Proper fetal development requires tight regulation of serotonin concentrations within the fetoplacental unit. This homeostasis is partly maintained by the placental transporter OCT3/SLC22A3, which takes up serotonin from the fetal circulation. Metformin, an antidiabetic drug commonly used to treat gestational diabetes mellitus, was shown to inhibit OCT3. We, therefore, hypothesized that its use during pregnancy could disrupt placental serotonin homeostasis. This hypothesis was tested using three experimental model systems: primary trophoblast cells isolated from the human term placenta, fresh villous human term placenta fragments, and rat term placenta perfusions. Inhibition of serotonin transport by metformin at three concentrations (1 μM, 10 μM, and 100 μM) was assessed in all three models. The OCT3 inhibitor decynium-22 (100 μM) and paroxetine (100 μM), a dual inhibitor of SERT and OCT3, were used as controls. In primary trophoblasts, paroxetine exhibited the strongest inhibition of serotonin uptake, followed by decynium-22. Metformin showed a concentration-dependent effect, reducing serotonin uptake by up to 57 % at the highest concentration. Its inhibitory effect was less pronounced in fresh villous fragments but remained statistically significant at all concentrations. In the perfused rat placenta, metformin demonstrated a concentration-dependent effect, reducing placental serotonin uptake by 44 % at the highest concentration tested. Our findings across all experimental models show inhibition of placental OCT3 by metformin, resulting in reduced serotonin uptake by the trophoblast. This sheds light on mechanisms that may underpin metformin-mediated effects on fetal development.

• Klíčová slova
• OCT3, gestational diabetes mellitus, metformin, placenta, pregnancy, serotonin,
• MeSH
• biologický transport účinky léků   MeSH
• hypoglykemika farmakologie   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• lidé MeSH
• metformin * farmakologie   MeSH
• oktamerní transkripční faktor 3 metabolismus   MeSH
• placenta * metabolismus   účinky léků   MeSH
• potkani Wistar MeSH
• proteiny přenášející organické kationty MeSH
• serotonin * metabolismus   MeSH
• těhotenství MeSH
• trofoblasty * metabolismus   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hypoglykemika MeSH
• metformin * MeSH
• oktamerní transkripční faktor 3 MeSH
• proteiny přenášející organické kationty MeSH
• serotonin * MeSH
• solute carrier family 22 (organic cation transporter), member 3 MeSH Prohlížeč

BACKGROUND: Despite the improvements in treatment over the last decades, periodontal disease (PD) affects millions of people around the world and the only treatment available is based on controlling microbial load. Diabetes is known to increase the risk of PD establishment and progression, and recently, glucose metabolism modulation by pharmaceutical or dietarian means has been emphasised as a significant modulator of non-communicable disease development. METHODS: The impact of pharmaceutically controlling glucose metabolism in non-diabetic animals and humans (REBEC, UTN code: U1111-1276-1942) was investigated by repurposing Metformin, as a mean to manage periodontal disease and its associated systemic risk factors. RESULTS: We found that glucose metabolism control via use of Metformin aimed at PD management resulted in significant prevention of bone loss during induced periodontal disease and age-related bone loss in vivo. Metformin also influenced the bacterial species present in the oral environment and impacted the metabolic epithelial and stromal responses to bacterial dysbiosis at a single cell level. Systemically, Metformin controlled blood glucose levels and age-related weight gain when used long-term. Translationally, our pilot randomized control trial indicated that systemic Metformin was safe to use in non-diabetic patients and affected the periodontal tissues. During the medication window, patients showed stable levels of systemic blood glucose, lower circulating hsCRP and lower insulin levels after periodontal treatment when compared to placebo. Finally, patients treated with Metformin had improved periodontal parameters when compared to placebo treated patients. CONCLUSION: This is the first study to demonstrate that systemic interventions using Metformin in non-diabetic individuals aimed at PD prevention have oral-systemic effects constituting a possible novel form of preventive medicine for oral-systemic disease management.

• MeSH
• diabetes mellitus 2. typu * MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• krevní glukóza MeSH
• lidé MeSH
• management nemoci MeSH
• metformin * farmakologie   terapeutické užití   MeSH
• nemoci parodontu * farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• hypoglykemika MeSH
• krevní glukóza MeSH
• metformin * MeSH

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

• Klíčová slova
• AMPK, AR, CREB, LKB1, Metformin, Prostate Cancer, STAT3, mTORC1,
• MeSH
• diabetes mellitus 2. typu * MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• metformin * farmakologie   MeSH
• mTORC1 metabolismus   MeSH
• myši MeSH
• nádory prostaty * genetika   patologie   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• transkripční faktor STAT3 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• metformin * MeSH
• mTORC1 MeSH
• proteinkinasy aktivované AMP MeSH
• STAT3 protein, human MeSH Prohlížeč
• Stat3 protein, mouse MeSH Prohlížeč
• Stk11 protein, mouse MeSH Prohlížeč
• transkripční faktor STAT3 MeSH

