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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 leaves 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 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 six rats each, receiving single oral doses of 5, 50, 300, 2,000, and 5,000 mg/kg body weight (BW) of EEMO. Observations was conducted daily till day 14 before 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/100g) and selenium (149 mg/100g) 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 ppm,182.66 ppm 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. [Open Vet J 2024; 14(9.000): 2294-2309]

Objective: This is to compare peripheral and central serum levels of Anti-Mullerian hormone (AMH) in experimental animals for predicting ovarian reserve. Methods: This is an experimental study involving 20 female Sprague-Dawley rats aged 8–10 weeks with normal estrus cycles as the young control group and 5 female rats aged 28–30 weeks as the old control group (n = 5/group): the young control group, the old control group, the 1x cisplatin group, the 2x cisplatin group, and the 3x cisplatin group. After treatment, tissue collection, histological staining, and blood collection through the retro-orbital bleeding (ROB) and heart were performed. Subsequently, measurements of ovarian weight, follicle counting, and levels of AMH and Follicle-stimulating hormone (FSH) were conducted. Results: The serum AMH levels from ROB in the young control, 1x cisplatin, 2x cisplatin, 3x cisplatin, and the old control groups were 1151, 1818, 2782.96, 1381.352, and 1544 ng/mL, respectively. Cisplatin 2x group was significantly (p

Background: Doxorubicin (DOX), an efficacious chemotherapy drug is compromised by cardiotoxicity, myelosuppression, and hepatotoxicity. Due to the limited success of current treatments for DOX toxicity, there is a pressing need to explore alternative medical interventions, particularly from plant sources. This study was conducted to investigate the potential protective effect of ethanolic extract of Andrographis paniculata leaves (EEAP) against DOX-induced cardiac inflammation, liver toxicity, and anemia. Materials and methods: Sprague-Dawley rats were intraperitoneally injected with DOX at a total dose of 16 mg/kgBW. EEAP was administered orally for 4 weeks at doses of 125, 250, and 500 mg/kgBW/day according to the assigned treatment groups. The mRNA expression levels of interleukin-1β (IL-1β) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) in the heart tissue, along with the concentrations of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and calcium level were examined. Additionally, the hematological parameters (including hematocrit, hemoglobin and red blood cells (RBCs)), aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and malondialdehyde (MDA) levels in blood were also analyzed. Results: EEAP dose-dependently decreased the mRNA expressions of IL-1β (p

Context: Cardiovascular diseases claim the lives of an estimated 17.9 million people worldwide (report by the World Health Organization), yet the drug pipeline compared to some other life-threatening diseases, including cancer and neurological disorders, is low. Aims: To investigate the potential of Andrographis paniculata as a supplementary therapy for cardiovascular diseases based on recent in vivo animal studies. Methods: This study adopted a systematic review approach to analyze preclinical evidence from in vivo animal studies. Three databases (PubMed, Scopus, and Embase) were searched using the keywords “Andrographis paniculata”, “cardiovascular disease”, “CVD”, “heart disease”, “cardioprotective”, “cardio*”, “inflammation”, “oxidative stress”, “obesity”, “lipopolysaccharide”, “hypertension”, “arrhythmia” and “aortic disease”. The search period was from April 20th, 2023, to April 26th, 2023, and included studies published from 2013 to 2023. Only in vivo animal studies were appraised. In contrast, clinical studies, in vitro studies, in silico studies, and review papers were excluded. SYRCLE’s risk of bias tool was used to assess the risk of bias. Results: Sixteen eligible in vivo animal studies showed that Andrographis paniculata extracts and isolated bioactive compounds have strong anti-inflammatory and antioxidant effects on cardiovascular diseases. These effects lead to lowering the risk of coronary artery disease and myocardial infarction, easing the effects of bad cardiac remodeling, stopping cardiac hypertrophy, and improving diabetic cardiomyopathy. Although SYRCLE's tool detected some bias, the studies were included since they met the inclusion criteria and had no conflicts of interest. Conclusions: Andrographis paniculata may have the potential to be used as a supplementary therapy for cardiovascular diseases, but more animal studies and clinical trials should be done to establish these findings.

