Alpha-Mangosteen lessens high-fat/high-glucose diet and low-dose streptozotocin induced-hepatic manifestations in the insulin resistance rat model.

CONTEXT: α-Mangosteen (α-MG) attenuates insulin resistance (IR). However, it is still unknown whether α-MG could alleviate hepatic manifestations in IR rats. OBJECTIVE: To investigate the effect of α-MG on alleviating hepatic manifestations in IR rats through AMP-activated protein kinase (AMPK) and sterol-regulatory element-binding protein-1 (SREBP-1) pathway. MATERIALS AND METHODS: IR was induced by exposing male Sprague-Dawley rats (180-200 g) to high-fat/high-glucose diet and low-dose injection of streptozotocin (HF/HG/STZ), then treated with α-MG at a dose of 100 or 200 mg/kg/day for 8 weeks. At the end of the study (11 weeks), serum and liver were harvested for biochemical analysis, and the activity of AMPK, SREBP-1c, acetyl-CoA carboxylase (ACC), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, insulin receptor substrate (IRS)-1, Bax and liver histopathology were analyzed. RESULTS: α-MG at both doses significantly lowered ALT, AST, triglyceride, and cholesterol total by 16.5, 15.7, 38, and 36%, respectively. These beneficial effects of α-MG are associated with the downregulation of the IR-induced inflammation in the liver. Furthermore, α-MG, at both doses, activated AMPK by 24-29 times and reduced SREBP-1c by 44-50% as well as ACC expression by 19-31% similar to metformin. All treatment groups showed liver histopathology improvement regarding fat deposition in the liver. CONCLUSIONS: Based on the findings demonstrated, α-MG protected against HF/HG/STZ-induced hepatic manifestations of the IR rats, at least in part via the modulation of the AMPK/SREBP-1c/ACC pathway and it could be a potential drug candidate to prevent IR-induced hepatic manifestations.

Evaluation of Potential Drug-Drug Interactions and Association with Adverse Drug Reactions in Predialysis Chronic Kidney Disease Patients at Indonesian National Referral Hospital.

BACKGROUND: Chronic kidney disease (CKD) is often accompanied by a variety of comorbidities that require several medications thus, polypharmacy is unavoidable. One of the consequences of polypharmacy is the occurrence of potential drug-drug interactions (DDI). The aim of this study is to evaluate the profile of DDI in pre-dialysis CKD patients and to identify the possible adverse drug reactions (ADR) due to DDI. METHODS: This cross-sectional study includes stage 3-5 pre-dialysis CKD patients at a referral hospital in Indonesia in 2019 - 2020. Data were collected from the electronic health record and the hospital's medical record. The prescriptions were analysed for potential DDI using Micromedex software and ADRs assessment through clinical symptoms and laboratory data abnormalities. RESULTS: A total of 106 patients were included in the study, around 60 (56.6%) patients received more than six medications. There were 111 types of medications prescribed with the most frequently prescribed drug was bisoprolol (36.5%). The proportion of patients who received treatment with a potential DDI was 76% (81 patients), while the proportion of patients who experienced ADR was 28% (23 patients). The most prevalent ADRs were hyperglycaemia, hypertension, hyperkalaemia, and hypotension. Cardiovascular disease had a statistically significant relationship with ADR suspected due to DDI (p = 0.03). CONCLUSION: A significant number of potential DDI were seen in the prescriptions of stage 3-5 pre-dialysis CKD patients at a referral hospital in Indonesia between 2019 - 2020. Cardiovascular disease was identified as the most common risk factor for ADR suspected caused by DDI.

6-gingerol ameliorates weight gain and insulin resistance in metabolic syndrome rats by regulating adipocytokines.