Since a detailed inventory of endothelial cell (EC) heterogeneity in breast cancer (BC) is lacking, here we perform single cell RNA-sequencing of 26,515 cells (including 8433 ECs) from 9 BC patients and compare them to published EC taxonomies from lung tumors. Angiogenic ECs are phenotypically similar, while other EC subtypes are different. Predictive interactome analysis reveals known but also previously unreported receptor-ligand interactions between ECs and immune cells, suggesting an involvement of breast EC subtypes in immune responses. We also identify a capillary EC subtype (LIPEC (Lipid Processing EC)), which expresses genes involved in lipid processing that are regulated by PPAR-γ and is more abundant in peri-tumoral breast tissue. Retrospective analysis of 4648 BC patients reveals that treatment with metformin (an indirect PPAR-γ signaling activator) provides long-lasting clinical benefit and is positively associated with LIPEC abundance. Our findings warrant further exploration of this LIPEC/PPAR-γ link for BC treatment.

• MeSH
• endoteliální buňky patologie   MeSH
• imunita MeSH
• lidé MeSH
• ligandy MeSH
• lipidy MeSH
• metformin * farmakologie   MeSH
• nádory prsu * patologie   MeSH
• PPAR gama genetika   MeSH
• retrospektivní studie MeSH
• RNA MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ligandy MeSH
• lipidy MeSH
• metformin * MeSH
• PPAR gama MeSH
• RNA MeSH

BACKGROUND: Drug-drug interactions are a major concern in oncology and may potentially affect the outcome of patients with cancer. OBJECTIVE: In this study, we aimed to determine whether the concomitant use of statins, metformin, or proton pump inhibitors affects survival in patients with metastatic renal cell carcinoma treated with first-line combination therapies. METHODS: Medical records of patients with documented metastatic renal cell carcinoma between January 2016 and November 2021 were reviewed at 17 participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. Patients were assessed for overall survival, progression-free survival, and overall clinical benefit. Univariate and multivariate analyses were conducted to explore the association of variables of interest with overall survival and progression-free survival. RESULTS: A total of 304 patients receiving dual immunotherapy (51%) or immunotherapy/vascular endothelial growth factor-tyrosine kinase inhibitor (49%) combinations were eligible for inclusion in this retrospective study. Statin use was a significant prognostic factor for longer overall survival in a univariate analysis (hazard ratio 0.48, 95% confidence interval 0.26-0.87; p = 0.016) and a multivariate analysis (hazard ratio 0.48, 95% confidence interval 0.31-0.74; p < 0.001) and was significantly associated with an overall clinical benefit (83% in statin users vs 71% in non-users; p = 0.045). Otherwise, the use of metformin or proton pump inhibitors did not affect the outcome of these patients. CONCLUSIONS: Our study suggests a prognostic impact of statin use in patients receiving first-line immuno-oncology combinations. The mechanism of this interaction warrants further elucidation.

• MeSH
• inhibitory angiogeneze terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• inhibitory protonové pumpy farmakologie   terapeutické užití   MeSH
• karcinom z renálních buněk * patologie   MeSH
• lidé MeSH
• metformin * farmakologie   terapeutické užití   MeSH
• nádory ledvin * patologie   MeSH
• retrospektivní studie MeSH
• statiny * farmakologie   terapeutické užití   MeSH
• vaskulární endoteliální růstový faktor A MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory angiogeneze MeSH
• inhibitory proteinkinas MeSH
• inhibitory protonové pumpy MeSH
• metformin * MeSH
• statiny * MeSH
• vaskulární endoteliální růstový faktor A MeSH

Metformin, an oral antidiabetic drug, recently demonstrated a reducing effect on bile acids (BA) plasma concentrations in one patient with intrahepatic cholestasis of pregnancy (ICP) by unknown mechanism. Therefore, the aim of the present study was to examine the effect of metformin on BA homeostasis and related molecular pathways in the liver and intestine using a mouse model of ICP. The cholestasis was induced in female C57BL/6 mice by repeated administration of ethinylestradiol (10 mg/kg BW s.c.) and/or metformin (150 mg/kg BW orally) over 5 consecutive days with subsequent bile collection and molecular analysis of samples. We demonstrated that metformin significantly increased the rate of bile secretion in control mice. This increase was BA dependent and was produced both by increased liver BA synthesis via induced cholesterol 7α-hydroxylase (Cyp7a1) and by increased BA reabsorption in the ileum via induction of the apical sodium-dependent BA transporter (Asbt). In contrast, metformin further worsened ethinylestradiol-induced impairment of bile secretion. This reduction was also BA dependent and corresponded with significant downregulation of Bsep, and Ntcp, major excretory and uptake transporters for BA in hepatocytes, respectively. The plasma concentrations of BA were consequently significantly increased in the metformin-treated mice. Altogether, our data indicate positive stimulation of bile secretion by metformin in the intact liver, but this drug also induces serious impairment of BA biliary secretion, with a marked increase in plasma concentrations in estrogen-induced cholestasis. Our results imply that metformin should be used with caution in situations with hormone-dependent cholestasis, such as ICP.