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. Keywords: Antimalaria, Anthraquinone, Mangrove, Plasmodium sp., Protozoa

Chemotherapy-induced nausea and vomiting (CINV) affects over 50% of pediatric patients undergoing chemotherapy, a higher proportion than in adults. CINV often occurs despite adequate antiemetic prophylaxis, hampering patients' willingness to continue the chemotherapy regimen. As an ayurvedic medicine, ginger (Zingiber officinale) has an antiemetic effect by inhibiting serotonin in gastrointestinal nerves and as an NK1 antagonist. Therefore, we aimed to review oral ginger supplementation in children with CINV systematically.Systematic searching was performed in June 2023 from Pubmed, Embase, CINAHL, Cochrane, and hand searching. The search consisted of PICO “children chemotherapy”, “ginger”, and “CINV incidence”. We limited the search to only human studies. Studies that meet inclusion and exclusion criteria were included for analysis.Out of 116 studies found with our selection criteria, four were compatible with inclusion and exclusion criteria. Two studies had a small Risk of Bias (RoB), while the others had a high RoB. All studies statistically significantly reduced acute and delayed CINV with the number needed to treat (NNT) 2–4. No adverse effects were reported. However, these studies still had high heterogeneity based on cancer treatment, chemotherapy regimen, ginger dosing, and ginger processing.Ginger has the potential to reduce both the acute and delayed phases of CINV in children. Additional research employing standardized methodologies is recommended to validate this effect.

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.

AbstractContext Cisplatin, as a first-line treatment for ovarian cancer, is associated with debilitating adverse effects, including nephrotoxic and haematotoxic effects.Objective This study determines whether nanocurcumin, combined with cisplatin, would give additional benefit to kidney function and haematological parameters in rats with ovarian cancer.Materials and methods 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.Results 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).Conclusions 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.

AbstractContext 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)-1β, 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.

BACKGROUND: Breast cancer stem cells (BCSCs) have been identified as playing a crucial role in therapeutic resistance. This resistance can be attributed to the anti-apoptotic protein survivin and the antioxidant MnSOD high expression. To overcome the resistance to doxorubicin (DOX), this study proposed the utilization of andrographolide (ANDRO), the primary bioactive compound in Andrographis paniculata leaves. The objective was to examine the role of andrographolide in regulating survivin, caspase-9, and caspase-3 gene expressions to reverse doxorubicin resistance in human BCSCs. METHODS: BCSCs were exposed to 0.1 µM DOX every two days or 50 µM rotenone (ROT) for 6 hours, subsequently supplemented with 0.3 mM ANDRO. Superoxide and peroxide levels were measured using DHE and DCFH-DA assay. The MnSOD, survivin, caspase-9, and caspase-3 mRNA expression levels were analyzed using qRT-PCR. Protein expressions were evaluated using Western blotting assay. MnSOD activity was determined using xanthine oxidase inhibition assay. The apoptotic cells were determined using Annexin-V/PI staining. RESULTS: This study indicated that the cytotoxic mechanisms of DOX, similar to ROT, in BCSCs were attributed to oxidative stress, as evidenced by an elevation in superoxide rather than peroxide levels, accompanied by a decrease in MnSOD activity. This study also highlighted that ANDRO reversed DOX resistance in BCSCs subjected to repeated DOX treatment by downregulating survivin and upregulating caspase-9 and caspase-3 mRNA expressions, thereby activating the intrinsic apoptotic pathway. CONCLUSION: This study provides insights into the role of ANDRO in modulating the expression of apoptotic genes, such as survivin, caspase-9, and caspase-3, to overcome DOX resistance in BCSCs. KEYWORDS: breast cancer, breast cancer stem cell, andrographolide, doxorubicin, oxidative stress, apoptosis

