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Background: Protein deficiency poses a significant challenge during the growth and development of children. Moringa oleifera Lam (MO) leaves, renowned for their high protein content, present a potential solution to address amino acid imbalances in protein-deficient conditions. Aim: This study aimed to evaluate the toxicity of MO leaf extract in Sprague-Dawley Rats. Methods: Protein extraction from Moringa oleifera (MO) leaves was performed using ultrasonic-assisted extraction (UAE) with ethanol. The ethanol leaf extract of MO (EEMO) was then characterized for protein content, amino acids, minerals, phytic acid, and phytochemicals. Antioxidant activity was assessed using the DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) test, while cytotoxicity was evaluated using the MTT (3-(4,5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide) assay on HepG2 and Madin-Darby canine kidney (MDCK) cells. EEMO was tested for acute toxicity in 60 healthy male and female Sprague-Dawley rats. The rats were divided into five groups of five rats each, receiving single oral doses of 5, 50, 300, 2,000, and 5,000 mg/kg body weight (BW) of EEMO. Observations were conducted daily till day 14 before the necropsy of rats. Liver and kidney tissues were harvested and preserved in 10% formalin for histopathological analysis. Results: The extraction process revealed a protein content of 45.5%, with phenylalanine being the predominant essential amino acid at 22.25 mg/g, and glutamic acid as the dominant non-essential amino acid at 60.03 mg/g. Potassium (1174.23 mg/100 g) and selenium (149 mg/100 g) were identified as the primary macro and micro minerals, respectively. The IC50 and CC50 values for antioxidant and cytotoxic activities in HepG2 and MDCK were found to be 41.04,182.66, and 121.04 ppm, respectively. Toxicity testing on experimental animals resulted in an LD50 value of 5,000 mg/kg BW for EEMO, indicating its relative safety upon oral administration. Conclusion: MO extract produced by the UAE extraction method, containing high-quality food-grade protein, showed no cytotoxic effects on HepG2 and MDCK cells and exhibited no acute toxicity in rats. [ABSTRACT FROM AUTHOR]

With the increase in life expectancy, aging has emerged as a significant health concern. Due to its various mechanisms of action, cardiometabolic drugs are often repurposed for other indications, including aging. This systematic review analyzed and highlighted the repositioning potential of cardiometabolic drugs to increase lifespan as an aging parameter in animal studies and supplemented by information from current clinical trial registries. Systematic searching in animal studies was performed based on PICO: "animal," "cardiometabolic drug," and "lifespan." All clinical trial registries were also searched from the WHO International Clinical Trial Registry Platform (ICTRP). Analysis of 49 animal trials and 10 clinical trial registries show that various cardiovascular and metabolic drugs have the potential to target lifespan. Metformin, acarbose, and aspirin are the three most studied drugs in animal trials. Aspirin and acarbose are the promising ones, whereas metformin exhibits various results. In clinical trial registries, metformin, omega-3 fatty acid, acarbose, and atorvastatin are currently cardiometabolic drugs that are repurposed to target aging. Published clinical trial results show great potential for omega-3 and metformin in healthspan. Systematic Review Registration: crd.york.ac.uk/prospero/display_record.php?RecordID=457358, identifier: CRD42023457358. [ABSTRACT FROM AUTHOR]

Background/Aim: Hematotoxicity is a lifethreatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix hydrolase 15 (NUDT15) gene polymorphism (c.415C>T) is reported to have an association with the hematotoxicity of 6-mercaptopurine (6-MP) as maintenance therapy in patients with ALL. However, the prevalence of this genetic polymorphism in the Indonesian population is unknown. This study aimed to assess the frequency of NUDT15 polymorphism among Indonesian pediatric patients with ALL and its association with the hematotoxicity of 6-MP. Patients and Methods: A total of 101 stored DNA samples from pediatric patients with ALL receiving 6-MP treatment were used for genetic testing. Direct sequencing was conducted to determine the NUDT15 c.415C>T genotype. Chi-square or Fisher's exact test were employed to examine the association between the NUDT15 c.415C>T genotype and hematotoxicity. Results: All (100%) of the DNA samples from patients with ALL treated with 6-MP exhibited a homozygous variant of the NUDT15 c.415C>T genotype, 70.3% of which showed hematotoxicity to some extent. We found no significant differences in NUDT15 gene polymorphism among patients with ALL with different states of hematotoxicity. Conclusion: The observed high frequency of NUDT15 c.415C>T in our study population might explain the elevated prevalence of 6-MPassociated hematotoxicity in pediatric patients with ALL within the Indonesian population. Our study provides new insight regarding the NUDT15 gene polymorphism and its relation to hematotoxicity. Further studies are required to determine the necessity of adjusting the initial dose of 6-MP for Indonesian pediatric patients with ALL. [ABSTRACT FROM AUTHOR]