Metabolic syndrome (MetS) can lead to increase of insulin resistance (IR) and visceral adipose tissue production of adipocytokines. 6-gingerol is known to have antioxidant and anti-inflammatory activities. Aim of this study is to investigate the effects of 6-gingerol on high-fat high-fructose (HFHF) diet-induced weight gain and IR in rats through modulation of adipocytokines. To induce MetS, male Sprague-Dawley rats were fed with a HFHF diet for 16 weeks and at Week 8, single-dose low-dose streptozotocin (22 mg/kg) were intraperitoneally injected. After 8 weeks of HFHF diet feeding, the rats were treated orally with 6-gingerol (50, 100, and 200 mg/kg/day) once daily for 8 weeks. At the end of the study, all animals were terminated, serum, liver, and visceral adipose tissues were harvested for biochemical analysis including the measurements of total cholesterol, triglycerides, HDL-cholesterol, fasting plasma glucose, insulin, leptin, adiponectin, proinflammatory cytokines (TNF-α and IL-6) and liver and adipose tissue histopathology. Biochemical parameters namely serum total cholesterol (243.7 ± 127.6 vs 72.6 ± 3 mg/dL), triglycerides (469.2 ± 164.9 vs 49.3 ± 6.3 mg/dL), fasting plasma glucose (334 ± 49.5 vs 121 ± 8.5 mg/dL), HOMA-IR (0.70 ± 0.24 vs 0.32 ± 0.06), and leptin (6.19 ± 1.24 vs 3.45 ± 0.33 ng/mL) were significantly enhanced, whereas HDL-cholesterol (26.2 ± 5.2 vs 27.9 ± 1.1 mg/dL) and adiponectin level (14.4 ± 5.5 vs 52.8 ± 10.7 ng/mL) were lowered in MetS vs normal control. Moreover, MetS were marked a significant increase in body weight and proinflammatory cytokines. Treatment with 6-gingerol dose-dependently restored all of those alterations towards normal values as well as the accumulation of lipid in liver and adipose tissues. These findings demonstrate that 6-gingerol, in a dose-dependent mode, showed capability of improving weight gain and IR in MetS rats through modulation of adipocytokines.

Cardioprotection mechanism of mangiferin on doxorubicin-induced rats: Focus on intracellular calcium regulation.

CONTEXT: The molecular mechanism of doxorubicin (DOX) cardiotoxicity involves overproduction of free radicals that leads to intracellular calcium dysregulation and apoptosis. Mangiferin (MGR), a naturally occurring glucosylxanthone, has antioxidant and cardioprotective properties. However, its cardioprotection mechanism has yet to be revealed. OBJECTIVE: This study determines whether the cardioprotective effect of MGR is caused by its effect on intracellular calcium regulation. MATERIALS AND METHODS: Male Sprague-Dawley rats were induced by DOX intraperitoneally with a total dose of 15 mg/kg bw. MGR was given orally at the doses of 30 and 60 mg/kg bw/d for seven consecutive weeks. The parameters examined were mRNA expression levels of proinflammatory cytokine gene (TNF-α), calcium regulatory gene (SERCA2a) and proapoptotic genes (caspase-9 and caspase-12), as well as cytosolic and mitochondrial calcium levels. RESULTS: Treatment with MGR at 60 mg/kg bw/d significantly decreased the mRNA expression levels of TNF-α by 44.55% and caspase-9 by 52.79%, as well as the cytosolic calcium level by 24.15% (p < 0.05). SERCA2a and caspase-12 expressions were only slightly affected (27.27% increase and 24.85% decrease for SERCA2a and caspase-12, respectively, p > 0.05). Meanwhile, MGR 30 mg/kg bw/d gave insignificant results in all parameters. DISCUSSION AND CONCLUSION: MGR protected against DOX-induced cardiac inflammation and apoptosis via down-regulation of proapoptotic and proinflammatory gene expressions, upregulation of SERCA2a gene expression, and normalization of cytosolic calcium level. Thus, the cardioprotective effect of MGR is at least in part due to the regulation of intracellular calcium homeostasis.

Beneficial Effects of 6-Gingerol on Fatty Pancreas Disease in High-Fat High-Fructose Diet-Induced Metabolic Syndrome Rat Model.

OBJECTIVE: To examine the effects of 6-gingerol (6-G) in overcoming fatty pancreas disease of high-fat high-fructose (HFHF) diet-induced metabolic syndrome in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly divided into 5 groups. The healthy-control group (normal diet, n = 5) received a standard diet. The HFHF group (HFHF; n = 20) received an HFHF diet and a single-dose intraperitoneal injection of streptozotocin (22 mg/kgBW) at week 8. Metabolic syndrome-confirmed rats received 6-G at doses of 50 (6-G 50, n = 5), 100 (6-G 100, n = 5), and 200 (6-G 200, n = 5) mg/kgBW, respectively, for 8 weeks. All rats were killed at week 16. Pancreatic tissue and blood samples were obtained for histological and amylase analysis. RESULTS: The serum amylase, MDA, mRNA of TNF-α, and IL-6 significantly increased, whereas GPx decreased in the HFHF group as compared with the normal diet group, respectively. Rats in the HFHF group showed pancreatic lipid accumulation and a decreased mean number of α- and ß-cells in the pancreas. Meanwhile, all rats in 6-G at all dose groups showed improvement in all parameters and histopathological scores for lipid accumulation. CONCLUSIONS: 6-Gingerol could attenuate pancreatic lipid accumulation and improve the cell number of α- and ß-cells in the pancreas, leading to improvements in fatty pancreas disease.