Background and objectives: COVID-19 is a respiratory condition frequently followed by an inflammatory reaction in addition to respiratory symptoms, which disrupts the blood coagulation process. One drug candidate known to have dual anti-inflammatory and anticoagulating effects is hydroxysafflor yellow A, an active compound found in the flowers of Carthamus tinctorius. Therefore, this study analysed the effect of C. tinctorius ethanol extract in combination with dexamethasone on coagulation biomarkers in mice induced with the SARS-CoV2 spike protein. Method: Flowers of Carthamus tinctorius were extracted with 98% ethanol. The concentrated extract was used in the study. Twenty-five Balb/c mice, comprising five healthy controls and twenty mice were induced with SARS-CoV2. The SARS-CoV2-induced mice were then randomized to receive seven days of treatment, which consisted of vehicle or dexamethasone 2.5 mg/kg BW, dexamethasone 2.5 mg/kg BW + C. tinctorius extract 400 mg/kg BW, or dexamethasone 2.5 mg/kg BW + C. tinctorius extract 800 mg/kg BW. Subsequently, the lungs and blood of the mice were analysed. Results: SARS-CoV2-induced mice increased all the coagulation markers studied. Treatment with dexamethasone alone or in combination with C. tinctorius extract 400 mg/kg BW did not cause reductions in D-dimer, plasminogen activator inhibitor-1, lactate dehydrogenase, platelet-to-leucocyte ratio, or neutrophil-to-leucocyte ratio. However, dexamethasone co-treatment with C. tinctorius extract at 800 mg/kg BW resulted in the normalization of D-dimer, PAI-1, and NLR in SARS-CoV2-induced mice. Conclusion: The administration of high dose of C. tinctorius flower extracts (800 mg/kg BW) in combination with dexamethasone showed the benefit of minimizing the coagulation disorder in SARS-CoV2.

Abstract Introduction Clopidogrel is recommended as an alternative to Acetyl Salicylic Acid (ASA), the first-line drug for secondary stroke prevention. Clopidogrel resistance in Indonesia is reportedly 15.8%. The Stent Thrombosis in Belgium (STIB) is a scoring system proposed to assess clopidogrel resistance which has not been tested for the reliability in Indonesian population. Objectives The objective of the study is to test the reliability of the STIB scoring and modified-STIB scoring system in Indonesian population. Methods This study was conducted cross-sectionally in Dr. Cipto Mangunkusumo Hospital and Universitas Indonesia Hospital from January 2020 to December 2021. Laboratory examinations of human CYP450 concentration in blood plasma from 112 subjects were carried out using the ELISA method. The clopidogrel resistance test was carried out using the VerifyNow method. Results Out of 112 ischemic stroke patients in this study, 14.3% of them did not respond to clopidogrel. Cross-tabulation between the STIB score and clopidogrel resistance showed significant results (p

Objective: This study was conducted to establish a rat model of acute exacerbation of idiopathic pul¬monary 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. [J Adv Vet Anim Res 2023; 10(2.000): 196-204]

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.

Abstract Background Alpha-mangostin (AM) has been shown to have hypoglycemic activity. This study aimed to analyze the effects of AM at a dose of 100 mg/kg and 200 mg/kg to alleviate hyperuricemia and renal dysfunction on high-fat/high-glucose diet and low dose streptozotocin (HF/HG/STZ) injection-induced IR rat model. IR was induced in male Wistar rats by giving a HF/HG diet for 11 weeks and single injection of STZ (35 mg/kg, i.p.), then divided randomly into IR rats, IR rats treated with AM 100 and 200 mg/kgBW given by gavage for 8 weeks. At the end of the 11th week, all rats were killed, and the kidneys were taken to be analyzed for urate transporters 1 (URAT1) and glucose transporters 9 (GLUT9). We also assessed serum uric acid, proteinuria, BUN, creatinine clearance, HOMA-IR, and fasting blood glucose (FBG). Results We have found the significant increase in HOMA-IR and FBG levels of the IR rats, in comparison with its control groups, which were decreased significantly after AM administration at both doses. URAT1 and GLUT9 mRNA and protein expressions in kidney in the IR + AM at both doses groups also decreased compared those in the IR without treatment group, though the decrease in GLUT9 did not appear to be statistically significant. Consequently, hyperuricemia and renal dysfunction were attenuated by AM treatment at both doses. Conclusion After considering all findings, AM might be a potential candidate to ameliorate IR-induced hyperuricemia and renal dysfunction at least in part by modulating the renal URAT1.