Atorvastatin calcium is an antihyperlipidemic agent with low bioavailability due to the first-pass metabolism after oral administration. To overcome the limitation, an alternative method for delivering drug molecules to the systemic circulation is needed, such as transethosomes produced for transdermal delivery. Therefore, this study aimed to produce atorvastatin calcium transethosomes with characteristics suitable for transdermal delivery using validated analytical method. Transethosomes formulations were prepared with different concentrations of soy lecithin and ethanol. All formulations were evaluated for particle size, zeta potential, polydispersity index (PDI), drug content, and deformability index. Validation of the analytical method of atorvastatin calcium was carried out using system suitability, selectivity, linearity, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy, and robustness. The result showed that transethosomes had a small particle size of 123.90 nm-165.10 nm, high zeta potential values, acceptable PDI, the highest atorvastatin calcium content, and good deformability index. In addition, the system suitability test results were acceptable and there was no interference in the atorvastatin calcium area. Linearity showed r =0.9999 with LOD and LOQ values of 0.388 µg/mL and 1.176 µg/mL, respectively. The % RSD in the precision was < 2 and the recovery in the accuracy was 98.76%-101.04%. The method proved to be robust with respect to mobile phase pH changes. Based on the results, atorvastatin calcium-loaded transethosomes were suitable for transdermal delivery and could be effectively produced with a 3% soy lecithin and 30% ethanol concentration. The analytical method for determining drug content of atorvastatin calcium-loaded transethosomes could be effectively applied. [ABSTRACT FROM AUTHOR]

Doxorubicin fights cancer effectively, but harms heart muscle. The current methods for managing doxorubicin's toxicity are limited. This study determined the acute toxicity and protective effect of a standardized Andrographis paniculata ethanolic leaf extract against doxorubicin- induced cardiotoxicity. The acute toxicity of the extract was first investigated before determining its protective effect. 24 Sprague-Dawley rats were allocated into four groups: normal, DOX, DOX+AP250, and DOX+AP125. Doxorubicin was administered intraperitoneally (4 mg/kg/week) for four weeks. Treatment groups received doxorubicin plus either 250 mg/kg or 125 mg/kg daily dose of Andrographis paniculata ethanolic extract for 4 weeks. The rats were subjected to echocardiography 24 hours prior to sacrifice. After sacrifice, blood and heart tissue were collected to analyze brain natriuretic peptide and troponin level by the enzyme-linked immunosorbent assay. Histopathology assessment of heart tissues was also performed using hematoxylin and eosin staining. Andrographolide content of the extract was determined by HPLC. The bulk capsule extract's lethal dose 50 (LD50) was determined to be above 4166 mg/kg BW and the andrographolide content was 8.98%. Andrographis paniculata extract (125 or 250 mg) mitigated doxorubicin-induced cardiotoxicity by decreasing serum brain natriuretic peptide and troponin level (p < 0.05), reversing histopathological alterations in heart tissue (p < 0.05), and improving fractional shortening, ejection fraction and heart rate. This study demonstrates that the standardized extract may be a non-toxic herbal and holds promise as a therapeutic agent for mitigating doxorubicin-induced damage in rats. Further studies are needed to elucidate its exact protective molecular mechanism of action. [ABSTRACT FROM AUTHOR]

Malaria is one of life threatening-infectious diseases with high mortality rate in African regions. Malaria is also one of public health problem in most of Southeast Asia (SEA) regions. This disease is caused by a Apicomplexan parasite; Plasmodium sp., which can be transmitted from humans to humans via Anopheles sp. To date, the need of a new antimalarial drug is still high, due to the rapid increase of drug resistance. Natural-derived drug candidates are still being used by researchers to develop new antimalarials. One of the natural resources which could potentially be a source of antimalarial agents are mangrove plants. Traditionally, mangrove plants have been employed as antibacterial, antioxidant, anticancer, and antidiabetic. Therefore, we conducted a scoping review to identify, evaluate and summarize findings of newly found antimalarial drug activity from mangrove plants and elaborate the possible mechanism of actions in killing the parasites. From several databases, we found six mangrove species which have been suggested as potential antimalarial sources. Various phytochemical compounds in extracts made from those plants were revealed to exert antimalarial activity. These include alkaloids, flavonoids, tannins, phenols, terpenoids, saponins, coumarins, triterpenes, glycosides, and anthraquinones which were indicated to have antimalarial activity against Plasmodium. From eight studies investigating mangrove plant extracts, no toxic effects were shown. Therefore, considering the available evidences, we suggested that mangrove plants can be used as a source for the discovery of antimalarial compounds with promising activities against Plasmodium sp. However, deeper understanding on the exact mechanisms of their actions still requires further elucidation. [ABSTRACT FROM AUTHOR]

