The occurrence of adverse drug reactions in the two groups was compared.Results:The levels of fasting plasma glucose (FPG), 2 h postprandial blood glucose (2hPG), and glycosylated hemoglobin (HbA 1c) in the observation group after treatment were lower than those in the control group :(5.14 ± 0.54) mmol/L vs. (5.92 ± 0.71) mmol/L, (5.91 ± 0.83) mmol/L vs. (6.84 ± 0.92) mmol/L, (5.33 ± 0.57)% vs. (6.30 ± 0.82)%, there were statistical differnces ( P<0.05). The triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels had no significant differences ( P>0.05). After treatment, the islet beta cell function index (HOMA-β) and insulin sensitivity index (ISI) in the observation group were higher than those in the control group: 26.84 ± 3.32 vs. 22.15 ± 3.11, -3.84 ± 0.17 vs. -4.09 ± 0.20, and the insulin resistance index (HOMA-IR) was lower than that in the control group: 2.01 ± 0.17 vs. 2.64 ± 0.21, the differences were statistically significant ( P<0.05). After treatment, the waist circumference (WC), body mass index (BMI) and hip-to-waist ratio in the observation group were lower than those in the control group: (95.10 ± 4.08) cm vs. (97.14 ± 4.48) cm, (24.33 ± 1.62) kg/m 2 vs. (26.15 ± 1.40) kg/m 2, 0.89 ± 0.11 vs. 1.11 ± 0.20, the differences were statistically significant ( P<0.05). There was no significant difference in the incidence of adverse drug reactions between the two groups during treatment ( P>0.05). Conclusions:Liraglutide combined with metformin has better clinical effect on overweight and obese T2DM patients after short-term intensive insulin pump therapy, and can better improve their pancreatic islet function.
ABSTRACT
To investigate the effects and mechanism of the combination of Morus alba L. (Sangzhi) alkaloids(SZ-A) and metformin (Met) on glucose metabolism in type 2 diabetic mice, KKAy mice were divided into four groups according to the glucose and lipid indexes: control group (control), Morus alba L. (Sangzhi) alkaloids group (SZ-A, 100 mg·kg-1), metformin group (Met, 100 mg·kg-1) and combined administration group (combination, Comb, 100 mg·kg-1 SZ-A + 100 mg·kg-1 Met). All groups were administered by gavage once daily for 7 weeks accompanied with monitoring food intake, water intake, body weight as well as glycemia. Additionally, oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and oral sodium pyruvate tolerance test (OPTT) were performed at week 2, week 5, week 6, respectively. The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (00004332). We determined the weight and lipid content of liver, and then performed the histopathological analysis after sacrificed. Furthermore, Western blot assay was used to detect the protein levels of key molecules of PI3K/PDK1/Akt/GLUT signaling pathway in liver, muscle and adipose tissue. Compared to the SZ-A or Met monotherapy group, SZ-A + Met significantly improved the glucose metabolism disorder, which was showed in reduced food intake, water intake, the level of fasting blood glucose, postprandial blood glucose and glycosylated hemoglobin A1c (HbA1c) of KKAy mice, as well as improved glucose tolerance, enhanced insulin sensitivity and inhibited gluconeogenesis. In addition, SZ-A + Met obviously up-regulated the protein expression levels in PI3K/PDK1/Akt/GLUT signaling pathway in liver, muscle and adipose tissue of KKAy mice. Moreover, the liver lipid accumulation and blood aminotransferase level of KKAy mice in the combined administration group were significantly reduced. Therefore, we concluded that the combination of SZ-A and Met improved glucose metabolism and inhibited the occurrence and development of T2DM via promoting glucose uptake and utilization, suggesting that the combination of SZ-A and Met is a more useful treatment for T2DM.