Acute exacerbation of idiopathic pulmonary fibrosis model in the rats using bleomycin and lipopolysaccharides.

Objective: This study was conducted to establish a rat model of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) using the combination of bleomycin (BLM) and lipopolysaccharides (LPS). Materials and Method: Twenty-four male Sprague Dawley rats were allocated into two equal groups: the sham or the bleomycin and lipopolysaccharides-induced AE-IPF group (BLM-LPS). On Day 7, BLM intratracheally and LPS intraperitoneally were both used to administer AE-IPF. The BLM-LPS group and its respective sham group were terminated on Days 8, 14, or 21. Samples of bronchoalveolar lavage fluid (BALF) and lungs were taken and investigated for cell count and histopathology. Results: On Day 8, histological analysis revealed inflammatory cell infiltration with edema and hyaline membrane, and the BALF differential cell count revealed high neutrophil counts. By having a higher collagen density area and Ashcroft modified score than the sham group on Day 14, the BLM-LPS group displayed significantly lower oxygen saturation, alveolar air area, and a fibrotic appearance. However, there was a spontaneous resolution in inflammation and fibrotic appearance on Day 21 after the BLM administration. Conclusions: By combining BLM and LPS, it was possible to create a successful rat model of AE-IPF. The present model showed the peak exacerbation on Day 8 and the fibrotic peak on Day 14, which gradually improved. The optimal time for the new AE-IPF therapeutic intervention was determined to be between Days 8 and 14.

Vitamin D supplementation alleviates insulin resistance in prediabetic rats by modifying IRS-1 and PPARγ/NF-κB expressions.

Background: Prediabetes is a condition of intermediate hyperglycemia that may progress to type 2 diabetes. Vitamin D deficiency has been frequently linked to insulin resistance and diabetes. The study aimed to investigate the role of D supplementation and its possible mechanism of action on insulin resistance in prediabetic rats. Method: The study was conducted on 24 male Wistar rats that were randomly divided into 6 rats as healthy controls and 18 prediabetic rats. Prediabetic rats were induced with a high-fat and high-glucose diet (HFD-G) combined with a low dose of streptozotocin. Rats with the prediabetic condition were then randomized into three groups of 12-week treatment: one group that received no treatment, one that received vitamin D3 at 100 IU/kg BW, and one group that received vitamin D3 at 1000 IU/kg BW. The high-fat and high-glucose diets were continuously given throughout the twelve weeks of treatment. At the end of the supplementation period, glucose control parameters, inflammatory markers, and the expressions of IRS1, PPARγ, NF-κB, and IRS1 were measured. Results: Vitamin D3 dose-dependently improves glucose control parameters, as shown by the reduction of fasting blood glucose (FBG), oral glucose tolerance test (OGTT), glycated albumin, insulin levels, and markers of insulin resistance (HOMA-IR). Upon histological analysis, vitamin D supplementation resulted in a reduction of the islet of Langerhans degeneration. Vitamin D also enhanced the ratio of IL-6/IL-10, reduced IRS1 phosphorylation at Ser307, increased expression of PPAR gamma, and reduced phosphorylation of NF-KB p65 at Ser536. Conclusion: Vitamin D supplementation reduces insulin resistance in prediabetic rats. The reduction might be due to the effects of vitamin D on IRS, PPARγ, and NF-κB expression.

Beneficial effects of edaravone, a novel antioxidant, in rats with dilated cardiomyopathy.