Objective. This study investigated several inflammatory markers' gene and protein expression in status epilepticus (SE) and their correlation with diazepam resistance. Materials and Methods. Peripheral blood samples were collected from 18 adult patients with SE in Cipto Mangunkusumo Central Hospital, consisting of 12 diazepam-responsive and six diazepam-resistant samples, within 72 hours of the onset of the seizure. We collected baseline demographic and clinical data from each subject. Peripheral blood mononuclear cells (PBMCs) were isolated, cultured, stimulated with lipopolysaccharide (LPS) 1 mg/ml, and harvested for RNA isolation. The RNA was used to determine the expression of Human Mobility Group Box 1 (HMGB1), Interleukin-6 (IL-6), IL-10, Toll-like Receptor 4 (TLR4), and Glial fibrillary acidic protein (GFAP). In addition, we performed serum protein assay of HMGB1, IL-6, IL-10, TLR4, and GFAP to compare with gene expression. Results. We found a significant difference between the responsive and resistant groups for serum HMGB1 and IL-6 concentration. The mRNA expression of HMGB1 and IL-6 was significantly higher in LPS-stimulated samples in the responsive but not in the resistant groups. The ratio of IL-6 to IL-10 showed a significant difference between LPS and control in the responsive group. Diazepam response was significantly correlated with seizure duration and serum protein concentration of HMGB1. Conclusion. HMGB1 was highly expressed in the resistant group and strongly correlated with diazepam response, and there was a significant increase in HMGB1 mRNA expression in response to LPS stimulation. These findings suggest that targeting HMGB1 may be a promising therapeutic strategy and that HMGB1 levels could be a valuable biomarker for predicting diazepam resistance in SE. [ABSTRACT FROM AUTHOR]

Cisplatin, as a first-line treatment for ovarian cancer, is associated with debilitating adverse effects, including nephrotoxic and haematotoxic effects. This study determines whether nanocurcumin, combined with cisplatin, would give additional benefit to kidney function and haematological parameters in rats with ovarian cancer. Twenty-five Wistar rats were divided into five untreated rats and 20-dimethylbenz(a)anthracene (DMBA)-induced ovarian cancer rats. The 20 ovarian cancer rats were divided into four treatment groups: vehicle, cisplatin, cisplatin-curcumin, and cisplatin-nanocurcumin. Cisplatin was given at the dose of 4 mg/kg BW once weekly, while curcumin or nanocurcumin was administered at 100 mg/kg BW daily for four weeks. At the end of treatment, we analysed kidney function, haematological parameters, and inflammatory and oxidative stress markers from plasma. Nanocurcumin alleviates the increase in kidney function markers and abnormalities in haematological indices in rats treated with cisplatin. Compared to cisplatin-treated rats, plasma urea levels decreased from 66.4 to 47.7 mg/dL, creatinine levels lowered from 0.87 to 0.82 mg/dL, and neutrophil gelatinase-associated lipocalin (NGAL) levels declined from 8.51 to 3.59 mIU/mg protein. Furthermore, the therapy increased glutathione activities (from 2.02 to 3.23 U/µL), reduced lipid peroxidation (from 0.54 to 0.45 nmol/mL), and decreased plasma TNF-α (from 270.6 to 217.8 pg/mL). Cisplatin with nanocurcumin in an ovarian cancer rat model may provide additional benefits as a preventive agent against renal impairment and cisplatin-induced haematological toxicity. However, further research is required to prove that using nanocurcumin for a more extended time would not affect its anticancer properties. [ABSTRACT FROM AUTHOR]

α-Mangosteen (α-MG) attenuates insulin resistance (IR). However, it is still unknown whether α-MG could alleviate hepatic manifestations in IR rats. 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. 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)-1β, IL-6, insulin receptor substrate (IRS)-1, Bax and liver histopathology were analyzed. 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. 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. [ABSTRACT FROM AUTHOR]

Objective: Thisstudy 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 modelshowed 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. [ABSTRACT FROM AUTHOR]