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Viruses Jun 2024Lipids, as a fundamental cell component, play an regulating role in controlling the different cellular biological processes involved in viral infections. A notable...
BACKGROUND
Lipids, as a fundamental cell component, play an regulating role in controlling the different cellular biological processes involved in viral infections. A notable feature of coronavirus disease 2019 (COVID-19) is impaired lipid metabolism. The function of lipophagy-related genes in COVID-19 is unknown. The present study aimed to investigate biomarkers and drug targets associated with lipophagy and lipophagy-based therapeutic agents for COVID-19 through bioinformatics analysis.
METHODS
Lipophagy-related biomarkers for COVID-19 were identified using machine learning algorithms such as random forest, Support Vector Machine-Recursive Feature Elimination, Generalized Linear Model, and Extreme Gradient Boosting in three COVID-19-associated GEO datasets: scRNA-seq (GSE145926) and bulk RNA-seq (GSE183533 and GSE190496). The cMAP database was searched for potential COVID-19 medications.
RESULTS
The lipophagy pathway was downregulated, and the lipid droplet formation pathway was upregulated, resulting in impaired lipid metabolism. Seven lipophagy-related genes, including , , , , , , and , were used as biomarkers and drug targets for COVID-19. Moreover, lipophagy may play a role in COVID-19 pathogenesis. As prospective drugs for treating COVID-19, seven potential downregulators (phenoxybenzamine, helveticoside, lanatoside C, geldanamycin, loperamide, pioglitazone, and trichostatin A) were discovered. These medication candidates showed remarkable binding energies against the seven biomarkers.
CONCLUSIONS
The lipophagy-related genes , , , , , , and can be used as biomarkers and drug targets for COVID-19. Seven potential downregulators of these seven biomarkers may have therapeutic effects for treating COVID-19.
Topics: Humans; SARS-CoV-2; COVID-19 Drug Treatment; Biomarkers; COVID-19; Lipid Metabolism; Antiviral Agents; Computational Biology; Machine Learning; Lactams, Macrocyclic; Hydroxamic Acids; Benzoquinones
PubMed: 38932215
DOI: 10.3390/v16060923 -
Microorganisms Jun 2024(), a protozoan parasite prevalent in North America, is a significant threat for human health. Given the regulatory role of pyruvate kinase I (PyK I) in glycolytic...
(), a protozoan parasite prevalent in North America, is a significant threat for human health. Given the regulatory role of pyruvate kinase I (PyK I) in glycolytic metabolism flux and ATP generation, PyK I has been considered the target for drug intervention for a long time. In this study, PyK I (BdPyK I) was successfully cloned, expressed, and purified. Polyclonal antibodies were confirmed to recognize the native BdPyK I protein (56 kDa) using Western blotting. AlphaFold software predicted the three-dimensional structure of BdPyK I, and molecular docking with small molecules was conducted to identify potential binding sites of inhibitor on BdPyK I. Moreover, inhibitory effects of six inhibitors (tannic acid, apigenin, shikonin, PKM2 inhibitor, rosiglitazone, and pioglitazone) on BdPyK I were examined under the optimal enzymatic conditions of 3 mM PEP and 3 mM ADP, and significant activity reduction was found. Enzyme kinetics and growth inhibition assays further confirmed the reliability of these inhibitors, with PKM2 inhibitor, tannic acid, and apigenin exhibiting the highest selectivity index as specific inhibitors for . Subsequently, key amino acid residues were mutated in both BdPyK I and Homo sapiens pyruvate kinase I (HPyK I), and two differential amino acid residues (isoleucine and phenylalanine) were identified between HPyK I and BdPyK I through PyK activity detection experiments. These findings lay foundation for understanding the role of PyK I in the growth and development of , providing insights for babesiosis prevention and drug development.
PubMed: 38930523
DOI: 10.3390/microorganisms12061141 -
Medicina (Kaunas, Lithuania) Jun 2024: The objective of this study is to investigate how different therapies modulating insulin resistance, either causally or consequently, affect metabolic parameters in...