BackgroundPrediabetes 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.MethodThe 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.ResultsVitamin 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.ConclusionVitamin 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.

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.

Purpose: Ovarian carcinoma is one of the gynaecological malignancies that have the highest mortality rates due to its progressivity. Endothelin signalling plays a leading role in the progression of ovarian cancer through Epithelial-to-Mesenchymal Transition (EMT). Cisplatin commonly used as potent chemotherapy; however, its application hindered by its nephrotoxic effect. Curcumin, a turmeric-derived compound, has an anticancer property, as well as a renal protective effect. Moreover, curcumin augments the affinity of the antioxidant enzyme, while inhibits endothelin-1 (ET-1) signalling. The effects of curcumin on ovarian cancer progression and cisplatin-induced kidney injury remain unknown. Methods: Curcumin was used as a supplementary therapy together with cisplatin in Human Ovarian Cancer Cell line (SKOV3) and also in rodent-induced ovarian cancer. The kidney phenotype in the ovarian cancer rat model after cisplatin ± curcumin administration will also be analyzed Results: Co-treatment of cisplatin with curcumin enhanced the expression of a gene involved in apoptosis in association with NRF2 enhancement, thus activated ETBR-mediated ET-1 clearance in SKOV3 cell and ovarian cancer model in rat. Moreover, curcumin treatment improved mitochondria biogenesis markers such as PGC-1α and TFAM and prevented the elevated of ET-1-mediated renal fibrosis and apoptosis in kidney isolated from cisplatin-treated ovarian cancer rat. Conclusion: Curcumin could be potentially added as an anticancer adjuvant with protective effects in the kidney; thus, improves the efficacy and safety of cisplatin treatment in the clinical setting.

BackgroundSilver 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).ObjectivesIsoproterenol (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.MethodsTwenty-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.ResultsThe 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.ConclusionThese 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.

Despite technological advances in cancer treatment, especially in radiotherapy, many efforts are being made in improving cancer cell radio-sensitivity to increase therapeutic ratio and overcome cancer cell radio-resistance. In the present review, we evaluated the anticancer mechanism of Annona muricata L. (AM) leaves extract and its bioactive compounds such as annonaceous acetogenins, annomuricin, annonacin, or curcumin; and further correlated them with the potential of the mechanism to increase or to reduce cancer cells radio-sensitivity based on literature investigation. We see that AM has a promising future potential as a radio-sensitizer agent.

Purpose: This study aimed to provide the method of preparation, characterization of curcumin-loaded chitosan-sodium tripolyphosphate (NaTPP) nanoparticle, and evaluate its pharmacokinetic profiles. Methods: Curcumin-loaded chitosan-NaTPP nanoparticles were synthesized using ionic gelation methods. Curcumin was dissolved using surfactants and cosurfactants. Chitosan polymer was then mixed in the curcumin solution and dripped with NaTPP solution until nanoparticle formation. The mucoadhesive study was evaluated by measuring the fluorescence of curcumin within the prepared nanoparticles. The pharmacokinetic profiles of curcumin particles and nanoparticles were then assessed in rats by administering a single oral dose of 100 mg/kg BW. Blood samples were taken from nine predetermined time points, and curcumin plasma concentrations were then analyzed using UPLC-MS/MS. Results: The particle size of the curcumin nanoparticles obtained were 11.5 nm. Entrapment efficiency (EE) of curcumin nanoparticles were exceeding 99.97%, and drug loading capacity (DLC) was 11.34%. The mucoadhesive properties of the nanoparticles were superior to that of curcumin particles. Pharmacokinetic evaluation in rats revealed that curcumin nanoparticles resulted in an increase of area under the curve (AUC), maximum concentration (Cmax), earlier time to reach maximum concentration (Tmax), and lower clearance (CL). Conclusion: Curcumin-loaded chitosan-NaTPP nanoparticles is an effective formulation to improve curcumin plasma concentrations. Thus, enable its applications for the treatment of various diseases.

