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American Journal of Physiology.... Oct 2023The potential interaction between metformin and exercise on glucose-lowering effects remains controversial. We studied the separated and combined effects of metformin...
The potential interaction between metformin and exercise on glucose-lowering effects remains controversial. We studied the separated and combined effects of metformin and/or exercise on fasting and postprandial insulin sensitivity in individuals with pre-diabetes and type 2 diabetes (T2D). Eight T2D adults (60 ± 4 yr) with overweight/obesity (32 ± 4 kg·m) under chronic metformin treatment (9 ± 6 yr; 1281 ± 524 mg·day) underwent four trials; ) taking their habitual metformin treatment (MET), ) substituting during 96 h their metformin medication by placebo (PLAC), ) placebo combined with 50 min bout of high-intensity interval exercise (PLAC + EX), and ) metformin combined with exercise (MET + EX). Plasma glucose kinetics using stable isotopes (6,6-H and [U-C] glucose), and glucose oxidation by indirect calorimetry, were assessed at rest, during exercise, and in a subsequent oral glucose tolerance test (OGTT). Postprandial glucose and insulin concentrations were analyzed as mean and incremental area under the curve (iAUC), and insulin sensitivity was calculated (i.e., MATSUDA and OGIS). During OGTT, metformin reduced glucose iAUC (i.e., MET and MET + EX lower than PLAC and PLAC + EX, respectively; = 0.023). MET + EX increased MATSUDA above PLAC (4.8 ± 1.4 vs. 3.3 ± 1.0, respectively; = 0.018) and OGIS above PLAC (358 ± 52 vs. 306 ± 46 mL·min·m, respectively; = 0.006). Metformin decreased the plasma appearance of the ingested glucose (R OGTT; MET vs. PLAC, -3.5; 95% CI -0.1 to -6.8 µmol·kg·min; = 0.043). Metformin combined with exercise potentiates insulin sensitivity during an OGTT in individuals with pre-diabetes and type 2 diabetes. Metformin's blood glucose-lowering effect seems mediated by decreased oral glucose entering the circulation (gut-liver effect) an effect partially blunted after exercise. Metformin is the most prescribed oral antidiabetic medicine in the world but its mechanism of action and its interactions with exercise are not fully understood. Our stable isotope tracer data suggested that metformin reduces the rates of oral glucose entering the circulation (gut-liver effect). Exercise, in turn, tended to reduce postprandial insulin blood levels potentiating metformin improvements in insulin sensitivity. Thus, exercise potentiates metformin improvements in glycemic control and should be advised to metformin users.
Topics: Adult; Humans; Metformin; Glucose; Prediabetic State; Insulin Resistance; Diabetes Mellitus, Type 2; Kinetics; Blood Glucose; Insulin
PubMed: 37584610
DOI: 10.1152/ajpendo.00118.2023 -
Biomedicines Feb 2024Endothelin-1 (ET-1) plays a physiological role as a potent vasoconstrictor. It is implicated in an array of diseases, and its signalling is often found to be... (Review)
Review
Endothelin-1 (ET-1) plays a physiological role as a potent vasoconstrictor. It is implicated in an array of diseases, and its signalling is often found to be overactivated within cancers. ET-1 has been found to potentiate hallmarks of cancer progression such as cell proliferation, invasion and metastasis, as well as angiogenesis. ET-1 has also been implicated in inducing the epithelial-mesenchymal transition (EMT) and promoting resistance to anticancer drugs. Many preclinical efforts have been made to target ET-1 expression within cancer, such as by using ET-1 receptor antagonists, many of which have been approved for treating pulmonary hypertension. Targeting ET-1 has been shown to improve the response to various other cancer therapeutics, highlighting the potential benefits targeting this peptide may exert. Drug repurposing is an attractive strategy, and exploration of this avenue may be promising for targeting ET-1 in cancer. There are many clinical trials which have been completed and are currently undergoing involving the repurposing of ET-1 receptor antagonists for cancer treatment. In this review, the pathways through which ET-1 potentiates cancer will be discussed, as well as where the opportunity for therapeutic intervention lies in relation to cancer.
PubMed: 38540124
DOI: 10.3390/biomedicines12030511 -
BioRxiv : the Preprint Server For... Mar 2024The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads...
The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify novel CFTR modulators. We docked ~155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered novel mid-nanomolar potentiators as well as inhibitors that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.
PubMed: 37745391
DOI: 10.1101/2023.09.09.557002 -
Biological Psychiatry Mar 2024Current diagnosis and treatment of psychiatric illnesses are still based on behavioral observations and self-reports, commonly leading to prolonged untreated illness.... (Review)
Review
Current diagnosis and treatment of psychiatric illnesses are still based on behavioral observations and self-reports, commonly leading to prolonged untreated illness. Biological markers (biomarkers) may offer an opportunity to revolutionize clinical psychiatry practice by helping provide faster and potentially more effective therapies. Transcranial magnetic stimulation concurrent with electroencephalography (TMS-EEG) is a noninvasive brain mapping methodology that can assess the functions and dynamics of specific brain circuitries in awake humans and aid in biomarker discovery. This article provides an overview of TMS-EEG-based biomarkers that may hold potential in psychiatry. The methodological readiness of the TMS-EEG approach and steps in the validation of TMS-EEG biomarkers for clinical utility are discussed. Biomarker discovery with TMS-EEG is in the early stages, and several validation steps are still required before clinical implementations are realized. Thus far, TMS-EEG predictors of response to magnetic brain stimulation treatments in particular have shown promise for translation to clinical practice. Larger-scale studies can confirm validation followed by biomarker-informed trials to assess added value compared to existing practice.