ABSTRACT
Ramulus Mori (Sangzhi) alkaloids (SZ-A) are a group of polyhydroxy alkaloids extracted and isolated from the traditional Chinese medicine mulberry twig, which is mainly used for the treatment of type 2 diabetes mellitus (T2DM). In addition to acting as a glycosidase inhibitor in the small intestine after oral administration, SZ-A can also be absorbed into blood and widely distributed to target organs related to diabetes, exerting multiple pharmacological effects. It is important to elucidate the possible pharmacokinetic influences of SZ-A for its clinical rational applications, such as drug interactions, the effects of food and alcohol on the absorption of SZ-A. However, studies in this area are limited. Therefore, the pharmacokinetic interactions between orally administrated SZ-A (50 mg·kg-1) and metformin hydrochloride (Met, 200 mg·kg-1) in Sprague-Dawley (SD) rats were examined. Then, the effect of food (standard feed) on the pharmacokinetics of SZ-A was investigated using fasting administration of SZ-A (50 mg·kg-1) in rats as a control. Finally, we investigated the pharmacokinetic characteristics of SZ-A (50 mg·kg-1) in different concentrations alcohol solutions using aqueous solution of SZ-A administered to rats as a control to evaluate the effect of alcohol on the bioabsorption of SZ-A. The results showed no significant pharmacokinetic interactions between SZ-A and Met after combination treatment. The standard feed had little effect on the pharmacokinetic profile of SZ-A. Alcohol retarded the absorption of SZ-A, resulting in a significant decrease in the Cmax of SZ-A. The decrease was greater at higher alcohol concentrations; however, no significant difference was observed in the AUC0-t. These results support the clinical rational applications of SZ-A. All animal protocols were approved by the Ethics Committee of Kangtai Medical Laboratory Service Hebei Co., Ltd. (Hebei, China) (No. MDL2022-01-17-1).
ABSTRACT
Objective To explore the effect of metformin hydrochloride tablets on the clinical efficacy, number of dominant follicles and ovarian volume of polycystic ovary syndrome. Methods 150 patients diagnosed with polycystic ovary syndrome who were diagnosed and treated in our hospital from January 2019 to March 2021 were selected .The patients were divided into observation group and control group by random number table. The control group was treated with letrozole + gonadotropin, and the observation group was treated with letrozole + gonadotropin + hydrochloric acid + Metformin tablets. The clinical efficacy, endometrial thickness, number of high-quality follicles, sex hormone levels, blood lipid levels, and adverse reactions were compared between the two groups. Results ① The effective rate of treatment in the observation group was 90.67%, which was significantly higher than that in the control group, 78.67% (P<0.05). ② After treatment, the endometrial thickness of the observation group was lower than that of the control group, and the number of high-quality follicles was more than that of the control group(P<0.05). ③ After treatment, the levels of Luteinizing Hormone-LH, Follicle Stimulating Hormone-FSH and Testosterone (T) in the observation group were lower than those in the control group (P<0.05). ④ After treatment, the total cholesterol (TC) and triglyceride (TG) in the observation group were lower than those in the control group (P<0.05). ⑤ The incidence of adverse reactions in the observation group was 8.00%, which was significantly lower than 20.00% in the control group (P<0.05). Conclusion Letrozole + gonadotropin + metformin hydrochloride tablets could significantly improve the sex hormone and blood lipid levels in patients with polycystic ovary syndrome, relieve the symptoms of the patients, and improve their uterine condition, which had a good clinical effect.
ABSTRACT
@#Introduction: The most common variety of lung cancer is non–small cell lung cancer (NSCLC) accounting for 84% of new cases. Surgery, chemotherapy and radiation are the primary treatment option. Metformin has recently been demonstrated to have an anti-tumour impact on various cancer cells. The goal of this investigation was to determine the growth inhibitory, antiproliferative, cytotoxic, apoptotic and cell cycle arrest properties of metformin HCl oral tablets on the A549 lung carcinoma cell line. Methods: The cells were treated with different dosages of an oral preparation of metformin, with untreated cells used as a control. The Trypan Blue Exclusion Assay was used to determine metformin’s inhibitory and cytotoxic effects. Flow cytometry was used to evaluate apoptosis and cell cycle arrest. Results: In a dose-dependent manner, metformin HCl was able to reduce the viability of treated cells compared to the untreated control. Cell proliferation was considerably inhibited in the treated group with the IC50 dose than in the untreated control group and the IC50 dose showed no cytotoxic effect on L929 cells. Induction of apoptosis and cell cycle arrest was observed in the IC50 dose-treated group by Flow cytometry analysis and data showed metformin oral drug causes early apoptosis and a considerable cell increase in the S phase of the cell cycle. Conclusion: Metformin inhibits cell growth and induces apoptosis and cell cycle arrest in the cell line. A comprehensive proteome examination is required to understand more about the mechanism of action of the oral metformin HCl on cancer cells
ABSTRACT
Colorectal cancer is a common gastrointestinal malignant tumor with morbidity and mortality rising year by year. In recent years, the studies in and out of China have reported that metformin could inhibit the growth of colorectal cancer cells and improve the prognosis of patients by indirectly reducing the levels of insulin and glucose in the blood, or directly activating the AMP-activated protein kinase signaling pathways, promoting apoptosis of tumor cells, enhancing sensitivity to chemotherapy, inhibiting inflammatory responses, affecting the intestinal flora, and regulating the immune function, etc. This article reviews the current research status and controversies related to metformin against colorectal cancer, in an effort to provide new evidences for the treatment of colorectal cancer.