• Klíčová slova
• Bile, Cholestasis, Ethinylestradiol, Metformin,
• MeSH
• cholestáza chemicky indukované   metabolismus   patologie   MeSH
• ethinylestradiol škodlivé účinky   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• homeostáza účinky léků   MeSH
• intestinální absorpce účinky léků   MeSH
• metformin farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ethinylestradiol MeSH
• metformin MeSH
• žlučové kyseliny a soli MeSH

Metformin can reduce cardiovascular risk independent of glycemic control. The mechanisms behind its non-glycemic benefits, which include decreased energy intake, lower blood pressure and improved lipid and fatty acid metabolism, are not fully understood. In our study, metformin treatment reduced myocardial accumulation of neutral lipids-triglycerides, cholesteryl esters and the lipotoxic intermediates-diacylglycerols and lysophosphatidylcholines in a prediabetic rat model (p < 0.001). We observed an association between decreased gene expression and SCD-1 activity (p < 0.05). In addition, metformin markedly improved phospholipid fatty acid composition in the myocardium, represented by decreased SFA profiles and increased n3-PUFA profiles. Known for its cardioprotective and anti-inflammatory properties, metformin also had positive effects on arachidonic acid metabolism and CYP-derived arachidonic acid metabolites. We also found an association between increased gene expression of the cardiac isoform CYP2c with increased 14,15-EET (p < 0.05) and markedly reduced 20-HETE (p < 0.001) in the myocardium. Based on these results, we conclude that metformin treatment reduces the lipogenic enzyme SCD-1 and the accumulation of the lipotoxic intermediates diacylglycerols and lysophosphatidylcholine. Increased CYP2c gene expression and beneficial effects on CYP-derived arachidonic acid metabolites in the myocardium can also be involved in cardioprotective effect of metformin.

• Klíčová slova
• arachidonic acid, cytochrome P450, fatty acid profile, lipotoxic intermediates, metformin, myocardial function, myocardial phospholipids, stearoyl-CoA desaturase,
• MeSH
• bazální metabolismus účinky léků   MeSH
• biologické markery krev   MeSH
• desaturasy mastných kyselin metabolismus   MeSH
• hyperlipoproteinemie typ IV farmakoterapie   metabolismus   MeSH
• hypoglykemika farmakologie   MeSH
• kardiotonika farmakologie   MeSH
• krysa rodu Rattus MeSH
• kyselina arachidonová metabolismus   MeSH
• mediátory zánětu krev   MeSH
• metabolismus lipidů účinky léků   MeSH
• metformin farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myokard metabolismus   MeSH
• potkani Wistar MeSH
• prediabetes farmakoterapie   metabolismus   MeSH
• rizikové faktory MeSH
• srdce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• desaturasy mastných kyselin MeSH
• hypoglykemika MeSH
• kardiotonika MeSH
• kyselina arachidonová MeSH
• mediátory zánětu MeSH
• metformin MeSH

BACKGROUND: Metformin is the most commonly used antidiabetic drug with a plethora of proven metabolic and cardiovascular beneficial effects and exceptional safety profile. On top of the established metabolic effects, retrospective epidemiologic evidence shows that metformin use is associated with decreased cancer risk and/or improved disease prognosis in diabetic cancer patients on metformin compared to those treated with different antidiabetic drugs. This is a sound argument for eventual repurposing metformin as an adjuvant drug in oncology; however, evidence-based data are currently needed to establish this. Metformin is a biguanide that in the context of type 2 diabetes primarily targets the liver. Metformin inhibits oxidative phosphorylation which leads to the suppression of gluconeogenesis and causes decrease of blood glucose concentration. Mechanisms responsible for metformin anti-neoplastic effect have been investigated extensively, and key events seem to centralize around its ability to induce intracellular energetic stress with subsequent changes of metabolism resulting in cytostatic or cytotoxic action. Large clinical experience with metformin in the treatment of diabetes together with its plausible effects on different cancer cell types initiated a number of clinical trials that tested the hypothesis that metformin might have a beneficial effect in the treatment of cancer. PURPOSE: The aim of this review is to compile recent advances in our understanding of metformin antineoplastic effects and to give a summary of the results of recent clinical trials of metformin for treatment of different cancer types.