Topics: Humans; Transcranial Magnetic Stimulation; Electroencephalography; Brain; Psychiatry; Biomarkers; Evoked Potentials
PubMed: 38142721
DOI: 10.1016/j.biopsych.2023.12.018 -
Cell Reports Nov 2023Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key...
Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti-tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises anti-tumor immunity in vivo. Mechanistically, VCP transcriptionally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC.
Topics: Animals; Mice; Humans; Valosin Containing Protein; B7-H1 Antigen; Immunotherapy; Oncolytic Viruses; Colorectal Neoplasms; Tumor Microenvironment; Cell Line, Tumor
PubMed: 37865914
DOI: 10.1016/j.celrep.2023.113318 -
Inflammation and Regeneration Nov 2023Inflammatory bowel disease (IBD) is a multifactorial intractable intestinal disease. Focusing on only one facet of the pathogenesis of IBD is insufficient to fully... (Review)
Review
Inflammatory bowel disease (IBD) is a multifactorial intractable intestinal disease. Focusing on only one facet of the pathogenesis of IBD is insufficient to fully capture the complexity of the disease, and results in limited advance in clinical management. Therefore, it is critical to dissect the interactions amongst the multifarious contributors to the pathogenesis to comprehensively understand its pathology and subsequently improve clinical outcomes. In this context, the systemic interactions between organs, particularly the oral-gut axis mediated by host immune cells and resident microorganisms, have garnered significant attention in IBD research. More specifically, periodontal disease such as periodontitis has been implicated in augmenting intestinal inflammation beyond the confines of the oral cavity. There is mounting evidence suggesting that potentially harmful oral resident bacteria, termed pathobionts, and pro-inflammatory immune cells from the oral mucosa can migrate to the gastrointestinal tract, thereby potentiating intestinal inflammation. This article aims to provide a holistic overview of the causal relationship between periodontal disease and intestinal inflammation. Furthermore, we will discuss potential determinants that facilitate the translocation of oral pathobionts into the gut, a key event underpinning the oral-gut axis. Unraveling the complex dynamics of microbiota and immunity in the oral-gut continuum will lead to a better understanding of the pathophysiology inherent in both oral and intestinal diseases and the development of prospective therapeutic strategies.
PubMed: 37932859
DOI: 10.1186/s41232-023-00304-3 -
Cell Reports Oct 2023The amygdala, cholinergic basal forebrain, and higher-order auditory cortex (HO-AC) regulate brain-wide plasticity underlying auditory threat learning. Here, we perform...
The amygdala, cholinergic basal forebrain, and higher-order auditory cortex (HO-AC) regulate brain-wide plasticity underlying auditory threat learning. Here, we perform multi-regional extracellular recordings and optical measurements of acetylcholine (ACh) release to characterize the development of discriminative plasticity within and between these brain regions as mice acquire and recall auditory threat memories. Spiking responses are potentiated for sounds paired with shock (CS+) in the lateral amygdala (LA) and optogenetically identified corticoamygdalar projection neurons, although not in neighboring HO-AC units. Spike- or optogenetically triggered local field potentials reveal enhanced corticofugal-but not corticopetal-functional coupling between HO-AC and LA during threat memory recall that is correlated with pupil-indexed memory strength. We also note robust sound-evoked ACh release that rapidly potentiates for the CS+ in LA but habituates across sessions in HO-AC. These findings highlight a distributed and cooperative plasticity in LA inputs as mice learn to reappraise neutral stimuli as possible threats.
Topics: Mice; Animals; Acoustic Stimulation; Learning; Basolateral Nuclear Complex; Amygdala; Acetylcholine; Cholinergic Agents
PubMed: 37742187
DOI: 10.1016/j.celrep.2023.113167 -
Signal Transduction and Targeted Therapy Dec 2023Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been the most challenging subtype of BC, consisting of 20% of BC with an apparent...