ABSTRACT
Objective:To observe the effect of metformin (Met) on inflammatory bodies and focal death in human retinal microvascular endothelial cells (hRMEC) in diabetes mellitus (DM) microenvironment.Methods:Experimental research was divided into in vivo animal experiment and in vitro cell experiment. In vivo animal experiments: 9 healthy C57BL/6J male mice were randomly divided into DM group, normal control group, and DM+Met group, with 3 mice in each group. DM group and DM+Met group mice were induced by streptozotocin to establish DM model, and DM+Met group was given Met 400 mg/ (kg · d) intervention. Eight weeks after modeling, the expression of NLRP3, cleaved-membrane perforating protein D (GSDMD) and cleaved-Caspase-1 in the retina of mice in the normal control group, DM group and DM+Met group were observed by immunohistochemical staining. In vitro cell experiments: hRMEC was divided into conventional culture cell group (N group), advanced glycation end products (AGE) group, and AGE+Met group. Joining the AGE, AGE+Met groups cells were induced by 150 μg/ml of glycation end products, and 2.0 mmol/L Met was added to the AGE+Met group. Pyroptosis was detected by flow cytometry; 2' ,7'-dichlorofluorescein diacetate (DCFH-DA) fluorescent probe was used to detect the expression of reactive oxygen species (ROS) in cells of each group. Real-time fluorescence quantitative polymerase chain reaction and Western blot were used to detect the relative mRNA and protein expression levels of NLRP3, cleaved-GSDMD, cleaved-Caspase-1 in each group of cells. Single factor analysis of variance was used for comparison among the three groups.Results:In vivo animal experiments: compared with the DM group, the expression of NLRP3, cleaved-GSDMD, and cleaved-Caspase-1 in the retina of normal control group and DM+Met group mice was significantly reduced, with significant difference among the 3 groups ( F=43.478, 36.643, 24.464; P<0.01). In vitro cell experiment and flow cytometry showed that the pyroptosis rate of AGE group was significantly higher than that of N group and AGE+Met group ( F=32.598, P<0.01). The DCFH-DA detection results showed that the intracellular ROS levels in the N group and AGE+Met group were significantly lower than those in the AGE group, with the significant difference ( F=47.267, P<0.01). The mRNA ( F=51.563, 32.192, 44.473; P<0.01) and protein levels ( F=63.372, 54.463, 48.412; P<0.01) of NLRP3, cleaved-GSDMD, and cleaved-Caspase-1 in hRMEC of the AGE+Met group were significantly reduced compared to the N group. Conclusion:Met can down regulate the expression of NLRP3 inflammatory body related factors in hRMEC and inhibit pyroptosis.