: The objective of this study is to investigate how different therapies modulating insulin resistance, either causally or consequently, affect metabolic parameters in treatment-naïve subjects with T2DM. : A total of 212 subjects were assigned to receive either a tight Japanese diet ( = 65), pioglitazone at doses ranging from 15-30 mg/day ( = 70), or canagliflozin at doses ranging from 50-100 mg/day ( = 77) for a duration of three months. Correlations and changes (Δ) in metabolic parameters relative to insulin resistance were investigated. : Across these distinct therapeutic interventions, ΔHOMA-R exhibited significant correlations with ΔFBG and ΔHOMA-B, while demonstrating a negative correlation with baseline HOMA-R. However, other parameters such as ΔHbA1c, ΔBMI, ΔTC, ΔTG, Δnon-HDL-C, or ΔUA displayed varying patterns depending on the treatment regimens. Participants were stratified into two groups based on the median value of ΔHOMA-R: the lower half (X) and upper half (Y). Group X consistently demonstrated more pronounced reductions in FBG compared to Group Y across all treatments, while other parameters including HbA1c, HOMA-B, TC, TG, HDL-C, non-HDL-C, TG/HDL-C ratio, or UA exhibited distinct regulatory responses depending on the treatment administered. : These findings suggest that (1) regression to the mean is observed in the changes in insulin resistance across these therapies and (2) the modulation of insulin resistance with these therapies, either causally or consequentially, results in differential effects on glycemic parameters, beta-cell function, specific lipids, body weight, or UA.
Topics: Humans; Diabetes Mellitus, Type 2; Insulin Resistance; Male; Female; Middle Aged; Pioglitazone; Hypoglycemic Agents; Canagliflozin; Blood Glucose; Aged; Glycated Hemoglobin; Adult
PubMed: 38929608
DOI: 10.3390/medicina60060991 -
PloS One 2024Stroke stands as a significant macrovascular complication among individuals with Type 2 diabetes mellitus (T2DM), often resulting in the primary cause of mortality and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Stroke stands as a significant macrovascular complication among individuals with Type 2 diabetes mellitus (T2DM), often resulting in the primary cause of mortality and disability within this patient demographic. Presently, numerous studies have been conducted to investigate the underlying causes of stroke in individuals with T2DM, yet the findings exhibit inconsistencies.
OBJECTIVE
This paper aims to consolidate and summarize the available evidence concerning the influential factors contributing to stroke among patients diagnosed with T2DM.
METHODS
We conducted a comprehensive search across multiple databases, including Cochrane Library, PubMed, Web Of Science, Embase, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Weipu up to August 2023. Google Scholar was also searched to retrieve gray literature. We calculated odds ratios (OR) and 95% confidence intervals (CI) using Stata software.
RESULTS
Our analysis encompassed 43 observational studies, exploring factors across sociodemographic, biochemical, complications, and hypoglycemic agent categories. The findings identified several risk factors for stroke in patients with T2DM: age, gender, T2DM duration, hypertension, body-mass index (BMI), smoking, Glycated hemoglobin (HbA1c), estimated Glomerular Filtration Rate (eGFR), albuminuria, Triglycerides (TG), Low density lipoprotein cholesterol (LDL-C), Coronary heart disease (CHD), Atrial fibrillation (AF), diabetic retinopathy (DR), Peripheral vascular disease (PVD), and carotid plaque. Conversely, exercise, High density lipoprotein cholesterol (HDL-C), metformin (MET), pioglitazone, and metformin combination therapy emerged as protective factors.
CONCLUSION
This study underscores the multitude of influencing factors contributing to stroke in people with T2DM patients, among which the microvascular complications of T2DM play an most important role. Therefore, we emphasize the importance of screening for microvascular complications in patients with T2DM. However, due to limitations arising from the number of articles reviewed, there remain areas where clarity is lacking. Further research efforts are warranted to expand upon and reinforce our current findings.
Topics: Diabetes Mellitus, Type 2; Humans; Stroke; Risk Factors; Hypoglycemic Agents; Glycated Hemoglobin
PubMed: 38913694
DOI: 10.1371/journal.pone.0305954 -
PPAR Research 2024Partial and full PPAR- agonists have shown promising effects and antihypertensive and antidiabetic agents through increased plasma adiponectin concentration. This study...
