Journal of Basic and Clinical Physiology and Pharmacology最新文献

Alzheimer's disease (AD) is spreading its root disproportionately among the worldwide population. Many genes have been identified as the hallmarks of AD. Based upon the knowledge, many clinical trials have been designed and conducted. Attempts have been made to alleviate the pathology associated with AD by targeting the molecular products of these genes. Irrespective of the understanding on the genetic component of AD, many clinical trials have failed and imposed greater challenges on the path of drug discovery. Therefore, this review aims to identify research and review articles to pinpoint the limitations of drug candidates (thiethylperazine, CT1812, crenezumab, CNP520, and lecanemab), which are under or withdrawn from clinical trials. Thorough analysis of the cross-talk pathways led to the identification of many confounding factors, which could interfere with the success of clinical trials with drug candidates such as thiethylperazine, CT1812, crenezumab, and CNP520. Though these drug candidates were enrolled in clinical trials, yet literature review shows many limitations. These limitations raise many questions on the rationale behind the enrollments of these drug candidates in clinical trials. A meticulous prior assessment of the outcome of clinical studies may stop risky clinical trials at their inceptions. This may save time, money, and resources.

Objectives: Lifestyle, overnutrition, socioeconomic status, environmental conditions, and genetics are factors that cause obesity. Lifestyle modification with a nonpharmacological approach based on physical exercise is the starting point in overcoming obesity. However, physical exercise with the appropriate and effective intensity for obese subjects is still debated. Therefore, this study aims to prove the effect of intensity differences with aerobic-resistance combination exercise on increasing irisin and IL-6 levels in obese women.

Methods: A total of 32 obese women were selected as subjects and administered the interventions of low-intensity combination exercise (Q₂), moderate-intensity combination exercise (Q₃), and high-intensity combination exercise (Q₄). ELISA was used to measure irisin and IL-6 levels in all samples. Statistical analysis used one-way ANOVA and Turkey's-Honest Significant Difference (HSD) post hoc test.

Results: The mean Δ IL-6 levels in the control groups (Q₁), Q₂, Q₃, and Q₄ were 0.27 ± 2.54, 2.07 ± 2.55, 5.99 ± 6.25, and 7.98 ± 2.82 pg/mL with (p=0.015). The mean Δ irisin levels were 0.06 ± 0.81 ng/mL in Q₁, 0.59 ± 0.67 ng/mL in Q₂, 1.99 ± 1.65 ng/mL in Q₃, 4.63 ± 3.57 ng/mL in Q₄ with (p=0.001).

Conclusions: This study proved that all three types of combined exercise intensity increased myokine levels, such as irisin and IL-6. However, high-intensity combination exercise provided the most optimal improvement in myokine levels in obese women. Future studies are needed to design long-term exercise programs specifically for obese adolescent women using the findings from this study.

Objectives: Empagliflozin, a sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, are commonly recognized for their cardiovascular benefits in individuals with type 2 diabetes (T2D). In prior studies, we have demonstrated that both drugs, alone or in combination, were able to protect cardiomyocytes from injury induced by diabetes. Mechanistic investigations also suggested that the cardioprotective effect may be independent of diabetes In this study, we utilized a hypoxia-reoxygenation (H/R) model to investigate the cardiovascular benefits of SGLT2 inhibitor empagliflozin and GLP-1 receptor (GLP-1R) agonist liraglutide, both alone and in combination, in the absence of T2D. Our hypothesis was that empagliflozin and liraglutide, either individually or in combination, would demonstrate cardioprotective properties against H/R-induced injury, with an additive and/or synergistic effect anticipated from combination therapy.

Methods: In this study, the cardiac muscle cell line, HL-1 cells, were treated with vehicle, empagliflozin, liraglutide, or a combination of the two drugs. The cells were then subjected to a hypoxia-reoxygenation (H/R) protocol, consisting of 1 h of hypoxia followed by 24 h of reoxygenation. The effects of the treatments on cytotoxicity, oxidative stress, endothelial nitric oxide synthase (eNOS) activity, phospho-protein kinase C (PKC) beta and phospho-eNOS (Thr⁴⁹⁵) expression were subsequently evaluated at the end of the treatments.

Results: We found that H/R increased cytotoxicity and reduces eNOS activity, empagliflozin, liraglutide or combination treatment attenuated some or all of these effects with the combination therapy showing the greatest improvement.

Conclusions: Empagliflozin, liraglutide or combination of these two have cardioprotective effect regardless of diabetes. Cardioprotective effects of SGLT2 inhibitor and GLP-1R agonist is additive and synergistic.

Objectives: The principal motive of this study is to explore the influence maternal separation (MS) exhibits on the mRNA expression of major drug metabolizing-cyp450s in parallel with the assessment of pathological changes that can be induced by MS in the livers of experimental mice.