Edaravone, a novel antioxidant, acts by trapping hydroxyl radicals, quenching active oxygen and so on. Its cardioprotective activity against experimental autoimmune myocarditis (EAM) was reported. Nevertheless, it remains to be determined whether edaravone protects against cardiac remodelling in dilated cardiomyopathy (DCM). The present study was undertaken to assess whether edaravone attenuates myocardial fibrosis, and examine the effect of edaravone on cardiac function in rats with DCM after EAM. Rat model of EAM was prepared by injection with porcine cardiac myosin 28 days after immunization, we administered edaravone intraperitoneally at 3 and 10 mg/kg/day to rats for 28 days. The results were compared with vehicle-treated rats with DCM. Cardiac function, by haemodynamic and echocardiographic study and histopathology were performed. Left ventricular (LV) expression of NADPH oxidase subunits (p47(phox), p67(phox), gp91(phox) and Nox4), fibrosis markers (TGF-ß(1) and OPN), endoplasmic reticulum (ER) stress markers (GRP78 and GADD 153) and apoptosis markers (cytochrome C and caspase-3) were measured by Western blotting. Edaravone-treated DCM rats showed better cardiac function compared with those of the vehicle-treated rats. In addition, LV expressions of NADPH oxidase subunits levels were significantly down-regulated in edaravone-treated rats. Furthermore, the number of collagen-III positive cells in the myocardium of edaravone-treated rats was lower compared with those of the vehicle-treated rats. Our results suggest that edaravone ameliorated the progression of DCM by modulating oxidative and ER stress-mediated myocardial apoptosis and fibrosis.

Involvement of AMPK and MAPK signaling during the progression of experimental autoimmune myocarditis in rats and its blockade using a novel antioxidant.

There are various reports suggesting the role of angiotensin (Ang) receptor blockers, Ang converting enzyme inhibitors, calcium channel blockers, diuretics and antioxidants against the progression of experimental autoimmune myocarditis (EAM) to dilated cardiomyopathy (DCM). Most of them were reported to be effective during this adverse cardiac remodeling. Recently much attention has been paid to studying the involvement of AMP-activated protein kinase (AMPK) and mitogen activated protein kinase (MAPK) in various cardiovascular ailments. AMPK acts as a master sensor of cellular energy balance via maintenance of lipid and glucose metabolism. Evidences also suggest the relation between AMPK and oxidative stress during physiological and pathological myocardial cellular function. Since, it is of interest to identify the roles of AMPK and MAPK during the progression of EAM to DCM and also the effect of edaravone, a novel free radical scavenger, against its progression. For this, we have carried out western blotting, histopathological staining and immunohistochemical analyses to measure the myocardial expressions of AMPK signaling and oxidative stress related parameters in normal and vehicle or edaravone-treated EAM rats, respectively. We identified the myocardial levels of phospho Akt and phosphoinositide 3-kinase, which are the upstream proteins of AMPK and MAPK activation and both were up-regulated in the vehicle-treated rats, whereas candesartan treatment significantly reversed these changes. We have also measured the myocardial levels of p-AMPKα, different isoforms of protein kinase C and MAPK signaling proteins. All of these protein levels were significantly elevated in the hearts of DCM rats whereas edaravone treatment significantly reversed these changes. In viewing these results, we can suggest that along with MAPK, AMPK signaling also plays a crucial role in the progression of EAM and it can be effectively blocked by the treatment with a novel antioxidant, edaravone.

Co-administration of ritonavir and primaquine decreases plasma concentration of primaquine: single- and multiple-dose study in the rats.

AIM: to explore the effects of ritonavir and primaquine combination given as a single-dose or multiple-dose compared to ritonavir alone on ritonavir plasma concentration in the rats. METHODS: in single-dose study, 30 male Spraque Dawley rats were randomly allocated to receive primaquine 12.5 mg/kgBW or primaquine 12.5 mg/kgBW + ritonavir 10 mg/kgBW or primaquine 12.5 mg/kgBW + ketokonazole 10 mg/kgBW. Ketokonazole was used as positive control for inhibitor of primaquine metabolism. In the multiple-dose study, thirty Spraque Dawley male rats were randomly allocated to receive primaquine 12.5 mg/kgBW/day or primaquine 12.5 mg/kgBW/day + ritonavir 10 mg/kgBW/day or primaquine 12.5 mg/kgBW/day + rifampicin 100 mg/kgBW/day. Rifampicin was used as a positive control for inducer of primaquine metabolism. RESULTS: in the single-dose study, ketokonazole increases the area under the plasma concentration (AUC) of primaquine (h45.8%, p<0.000), while the ritonavir decreases the AUC of primaquine (i64.6%, p<0.000). Multiple-dose study shows that both rifampicin and ritonavir decreases the AUC of primaquine by 60.2% (p<0.000) and 67.7% (p<0.000), respectively. CONCLUSION: concomitant administration of primaquine and ritonavir decreases the AUC of ritonavir. This effect could result in the insufficient concentration of primaquine as anti-relapse therapy in malaria caused by Plasmodium vivax, which might lead to treatment failure with primaquine.