Partial and full PPAR- agonists have shown promising effects and antihypertensive and antidiabetic agents through increased plasma adiponectin concentration. This study is aimed at examining the role of PPAR-, alpha-adrenoceptors, and adiponectin receptors in the modulation of vasopressor responses to angiotensin II (Ang II) and adrenergic agonists, after a subset treatment of partial and full PPAR- agonists, each individually, and also when coupled with adiponectin in SHRs. The antioxidant potential and metabolic indices for these animals were also determined. Group I (WKY) and group II (SHR) were designated as normotensive control and hypertensive control, respectively. Groups III (SHR) and IV (SHR) received irbesartan (30 mg/kg) and pioglitazone (10 mg/kg) orally for 28 days, and groups V (SHR), VI (SHR), and VII (SHR) were treated with adiponectin (2.5 g/kg) intraperitoneally alone, in combination with irbesartan, and in combination with pioglitazone, respectively, from days 21 to 28 only. On day 29, sodium pentobarbitone (60 mg/kg) was used to anesthetize all test animals, and systemic hemodynamic and plasma adiponectin concentrations and and antioxidant potential were measured. As compared to the WKY control, the SHR control group's noninvasive blood pressure and basal mean arterial pressure were significantly greater, along with increased arterial stiffness, lower plasma nitric oxide, adiponectin concentration, and antioxidant enzyme levels (all < 0.05). However, they were gradually normalized by single drug treatments in all groups, and to a greater extent in the SHR + Irb + Adp group ( < 0.05). In the acute study, the dose dependant mean arterial pressure responses to intravenously administered adrenergic agonists and angiotensin-II were significantly larger in SHRs as compared to WKY by 20-25%. Adiponectin alone and in combination significantly blunted vasopressor responses to these alpha-adrenergic agonists in the SHR + Pio + Adp group by 63%, whereas attenuated responses to ANG-II administration to 70% in SHR + Irb + Adp. In conclusion, the combined treatment of adiponectin with PPAR-agonists reduced the systemic vascular responses to adrenergic agonists and improved arterial stiffness. This an evidence of the interaction of adiponectin receptors, PPAR-, alpha-adrenoceptors, and ANG-II in the systemic vasculature of SHRs. A significant level of synergism has also been proved among full PPAR- agonists and adiponectin receptors.
PubMed: 38899161
DOI: 10.1155/2024/5868010 -
Frontiers in Endocrinology 2024The progression of carotid intima-media thickness (cIMT) can partially predict the occurrence of future cardiovascular events. This network meta-analysis compared the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The progression of carotid intima-media thickness (cIMT) can partially predict the occurrence of future cardiovascular events. This network meta-analysis compared the effects of 14 antidiabetic drugs (acarbose, alogliptin, exenatide, glibenclamide, glimepiride, ipragliflozin, metformin, nateglinide, pioglitazone, rosiglitazone, sitagliptin, tofoglifozin, troglitazone, voglibose) on the progression of cIMT.
METHOD
PubMed, EMBASE, Cochrane Library, and Web of Science were searched to screen all clinical trials of treatment of cIMT with hypoglycemic agents before March 1, 2024. The differences in the changes in cIMT between the treatment group and control group were evaluated.
RESULT
After screening 8395 citations, 25 studies (6675 patients) were included. The results indicated that exenatide had the best efficacy in slowing down cIMT progress, and exenatide [MD=-0.13,95%CI (-0.25, -0.01)], alogliptin [MD=-0.08,95%CI (-0.13, -0.02)] and metformin [MD=-0.05, 95%CI (-0.09, -0.02)] are more effective than placebo.
CONCLUSION
Long-term treatment of exenatide, alogliptin, and metformin may be more effective than other hypoglycemic drugs in slowing the progression of cIMT.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024519474.