Methods: Eighteen Balb/c mouse pups, comprising of both males and females, were separated from their mothers after birth. Following a six-week period during when the pups became adults, the mice were sacrificed and their livers were isolated for analysis of weight, pathohistological alterations, and the mRNA expression of drug metabolizing cyp450 genes: cyp1a1, cyp3a11, cyp2d9, and cyp2c29.

Results: The study demonstrated that MS markedly downregulated (p<0.05) the mRNA expression of all tested drug-metabolizing cyp450s in livers of female and male mice. Furthermore, the mRNA levels of major drug-metabolizing cyp450s were notably lower (p<0.05) in livers of female MS mice as compared with male MS mice. It was found that values of the total body weight and liver weight of MS mice did not vary significantly (p>0.05) from those of the control groups. Additionally, histological examination revealed that the hepatic tissue of MS mice was normal, similar to that of the control mice.

Conclusions: In summary, MS downregulates the gene expression of major hepatic drug-metabolizing cyp450s without inducing pathological alterations in the livers of mice. These findings provide an explanation for the heterogeneity in pharmacokinetics and drug response of patients with early life stress.

Objective: The objective of our study was to assess the impact of heat stress on hydration and cognition among outdoor workers in hot environment.

Methods: Area heat stress assessments were measured using Quest Temp WBGT monitor. Sweat rate for dehydration and reaction time for acute cognitive processing were recorded using standard procedures.

Results: Heat stress measurements ranged from 23.8 °C - 42 °C. More than 50 % of the workers had high sweat rate (>1.2 L/h) when exposed to high environmental temperatures. Positive correlation was obtained between WBGT, sweat rate and reaction time which indicates that hyperthermia has an impact on neural network processing. Heart rate and reaction time also increased with rise in WBGT and heavy physical activity.

Conclusions: There was impairment of cognitive functions (reaction time) under heat stress conditions. Hence, reaction time can be used to assess the short-term impact of heat stress on neural modulation and will help to plan effective intervention strategies to reduce morbidity and mortality among workers.

Introduction: In view of limited treatment options (those too may fail) for Crohn's disease, cannabinoids have been tried as a therapeutic. However, their efficacy is not unequivocally established. This systematic review and meta-analysis was planned to pool data from randomised controlled trials (RCTs) evaluating effect of cannabinoids in Crohn's disease with an intention to take this uncertainty away.

Content: Following literature search in Medline, EMBASE, Scopus and Google Scholar databases, RCTs assessing the effect of cannabinoids on mild-to-moderate Crohn's disease in adults were included. Crohns' disease activity index (CDAI), QoL (Quality of life), number participants achieving full remission and serum CRP at eight weeks of treatment were the outcomes considered for meta-analysis. Quality of studies was assessed using Cochrane's RoB2 tool. Random effect model was applied for meta-analysis. Heterogeneity was assessed by Cochrane 'Q' statistics and I² test. Sensitivity analysis was performed to identify the major contributor(s) to heterogeneity and assess robustness of the results.

Summary: Risk of bias for the four included studies varied from 'low' to 'some concern'. Overall effect estimate (SMD -0.92; 95 % CI -1.80, -0.03) indicated a statistically significant effect of cannabinoids as compared to control (p<0.05) on CDAI score. Effect of cannabinoids on rest of the outcome parameters was comparable to that of placebo. Magnitude of heterogeneity for different outcome parameters ranged from 'low' to 'substantial'.

Outlook: Cannabinoids were superior to placebo for favourably affecting the disease severity in terms of CDAI score. However, no statistically significant difference was found between the two for improving QoL, causing full disease-remission and reducing inflammatory markers. The results must be interpreted with caution in view of relatively high heterogeneity among the studies.

Objectives: Psoriasis is a persistent autoimmune inflammatory condition that is primarily affecting the skin. Pioglitazone (PGZ), a peroxisome proliferator activated receptor gamma (PPARγ) agonist, has been reported to have anti-inflammatory effects. However, the role of PGZ in psoriatic disease remains unclear. In this study, we aimed to repurpose the use of the PGZ for the treatment of psoriasis.

Methods: To investigate its efficacy, we employed an imiquimod (IMQ)-induced rat model. Wistar rats are randomly allocated to four different groups. Group, I served as a negative control, Group II IMQ control, Group III was treated with pioglitazone hydrogel and Group IV received standard drug betamethasone cream. PASI score was monitored on every alternative day and on day 7 animals were sacrificed and histopathology of skin was performed. Level of nitric oxide (NO) and myeloperoxidase (MPO) was also performed using established methods.

Results: The results of the experiment revealed that treatment with PGZ significantly (p<0.05) reduced redness, scaling, and skin thickening, surpassing the effectiveness of standard drugs. Our result also indicates that PGZ significantly (p<0.05) inhibits the release of both MPO and NO from the psoriatic lesions.

Conclusions: PGZ effectively reduces the severity of psoriasis possibly by inhibiting the accumulation of neutrophil at the psoriatic area which indirectly regulates the release of NO in the affected area. Our study showed we can repurpose the PGZ for the management of psoriasis.