ABSTRACT
Objective:To observe the effect of metformin on the polarization state and photoreceptor cell activity of microglia (BV2 cells) in a high glucose environment.Methods:An experimental study. BV2 cells were divided into a control group, a high glucose group, and a metformin+high glucose group. The cells in the high glucose group were cultured with 75 mmol/L glucose in the medium; the cells in the metformin+high glucose group were pretreated with 2 mmol/L metformin for 12 h and then placed in 75 mmo/L glucose concentration medium. The relative expression of M1 marker inducible nitric oxide synthase (iNOS), CD86 and M2 markers arginase 1 (Arg-1), and CD206 protein were detected by Western blot. Interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-4 were detected by enzyme-linked immunosorbent assay (ELISA). BV2 cells were co-cultured with mouse retinal photoreceptor cells (661W cells) for 24 h. The proliferation rate of 661W cells in each group was measured by methyl thiazolyl tetrazolium (MTT) colorimetric assay; the apoptosis rate of 661W cells in each group was measured by flow cytometry and terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL). An independent sample t-test was used for comparison between groups. Results:Western blot assay showed that the relative expression of iNOS and CD86 protein was increased and the relative expression of Arg-1 and CD206 protein was decreased in BV2 cells in the high glucose group compared with the control group, and the differences were all statistically significant ( t=-16.783, -11.605, 4.325, 4.649; P<0.05); compared with the high glucose group, the relative expression of iNOS and CD86 protein was decreased and the relative expression of Arg-1 and CD206 protein was increased in BV2 cells in the metformin + high glucose group compared with the high glucose group, and the differences were all statistically significant ( t=7.231, 5.560, -8.035, -8.824; P<0.01). ELISA results showed that compared with the control group, the BV2 cells in the high glucose group had increased IL-6, TNF-α content and IL-4 content was decreased in BV2 cells in the high glucose group compared with the control group, and the differences were all statistically significant ( t=-64.312, -127.147, 71.547; P<0.001); compared with the high glucose group, IL-6 and TNF-α content was significantly decreased and IL-4 content was significantly increased in BV2 cells in the metformin+high glucose group, and the differences were all statistically significant ( t=44.426, 83.232,-143.115; P<0.001). After co-culture of BV2 cells with 661W cells for 24 h, the results of MTT colorimetric assay showed that compared with the control group, the activity of 661W cells in the high glucose group was significantly reduced, and the difference was statistically significant ( t=7.456, P<0.01); compared with the high glucose group, the activity of 661W cells in the metformin+high glucose group was increased ( t=-3.076, P<0.05). TUNEL method and flow cytometry showed that the apoptosis rate of 661W cells in the high glucose group was significantly higher compared with the control group, and the differences were both statistically significant ( t=-22.248, -22.628; P<0.001); compared with the high glucose group, the apoptosis rate of 661W cells in the metformin+high glucose group was significantly decreased, and the difference was statistically significant ( t=11.767, 6.906; P<0.001, 0.01). Conclusion:In the high glucose environment, metformin inhibited the inflammatory response and attenuated the apoptosis of photoreceptor cells by regulating the polarization of microglia toward the M2 type.
ABSTRACT
Objective:To evaluate the effect of metformin preconditioning on adenosine monophosphate-activated protein kinase(AMPK)/PTEN-induced putative protein kinase(PINK1) signaling pathway during ischemia-reperfusion (I/R) injury in diabetic rats.Methods:Thirty-six clean-grade healthy male Sprague-Dawley rats, aged 6 weeks, weighing 120-160 g, were divided into 3 groups ( n=12 each) by the random number table method: diabetic sham operation group (DS group), diabetic myocardial I/R group (DI/R group) and diabetic myocardial I/R+ metformin preconditioning group(DI/R+ Met group). After 4 weeks of feeding a high-fat and high-glucose diet, the model of type 2 diabetes mellitus was induced by a single intraperitoneal injection of 1% streptozotocin 40 mg/kg. The myocardial I/R injury was induced by blocking the anterior descending branch of the left coronary artery for 30 min followed by 120-min reperfusion in anesthetized animals. In DI/R+ Met group, metformin 200 mg/kg was given by intragastric gavage once a day within 1 week before myocardial ischemia. Blood samples from the femoral vein were collected at 120 min of reperfusion for determination of the serum creatine kinase isoenzymes (CK-MB) and cardiac troponin I (cTnI) concentrations by enzyme-linked immunosorbent assay. Then the rats were sacrificed and myocardial tissues were obtained for examination of the pathological changes(by HE staining) and for determination of the percentage of myocardial infarct size (by the double staining of Ewan blue and TTC) and expression of myocardial autophagy-related protein Beclin-1, PTEN-induced putative kinase 1 (PINK1), phosphorylated 5′-adenosine monophosphate-activating protein kinase (p-AMPK), and ratio of microtubule-associated protein 1 light chain 3Ⅱ/Ⅰ (LC3Ⅱ/Ⅰ) (by Western blot). Results:Compared with DS group, the percentage of myocardial infarct size and serum CK-MB and cTnI concentrations were significantly increased, the expression of Beclin-1, p-AMPK and PINK1 in myocardial tissues was up-regulated, the ratio of LC3II/I was increased( P<0.05), and the pathological changes were aggravated in DI/R group and DI/R+ Met group. Compared with DI/R group, the percentage of myocardial infarct size and serum CK-MB and cTnI concentrations were significantly decreased, the expression of Beclin-1, p-AMPK and PINK1 in myocardial tissues was up-regulated, the ratio of LC3Ⅱ/Ⅰ was increased ( P<0.05), and the pathological changes were significantly reduced in DI/R+ Met group. Conclusions:The mechanism by which metformin preconditioning reduces myocardial I/R injury is related to activation of AMPK/PINK1 signaling pathway and up-regulation of mitochondrial autophagy in diabetic rats.