Topics: Humans; Hypoglycemic Agents; Carotid Intima-Media Thickness; Network Meta-Analysis; Disease Progression; Diabetes Mellitus, Type 2
PubMed: 38883606
DOI: 10.3389/fendo.2024.1403606 -
Progress in Neuro-psychopharmacology &... Jun 2024The various pharmacological interventions, ranging from mood stabilizers and antipsychotics to antidepressants, reflect the diff/iculty of treating depressive/manic... (Review)
Review
BACKGROUND
The various pharmacological interventions, ranging from mood stabilizers and antipsychotics to antidepressants, reflect the diff/iculty of treating depressive/manic symptomatology of bipolar disorder (BD). Among a broad range of mechanisms implicated, immune dysregulation may contribute to the increased inflammation that influences the course of BD. Inflammatory, neurotrophic and oxidative stress factors may be identified as promising peripheral biomarkers in brain functioning, perhaps serving as predictors of an effective response to treatment for BD. The present systematic review aimed to examine the evidence supporting the pharmacotherapeutic value of inflammatory and neurotrophic biomarkers in BD.
METHODS
PubMed, PsychINFO, Scopus and Web of Science were searched from inception to May 2024 by two independent reviewers. A total of 40 studies with 3371 patients with diagnosis and intervention of BD were selected.
RESULTS
Inconsistencies in the effects of pharmacological treatments on the connection between the expected anti-inflammatory response and symptomatologic improvement were identified. Mood stabilizers (lithium), antipsychotics (quetiapine), antidepressants (ketamine) or their combination were described to increase both pro-inflammatory (TNFα, IL-6) and anti-inflammatory (IL-4, IL-8) factors. Other medications, such as memantine and dextromethorphan, autoimmune (infliximab) non-steroidal anti-inflammatory (aspirin, celecoxib) drugs, antidiabetics (pioglitazone), and even dietary supplementation (omega-3), or their combination, clearly decrease inflammatory factors (TNFα, IL-6, IL-1β, C-reactive protein) and/or increase the neurotrophic factor BDNF in BD patients.
CONCLUSION
Inflammation in BD requires further investigation to understand the underlying immunologic mechanism, to identify predictors of treatment response, and to make informed decisions about the use and development of more effective pharmacological interventions for BD.
PubMed: 38879067
DOI: 10.1016/j.pnpbp.2024.111056 -
Frontiers in Pharmacology 2024Drug-induced liver injury is a prevalent adverse event associated with pharmaceutical agents. More significantly, there are certain drugs that present severe...
Drug-induced liver injury is a prevalent adverse event associated with pharmaceutical agents. More significantly, there are certain drugs that present severe hepatotoxicity only during the clinical phase, consequently leading to the termination of drug development during clinical trials or the withdrawal from the market after approval. The establishment of an evaluation model that can sensitively manifest such hepatotoxicity has always been a challenging aspect in drug development. In this study, we build a liver-immune-microphysiological-system (LIMPS) to fully demonstrate the liver injury triggered by troglitazone (TGZ), a drug that was withdrawn from the market due to hepatotoxicity. Leveraging the capabilities of organ-on-chip technology allows for the dynamic modulation of cellular immune milieu, as well as the synergistic effects between drugs, hepatocytes and multiple immune cells. Through the LIMPS, we discovered that 1) TGZ can promote neutrophils to adhered hepatocytes, 2) the presence of TGZ enhances the crosstalk between macrophages and neutrophils, 3) the induction of damage in hepatocytes by TGZ at clinically relevant blood concentrations not observed in other experiments, 4) no hepatotoxicity was observed in LIMPS when exposed to rosiglitazone and pioglitazone, structurally similar analogs of TGZ, even at the higher multiples of blood drug concentration levels. As an immune-mediated liver toxicity assessment method, LIMPS is simple to operate and can be used to test multiple drug candidates to detect whether they will cause severe liver toxicity in clinical settings as early as possible.
PubMed: 38873410
DOI: 10.3389/fphar.2024.1335836 -
Cureus May 2024The relationship between type 2 diabetes mellitus (T2DM) and depression presents a significant area of medical concern, characterized by a higher incidence of depression...