Lack of Correlation Between Soluble Angiotensin-Converting Enzyme 2 and Inflammatory Markers in Hospitalized COVID-19 Patients with Hypertension.

Purpose: This study aimed to investigate the correlation of plasma soluble angiotensin-converting enzyme 2, sACE2, and several inflammatory markers in COVID-19 patients requiring hospitalization with hypertension. Additionally, we analyzed the effects of renin-angiotensin-aldosterone-system, RAAS, inhibitors on the levels of sACE2 and inflammatory marker levels in patients with COVID-19. Patients and Methods: This cross-sectional study involved patients with COVID-19 who required hospitalization on a stable dose of antihypertensive drugs. The study included three hospitals in Jakarta and Tangerang, Indonesia, between December 2020 and June 2021. We classified eligible subjects into two groups: patients with COVID-19 treated with antihypertensive RAAS inhibitors or non-RAAS inhibitors. Results: We found no correlation between sACE2 and all the inflammatory and coagulation markers studied (high-sensitivity C-reactive protein, IL-6, IL-10, IL6/IL10, tumor necrosis factor-α, neutrophil-to-lymphocyte ratio, and D-dimer) in COVID-19 patients with hypertension. Further analysis showed lower sACE2 concentrations and IL-6/IL-10 ratio in patients treated with RAAS inhibitors vs those treated with non-RAAS inhibitors. Conclusion: We found no correlation between ACE2 and inflammatory markers. Using RAAS inhibitors resulted in a lower sACE2 and IL-6/IL-10 ratio. The type of antihypertensive treatments has a neutral effect on disease severity and outcome in COVID-19 patients with hypertension. However, to firmly-established these effects, our findings should be confirmed in a much larger population.

Hematological indices and their correlation with glucose control parameters in a prediabetic rat model.

Background and Aim: Chronic hyperglycemia in prediabetic individuals would progress to diabetes and lead to several systemic disruptions, including hematological parameters. This study aimed to investigate the correlation between prediabetes and hematological indices in a prediabetic rat model. Materials and Methods: Eighteen male rats were randomly divided into two groups of nine. Prediabetes was induced in nine rats by a 3-week high-fat and high-glucose diet, followed by low-dose streptozotocin (STZ) injection (30 mg/kg body weight). The oral glucose tolerance test was performed, and the fasting blood glucose (FBG) and insulin levels were measured 72 h after STZ administration. The control group of nine rats was given standard diets. At the end of the 3rd week, the animals fasted overnight before blood collection. Blood samples were drawn and used for the analysis of the FBG and fasting insulin levels and glycated albumin to define prediabetes criteria before hematology analysis. Results: We found a significant increase in the FBG and insulin levels in the prediabetic versus the control group. There were decreases in red blood cells, hemoglobin, and hematocrit levels and red cell distribution in prediabetic rats versus the control. At the same time, a significant increase in the platelet count was observed in the prediabetic group. There was a positive correlation between FBG and lymphocytes and neutrophil-lymphocyte ratio in prediabetic rats. On the other hand, we found a negative correlation between white blood cell count and glycated albumin. Conclusion: Correlations were found in several hematological parameters in the prediabetic rat models. The changes in hematological indices in prediabetic rats may be further used as a valuable indicator of glycemic control.

Protective effects of silver nanoparticles in isoproterenol-induced myocardial infarction in rats.