• Klíčová slova
• AMPK, cancer, clinical trial, diabetes, metformin, treatment,
• MeSH
• adjuvantní chemoterapie MeSH
• diabetes mellitus 2. typu farmakoterapie   epidemiologie   MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• lékařská onkologie MeSH
• lidé MeSH
• metformin farmakologie   terapeutické užití   MeSH
• nádory farmakoterapie   epidemiologie   MeSH
• přehodnocení terapeutických indikací léčivého přípravku MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• hypoglykemika MeSH
• metformin MeSH
• protinádorové látky MeSH

Osteoporosis is an increasingly widespread disease, as well as diabetes mellitus. It is now accepted that osteoporotic fractures are a serious co-morbidity and complication of diabetes. Despite of good bone mineral density in Type 2 Diabetes (T2DM) patients is the fracture risk elevated. It is due to reduced bone quality. To determine the effect of glycemic compensation on bone density and trabecular bone score (TBS) in T2DM. We analyzed a cohort of 105 postmenopausal women with T2DM. For all patients, central bone density (spinal and lumbar spine) was tested by DXA methodology, glycemic control parameters were assessed, and anthropometric parameters were measured. Bone quality was analyzed using TBS software. The results were statistically processed. Good glycemic compensation with glycated hemoglobin (A1c) value <7.0 % DCCT did not lead to BMD changes in patients with T2DM. However, patients with HbA1c <7 % DCCT had significantly better TBS (1.254±0.148 vs. 1.166±0.094, p=0.01). There was a negative correlation between TBS and glycated hemoglobin (r= -0,112, p<0.05) with glycemic fasting (r= -0.117, p<0.05). The optimal effect on TBS is achieved when all three markers of glycemic compensation (glycated hemoglobin, fasting plasma glucose and postprandial glycemia) are in optimal range. By using ROC curves glycated hemoglobin has the most significant effect on TBS. Optimal glycemic compensation, evaluated by glycated hemoglobin, does not lead to changes in BMD but has a beneficial effect on TBS in T2DM. Good glycemic control is required also for reduction of the risk of osteoporosis and osteoporotic fractures.

• MeSH
• diabetes mellitus 2. typu krev   farmakoterapie   patologie   MeSH
• glykovaný hemoglobin metabolismus   MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• kostní denzita * MeSH
• lidé středního věku MeSH
• lidé MeSH
• metformin farmakologie   terapeutické užití   MeSH
• postmenopauza MeSH
• průřezové studie MeSH
• sitagliptin fosfát farmakologie   terapeutické užití   MeSH
• trabekulární kostní tkáň účinky léků   patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glykovaný hemoglobin MeSH
• hemoglobin A1c protein, human MeSH Prohlížeč
• hypoglykemika MeSH
• metformin MeSH
• sitagliptin fosfát MeSH

Patients with diabetes mellitus are at an increased risk of bone fractures. Several groups of effective antidiabetic drugs are available, which are very often given in combination. The effects of these medications on bone metabolism and fracture risk must not be neglected. Commonly used antidiabetic drugs might have a positive, neutral or negative impact on skeletal health. Increased risk of fracture has been identified with use of thiazolidinediones, most definitively in women. Also treatment with sulfonylureas can have adverse effects on bone. One consequence of these findings has been greater attention to fracture outcomes in trails of new diabetes medication (incretins and SGLT-2 inhibitors). The effect of insulin on bone is discussed and the risk of fractures in patients using insulin seems to be unrelated to insulin as itself. The aim of the review is to summarize effects of antidiabetic treatment on bone - bone mineral density, fractures and bone turnover markers. The authors also try to recommend a strategy how to treat patients with diabetes mellitus regarding the risk of osteoporotic fractures. In this review the problem of how to treat osteoporosis in patient with diabetes is also discussed.

• MeSH
• diabetes mellitus 2. typu komplikace   farmakoterapie   MeSH
• hypoglykemika škodlivé účinky   MeSH
• inhibitory kostní resorpce terapeutické užití   MeSH
• inkretiny farmakologie   MeSH
• inzulin farmakologie   MeSH
• kosti a kostní tkáň účinky léků   MeSH
• lidé MeSH
• metformin farmakologie   MeSH
• osteoporóza komplikace   diagnóza   farmakoterapie   MeSH
• sulfonylmočovinové sloučeniny škodlivé účinky   MeSH
• thiazolidindiony škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• hypoglykemika MeSH
• inhibitory kostní resorpce MeSH
• inkretiny MeSH
• inzulin MeSH
• metformin MeSH
• sulfonylmočovinové sloučeniny MeSH
• thiazolidindiony MeSH