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been the most challenging subtype of BC, consisting of 20% of BC with an apparent correlation with poor prognosis. Despite that pyrotinib, a new HER2 inhibitor, has led to dramatic improvements in prognosis, the efficacy of pyrotinib monotherapy remains largely restricted due to its acquired resistance. Therefore, identifying a new potential antitumor drug in combination with pyrotinib to amplify therapeutic efficacy is a pressing necessity. Here, we reported a novel combination of pyrotinib with chrysin and explored its antitumor efficacy and the underlying mechanism in HER2-positive BC. We determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce more evident cell cycle arrest, inhibit the proliferation of BT-474 and SK-BR-3 BC cells, and repress in vivo tumor growth in xenograft mice models. This may be attributed to enhanced autophagy induced by endoplasmic reticulum stress. Furthermore, the combined treatment of pyrotinib and chrysin induced ubiquitination and glucose-6-phosphate dehydrogenase (G6PD) degradation by upregulating zinc finger and BTB/POZ domain-containing family protein 16 (ZBTB16) in tumorigenesis of BC. Mechanistically, we identified that miR-16-5p was a potential upstream regulator of ZBTB16, and it showed a significant inverse correlation with ZBTB16. Inhibition of miR-16-5p overexpression by restoring ZBTB16 significantly potentiated the overall antitumor efficacy of pyrotinib combined with chrysin against HER2-positive BC. Together, these findings demonstrate that the combined treatment of pyrotinib and chrysin enhances autophagy in HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis.
Topics: Humans; Mice; Animals; Female; Breast Neoplasms; MicroRNAs; Autophagy
PubMed: 38110365
DOI: 10.1038/s41392-023-01689-w -
Behavioural Pharmacology Sep 2023Stress contributes to numerous psychopathologies, including memory impairment, and threatens one's well-being. It has been reported that creatine supplementation...
Stress contributes to numerous psychopathologies, including memory impairment, and threatens one's well-being. It has been reported that creatine supplementation potentially influences cognitive processing. Hence, in this study, we examined the effects of creatine supplementation on memory, synaptic plasticity, and neuronal arborization in the CA1 region of the hippocampus in rats under chronic restraint stress (CRS). Thirty-two adult male Wistar rats (8 weeks old) weighing 200-250 g were randomly divided into four groups (n = 8/per group): control, stress, creatine, and stress + creatine. CRS was induced for 6 h per day for 14 days, and creatine supplementation was carried out by dissolving creatine (2 g/kg body weight per day) in the animals' drinking water for 14 days. We used the Barnes maze and shuttle box for spatial and passive avoidance memory examination. The in-vivo field potential recording and Golgi-Cox staining were also used to investigate long-term potentiation (LTP) and dendrite arborization in the CA1 pyramidal neurons. Chronic stress impaired spatial memory, dysregulated LTP parameters, and decreased the number of dendrites in the CA1 pyramidal neurons of stressed rats, and creatine supplementation modified these effects in stressed rats. It seems that creatine supplementation can improve spatial memory deficits and synaptic plasticity loss induced by CRS in hippocampal CA1 neurons, possibly by reducing the dendrite arborization damages. However, understanding its mechanism needs further investigation.
Topics: Rats; Male; Animals; Long-Term Potentiation; Creatine; Spatial Memory; Rats, Wistar; Hippocampus; Neuronal Plasticity; Memory Disorders; Dietary Supplements; Maze Learning
PubMed: 37462147
DOI: 10.1097/FBP.0000000000000739 -
Translational Research : the Journal of... Oct 2023In hepatocellular carcinoma (HCC), sorafenib (Sora) efficacy is limited by primary and/or acquired resistance. Emerging evidence shows that the inflammatory factor...
In hepatocellular carcinoma (HCC), sorafenib (Sora) efficacy is limited by primary and/or acquired resistance. Emerging evidence shows that the inflammatory factor interleukin 6 (IL-6) plays a role in Sora resistance. Norcantharidin (NCTD), a derivative of cantharidine, was identified as a potent IL-6 inhibitor. Thus, in this study, we evaluated NCTD ability to improve the Sora efficacy in HCC and its underlying molecular mechanisms. Male Sprague Dawely rats were administered NCTD (0.1 mg/kg/day; orally) or Sora (10 mg/kg day; orally) or combination for 6 weeks after HCC induction using thioacetamide (200 mg/kg; ip; 2 times/wk) for 16 weeks. Our results showed that NCTD greatly enhanced Sora activity against HCC and potentiated Sora-induced oxidative stress. NCTD enhanced Sora-induced tumor immunity reactivation by decreasing both fibrinogen-like protein 1 level and increasing both tumor necrosis factor-α gene expression along with CD8+ T cells number. Also, NCTD augmented Sora attenuation activity against TAA-induced angiogenesis and metastasis by decreasing VEGFA, HIF-1α, serum lactate dehydrogenase enzyme, and vimentin levels. The combined use of NCTD/Sora suppressed drug resistance and stemness by downregulating ATP-binding cassette subfamily G member 2, neurogenic locus notch homolog protein, spalt-like transcription factor 4, and CD133. NCTD boosted Sora antiproliferative and apoptotic activities by decreasing Ccnd1 and BCL2 expressions along with increasing BAX and caspase-3 expressions. To our knowledge, this study represents the first study providing evidence for the potential novel therapeutic use of NCTD/Sora combination for HCC. Moreover, no previous studies have reported the effect of NCTD on FGL1.
Topics: Male; Rats; Animals; Carcinoma, Hepatocellular; Sorafenib; Interleukin-6; Liver Neoplasms; Cell Line, Tumor; Antineoplastic Agents
PubMed: 37257560
DOI: 10.1016/j.trsl.2023.05.005