Background: Silver nanoparticles (AgNPs) are widely used in the medical field, including cardiovascular. However, limited research has investigated the effect of AgNPs on the protection of myocardial infarction (MI). Objectives: Isoproterenol (Iso)-induced MI and the cardiac protection offered by AgNPs were investigated in the present study. Additionally, we characterized the profile of Ag in the form of nanoparticles. Methods: Twenty-four male Wistar rats were randomly divided into four groups as follows: normal, Iso, Iso + AgNO3, and Iso + AgNP groups. AgNPs and silver ion (AgNO3) were administered intraperitoneally at 2.5 mg/kg BW for 14 days. Iso induction was performed using two doses of 85 mg/kg BW given subcutaneously on days 13 and 14. Blood and cardiac tissue samples were taken 24 h after the last dose of Iso and checked for Creatine Kinase-MB (CK-MB), lactate dehydrogenase in plasma along with oxidative stress parameters, mitochondria biogenesis markers, and inflammation representative genes in cardiac tissue. Additionally, we analyzed the histopathological features in cardiac tissue. Results: The silver was confirmed in the form of nanoparticles by its size at intervals of 8.72-37.84 nm. Both AgNO3 and AgNPs showed similar cardioprotective effects, as shown by the decrease in biochemical markers of cardiac toxicity, namely, CK-MB. Additionally, AgNPs group have better efficacy compared with AgNO3 group in ameliorating Iso-mediated oxidative stress production, as evidenced by the significant decrease in malondialdehyde level and increased superoxide dismutase activity (P < 0.0001 and P < 0.01, respectively) in cardiac tissue compared with the Iso group. Mechanistically, AgNPs, but not AgNO3, enhanced the expression levels of mitochondrial transcription factor A and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha in post-MI heart and reduced the protein expression of nuclear factor-kappa B (NF-κB) assessed by western blot analysis. Furthermore, these results were confirmed with the histopathological evaluation of cardiac tissue. Nevertheless, pretreatment with either AgNO3 or AgNPs improved the aspartate aminotransferase level. Conclusion: These results suggested that AgNPs have more superior cardioprotective effect compared with AgNO3 against Iso-induced MI, at least in part through amelioration of NF-κB expression level induced by oxidative stress overproduction.

Effect of primary balloon angioplasty on draining vein diameter and volume flow in patients with arteriovenous fistula: A cohort study.

Background: Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) cause major morbidity and mortality in 10% of the global population with CKD. The most common renal replacement therapy is hemodialysis with arteriovenous fistula (AVF) access. AVF often undergoes maturation failure due to feeding artery and draining vein inadequacy. Mechanical dilatation, such as primary balloon angioplasty (PBA), can overcome AVF maturation failure. The volume flow (VF) and diameter of the draining veins in AVF patients must be known to evaluate the effect of PBA on AVF maturation. This study aims to analyze the impact of PBA on VF and draining vein diameter in ESKD patients undergoing AVF surgery. Methods: A retrospective cohort clinical trial was conducted at our institution. A total of 75 participants had AVF with an arterial diameter >1.5 mm or vein diameter at the AVF creation site of 2-4 mm. The subjects were divided into 2 groups: the intervention group undergoing PBA (n = 36) and the control group, without PBA (n = 39). PBA was performed using a Mustang ballon (3-6 mm, Medtronic). Follow-ups were conducted at 1 week, 2 weeks, and 6 weeks after AVF creation. Results: Based on the data, the diameter and VF of the draining veins were significantly larger in the intervention group than in the control group (p < 0.001). Furthermore, we found significant differences in the mean diameter and VF of the draining veins between the control and intervention groups at all stages of examination, from preoperatively to 6 weeks postoperatively (p < 0.001). The strength of the analysis was more than 80%. Conclusion: PBA can increase the diameter and VF of the draining veins in patients with AVF.

Development of rat metabolic syndrome models: A review.

Metabolic syndrome (MetS) has become a global problem. With the increasing prevalence of MetS worldwide, understanding its pathogenesis and treatment modalities are essential. Animal models should allow an appropriate representation of the clinical manifestations of human conditions. Rats are the most commonly used experimental animals for the study. The development of a proper MetS model using rats will contribute to the successful application of research findings to the clinical setting. Various intervention methods are used to induce MetS through diet induction with various compositions, chemicals, or a combination of both. This review will provide a comprehensive overview of several studies on the development of rat MetS models, along with the characteristics of the clinical manifestations resulting from each study.

Safety and Pharmacokinetic Profiles of Long-Acting Injectable Antiretroviral Drugs for HIV-1 Pre-Exposure Prophylaxis: A Systematic Review and Meta-analysis of Randomized Trials.