The relationship between type 2 diabetes mellitus (T2DM) and depression presents a significant area of medical concern, characterized by a higher incidence of depression among T2DM patients compared to the general population. This connection is not only evidenced in the prevalence of depressive symptoms in diabetic patients but also in the way these symptoms impact diabetes management. Furthermore, the influence of antidiabetic medications, especially sodium-glucose cotransporter-2 (SGLT2) inhibitors, on depression risk is a topic of ongoing research, with contrasting findings regarding the effects of drugs like metformin and pioglitazone. The aim of this study is to provide a comprehensive analysis of the relationship between T2DM and depression, focusing on the prevalence of depressive symptoms among diabetic patients, and the role of antidiabetic medications in modulating depression risk. Methods Utilizing data from the National Health and Nutrition Examination Survey (NHANES), we focused on individuals with T2DM. Depression status was assessed using the nine-item Patient Health Questionnaire (PHQ-9), a validated tool for evaluating depressive symptoms. Participants' depression status was categorized based on PHQ-9 composite scores. The analysis included demographic variables and the use of antidiabetic medications, with a focus on SGLT2 inhibitors. Logistic regression models adjusted for age, race/ethnicity, and BMI were employed. Results Our study involved 23,575 participants, of which 7,862 had T2DM. A significant difference in age and BMI was observed between diabetic and non-diabetic groups. Logistic regression analysis indicated that non-diabetic individuals had a significantly lower likelihood of depression compared to diabetic patients not on SGLT2 inhibitors. However, no statistically significant difference in depression levels was found between diabetic patients on SGLT2 inhibitors and those not on these medications. Conclusion These findings highlight the complex relationship between diabetes, antidiabetic medication, and depression. Notably, we found no significant impact of SGLT2 inhibitors on depression in diabetic patients, challenging previous assumptions about the role of specific antidiabetic drugs in mental health. We also revealed that older diabetic individuals reported fewer depressive symptoms, suggesting the influence of psychosocial factors and the need for age-specific depression management strategies. This research underscores the necessity of further studies to explore the nuanced effects of different antidiabetic medications on mental health outcomes, guiding toward more personalized treatment approaches for the mental health challenges in T2DM.
PubMed: 38872673
DOI: 10.7759/cureus.60270 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Jun 2024This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing...
BACKGROUND
This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing histopathological, immunohistochemical, and biochemical analyses in an experimental adhesion model.
METHODS
Fifty Wistar-Albino rats were divided into five groups: Group I (Control), Group II (Sham Treatment), Group III (Hy-aluronic Acid), Group IV (Metformin), and Group V (Pioglitazone). Adhesions were induced in the experimental groups, except for the sham group, using the scraping method. After 10 days, rats were euthanized for evaluation. Macroscopic adhesion degrees were assessed using Nair's scoring system. Immunohistochemical and enzyme-linked immunosorbent assay (ELISA) methods were utilized to assess serum, peritoneal lavage, and intestinal tissue samples. Fructosamine, interleukin-6 (IL-6), transforming growth factor-beta (TGF-β), and fibronectin levels were measured in serum and peritoneal lavage samples.
RESULTS
The groups exhibited similar Nair scores and Type I or Type III Collagen staining scores (all, p>0.05). Pioglitazone significantly reduced serum IL-6 and TGF-β levels compared to controls (p=0.002 and p=0.008, respectively). Both metformin and pioglitazone groups showed elevated IL-6 in peritoneal lavage relative to controls, while fibronectin levels in the lavage were lower in pioglitazone-treated rats compared to the sham group (all, p<0.005).
CONCLUSION
Pioglitazone, but not metformin, demonstrated a positive biochemical impact on preventing PIAA formation in an experimental rat model, although histological impacts were not observed. Further experimental studies employing different dose/duration regimens of pioglitazone are needed to enhance our understanding of its effect on PIAA formation.
Topics: Animals; Pioglitazone; Metformin; Tissue Adhesions; Rats, Wistar; Rats; Disease Models, Animal; Hypoglycemic Agents; Male; Thiazolidinediones; Postoperative Complications
PubMed: 38863295
DOI: 10.14744/tjtes.2024.61732