ABSTRACT
Age-related eye diseases are a series of ophthalmic diseases caused by degenerative disease of ocular tissues, and age-related macular degeneration(ARMD), age-related cataract(ARC), diabetic retinopathy(DR)and glaucoma are the four most common age-related eye diseases. With the increasing aging of the global social population, the incidence of these eye diseases is also increasing year by year. Metformin is currently one of the most commonly used hypoglycemic agents in clinical practice. It has become the drug of choice for treating type 2 diabetes after more than 60 years of clinical practice. In recent years, metformin has shown great potential in the prevention and treatment of tumors, systemic diseases and age-related diseases, and the mechanisms of action involved in anti-oxidative stress, anti-inflammation, and induction of autophagy are also closely related to the pathological changes of age-related eye diseases. The paper aims to review the current research status and potential application value of metformin in age-related eye diseases.
ABSTRACT
Objective:To evaluate the effect of Tongbu Qijing Acupuncture combined with metformin hydrochloride tablet on polycystic ovary syndrome (PCOS) combined with insulin resistance (IR) of kidney-deficiency phlegm dampness type.Methods:Randomized controlled trial. 84 patients with PCOS and IR in the hospital were enrolled as the observation objects between November 2019 and November 2021. According to random number table method, they were divided into observation group (Tongbu Qijing Acupuncture combined with metformin hydrochloride tablets) and control group (oral metformin hydrochloride tablets), 42 in each group. All were treated for 3 courses of treatment (1 month/course). TCM syndromes were scored before and after treatment. The height, weight, waist circumference and hip circumference of patients were measured to calculate body mass index (BMI) and waist-hip ratio (WHR). The levels of serum TG, TC, LDL-C and HDL-C were detected by biochemical analyzer, fasting blood glucose (FPG) was detected by glucose oxidase method, fasting insulin (FINS) was detected by electrochemiluminescence method, and insulin resistance index (HOMA-IR) was calculated. The recovery rates of menstruation and ovulation were observed and compared after treatment, and the clinical curative effect was evaluated.Results:There were significant differences in total response rate between observation group and control group [95.24% (40/42) vs. 80.95% (34/42); χ2=4.09, P=0.043]. After treatment, scores of TCM syndromes, BMI and WHR in observation group were significantly lower than those in the control group ( t=20.36, 23.77, 3.44, P<0.01). After treatment, serum FPG [(4.86±0.51) nmol/L vs. (5.41±0.55) nmol/L, t=4.75], FINS [(8.31±0.85) mU/L vs. (10.11±1.02) mU/L, t=8.79] levels and HOMA-IR [(1.88±0.19) vs. (2.44±0.25), t=11.97] in observation group were significantly lower than those in the control group ( P<0.01). After treatment, levels of serum TG, TC and LDL-C in observation group were significantly lower than those in the control group ( t=16.54, 4.81, 5.35, P<0.01), while HDL-C was significantly higher than that of the control group ( t=6.78, P<0.01). After treatment, there were significant differences in recovery rates of menstruation and ovulation between observation group and control group [57.14% (24/42), 47.62% (20/42) vs. 80.95% (34/42), 69.05% (29/42); χ2=5.57, 3.97, P<0.05]. Conclusion:Tongbu Qijing Acupuncture combined with metformin hydrochloride tablet can effectively improve syndromes and signs, regulate glucose-lipid metabolism, reduce IR and promote the recovery of menstruation and ovulation in patients with PCOS and IR.