Objectives: To investigate the safety and pharmacokinetic profiles of long-acting injectable pre-exposure prophylaxis (LAI PrEP), notably cabotegravir (CAB-LA) and rilpivirine (RPV-LA), for the prevention of human immunodeficiency virus-1 (HIV-1) infection. Methods: Eligible randomized trials of LAI PrEP in HIV-uninfected and/or healthy patients were included and assessed with the Revised Cochrane risk-of-bias tool for randomized trials. Where feasible, a meta-analysis was performed for safety outcomes by using a random-effects model with risk ratios and their 95% confidence intervals as the common effect measure. The protocol was registered with PROSPERO CRD42020154772. Results: Eight studies cumulating a total of 666 participants were included in this systematic review, including five (362 intervention-arm volunteers) and four trials (194 intervention-arm volunteers) that investigated CAB-LA and RPV-LA, respectively. We found that both CAB-LA and RPV-LA were generally well-tolerated as their safety profiles were similar to placebo in terms of any adverse event (AE), serious AE, and AE-related withdrawals. Furthermore, pharmacokinetic analyses revealed favorable prospects in viral inhibitory activity of CAB-LA and RPV-LA. Intramuscular (IM) injection of CAB-LA 600 mg Q8W was superior to CAB-LA 800 mg Q12W in male participants, while the same was true for RPV-LA 1200 mg IM Q8W over other dosing regimens. Although these results are promising, further research is required to confirm the findings on RPV-LA as current evidence is limited. Conclusion: CAB-LA and RPV-LA have promising safety and pharmacokinetic profiles. The preventive efficacy of these agents is being evaluated in Phase 3 trials.

The effect of human immunodeficiency virus infection on adverse events during treatment of drug-resistant tuberculosis: A systematic review and meta-analysis.

BACKGROUND: Adverse events (AEs) during drug-resistant tuberculosis (DR-TB) treatment, especially with human immunodeficiency virus (HIV) co-infection, remains a major threat to poor DR-TB treatment adherence and outcomes. This meta-analysis aims to investigate the effect of HIV infection on the development of AEs during DR-TB treatment. METHODS: Eligible studies evaluating the association between HIV seropositivity and risks of AE occurrence in DR-TB patients were included in this systematic review. Interventional and observational studies were assessed for risk of bias using the Risk of Bias in Nonrandomized Studies of Intervention and Newcastle-Ottawa Scale tool, respectively. Random-effects meta-analysis was performed to estimate the pooled risk ratio (RR) along with their 95% confidence intervals (CIs). RESULTS: A total of 37 studies involving 8657 patients were included in this systematic review. We discovered that HIV infection independently increased the risk of developing AEs in DR-TB patients by 12% (RR 1.12 [95% CI: 1.02-1.22]; I2 = 0%, p = 0.75). In particular, the risks were more accentuated in the development of hearing loss (RR 1.44 [95% CI: 1.18-1.75]; I2 = 60%), nephrotoxicity (RR 2.45 [95% CI: 1.20-4.98], I2 = 0%), and depression (RR 3.53 [95% CI: 1.38-9.03]; I2 = 0%). Although our findings indicated that the augmented risk was primarily driven by antiretroviral drug usage rather than HIV-related immunosuppression, further studies investigating their independent effects are required to confirm our findings. CONCLUSION: HIV co-infection independently increased the risk of developing AEs during DR-TB treatment. Increased pharmacovigilance through routine assessments of audiological, renal, and mental functions are strongly encouraged to enable prompt diagnosis and treatment in patients experiencing AEs during concomitant DR-TB and HIV treatment.

Selected Indonesian Medicinal Plants for the Management of Metabolic Syndrome: Molecular Basis and Recent Studies.

Increased prevalence of metabolic syndrome (MetS) in the world influences quality of health in all respective countries, including Indonesia. Data from Indonesian Family Life Survey reported in 2019 showed that the prevalence of MetS in Indonesia currently is 21.66%, estimated with the provincial incidence ranging up to 50%; additionally, the most common components of MetS discovered in Indonesia were poor high-density lipoprotein (HDL) cholesterol and hypertension. Management treatment of MetS involves a combination of lifestyle changes and pharmacological interventions to decrease cerebrovascular disease. Various natural substances have been shown to govern any cardiovascular or metabolic disorders through different mechanisms, such as triggering anti-inflammation, lipid profile correction, sensitization of insulin reception, or blood glucose control. In Indonesia, the utilization of natural compounds is part of the nation's culture. The community widely uses them; even though in general, their effectiveness and safety have not been thoroughly assessed by rigorous clinical trials. Scientific evidence suggested that cinnamon, mangosteen, and curcumin, as well as their derived components possess a broad spectrum of pharmacological activity. In this review, an enormous potential of cinnamon, mangosteen, and curcumin, which originated and are commonly used in Indonesia, could be treated against MetS, such as diabetes, hyperlipidemia, hypertension, and obesity. The findings suggested that cinnamon, mangosteen, curcumin and their derivatives may reflect areas of promise in the management of MetS.

The Effect of Alpha Mangostin on Epithelial-Mesenchymal Transition on Human Hepatocellular Carcinoma HepG2 Cells Surviving Sorafenib via TGF-ß/Smad Pathways.

Purpose: This study was intended to find out the impact of alpha mangostin administration on the epithelial-mesenchymal transition (EMT) markers and TGF-ß/Smad pathways in hepatocellular carcinoma Hep-G2 cells surviving sorafenib. Methods: Hepatocellular carcinoma HepG2 cells were treated with sorafenib 10 µM. Cells surviving sorafenib treatment (HepG2surv) were then treated vehicle, sorafenib, alpha mangostin, or combination of sorafenib and alpha mangostin. Afterward, cells were observed for their morphology with an inverted microscope and counted for cell viability. The concentrations of transforming growth factor (TGF)-ß1 in a culture medium were examined using ELISA. The mRNA expressions of TGF-ß1, TGF-ß1-receptor, Smad3, Smad7, E-cadherin, and vimentin were evaluated using quantitative reverse transcriptase-polymerase chain reaction. The protein level of E-cadherin was also determined using western blot analysis. Results: Treatment of alpha mangostin and sorafenib caused a significant decrease in the viability of sorafenib-surviving HepG2 cells versus control (both groups with P <0.05). Our study found that alpha mangostin treatment increased the expressions of vimentin (P <0.001 versus control). In contrast, alpha mangostin treatment tends to decrease the expressions of Smad7 and E-cadherin (both with P >0.05). In line with our findings, the expressions of TGF-ß1 and Smad3 are significantly upregulated after alpha mangostin administration (both with P <0.05) versus control. Conclusion: Alpha mangostin reduced cell viability of sorafenib-surviving HepG2 cells; however, it also enhanced epithelial-mesenchymal transition markers by activating TGF-ß/Smad pathways.

Alpha-Mangostin Improves Cardiac Hypertrophy and Fibrosis and Associated Biochemical Parameters in High-Fat/High-Glucose Diet and Low-Dose Streptozotocin Injection-Induced Type 2 Diabetic Rats.

PURPOSE: The aim of present study was to analyze the effect of alpha-mangostin on cardiac hypertrophy and fibrosis and biochemical parameters in high-fat/high-glucose diet and low-dose streptozotocin injection (HF/HG/STZ)-induced type 2 diabetic rats. METHODS: Diabetes was induced in male Wistar rats by giving a combination of high-fat/high-glucose (HF/HG) diet for 3 weeks and followed by low-dose streptozotocin intraperitoneal injection (STZ; 35 mg/kg) at Week-3 and the HF/HG diet was continued until 8 weeks. The diabetic rats were then divided into four groups (each, n=6): untreated diabetic group (HF/HG/STZ); diabetic group treated with metformin 200 mg/kg/day (HF/HG/STZ+Metformin); diabetic group treated with alpha-mangostin 100 mg/kg/day (HF/HG/STZ+AM100); and diabetic group treated with alpha-mangostin 200 mg/kg/day (HF/HG/STZ+AM200) and all were given by oral gavage for 8 weeks. We also included a control group (C) treated with AM200 (C+AM200). The role of alpha-mangostin was assessed through its effect on blood glucose levels, HOMA-IR, blood pressure, body weight, pro-inflammatory cytokines in cardiac tissue, serum aminotransferases (ALT and AST), lipid profiles (cholesterol and triglyceride), blood urea nitrogen (BUN), uric acid, cardiac hypertrophy and fibrosis. RESULTS: Diabetic rats treated with alpha-mangostin in both doses for 8 weeks showed decrease in blood glucose levels, HOMA-IR, and blood pressure. Alpha-mangostin treatment also prevented HF/HG/STZ-induced changes in the activities of ALT, AST, BUN, uric acid, lipid profiles, and pro-inflammatory cytokines, which were comparable with the standard drug metformin, while alpha-mangostin did not show any significant effects on control rats (p>0.05). The cardiac hypertrophy and fibrosis were also attenuated in diabetic rats treated with alpha-mangostin in both doses. CONCLUSION: These data suggest that administration of alpha-mangostin can effectively attenuate diabetes-induced alteration in cardiac hypertrophy and fibrosis as well as biochemical parameters in HF/HG/STZ rats.