Cardiometabolic disorders (CMD) have become a global emergency and increasing burden on health and economic problems. Due to the increasing need for new drugs for cardiometabolic diseases, many alternative medicines from plants have been considered and studied. Moringa oleifera Lam. (MO), one of the native plants from several Asian countries, has been used empirically by people for various kinds of illnesses. In the present systematic review, we aimed to investigate the recent studies of MO in CMD and its possible mechanism of action. We systematically searched from three databases and summarized the data. This review includes a total of 108 papers in nonclinical studies and clinical trials of MO in cardiometabolic-related disorders. Moringa oleifera, extracts or isolated compound, exerts its effect on CMD through its antioxidative, anti-inflammatory actions resulting in the modulation in glucose and lipid metabolism and the preservation of target organ damage. Several studies supported the beneficial effect of MO in regulating the gut microbiome, which generates the diversity of gut microbiota and reduces the number of harmful bacteria in the caecum. Molecular actions that have been studied include the suppression of NF-kB translocation, upregulation of the Nrf2/Keap1 pathway, stimulation of total antioxidant capacity by reducing PKCζ activation, and inhibiting the Nox4 protein expression and several other proposed mechanisms. The present review found substantial evidence supporting the potential benefits of Moringa oleifera in cardiovascular or metabolic disorders.

Background: The liver microenvironment plays a key role in liver fibrosis and carcinogenesis. This study aimed to fill the gap in knowledge on the interaction between hepatic stellate cells and endothelial progenitor cells with biomarkers of liver fibrosis and/or carcinogenesis, including Col1A1, TGF-β, and tenascin-C. Methods: CD34+ stem cells were isolated from umbilical-cord-blood mononuclear cells. 2D and 3D co-culture of CD34+ UCB SCs and LX2 was performed. The cells were incubated in a CO2 incubator for three days. Morphological observation, qRT-PCR of TGF-β1 and COL1A1, and immunocytochemistry of tenascin-C were performed. Results: CD34+ UCB SCs were viable in the 2D and 3D co-culture for 24 h. 3D co-culture of CD34+ UCB SCs and LX2 inhibited in vitro liver fibrosis by lowering Col 1A1 expression as compared to control. We observed lower TGF-β expression in 3D co-culture on days 1 and 2 followed by higher expression of TGF-β on day 3. 2D co-culture of CD34+ UCB SCs and LX2 showed a different level of COL1A1 and TGF- β expression compared with 3D co-culture. Spheroids from 2D co-culture of CD34+ UCB SCs and LX-2 showed immunoreactivity against tenascin-C. Conclusion: Interaction between LX-2 and CD34+ UCB SCs in 3D co-culture inhibits in vitro liver fibrosis. The viability of CD34+ UCB SCs is essential for attenuation of TGF-β signaling in LX-2.

Purpose: This study was intended to find out the impact of alpha mangostin administration on the epithelial-mesenchymal transition (EMT) markers and TGF-β/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)-β1 in a culture medium were examined using ELISA. The mRNA expressions of TGF-β1, TGF-β1-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 P0.05). In line with our findings, the expressions of TGF-β1 and Smad3 are significantly upregulated after alpha mangostin administration (both with P

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.

Background: Cisplatin is a first-line chemotherapeutic agent for various solid tumors including ovarian and breast cancer. Thereby, it has been proven effective as an antineoplastic agent, but its clinically use is limited because of its nephrotoxicity side effect. Aims and Objectives: This study aimed to investigate curcumin as a renoprotector agent against cisplatin nephrotoxicity. Materials and Methods: The samples used were curcumin and its nanoparticles formulated using ionic gelation method. The nephrotoxicity was investigated through several parameters such as serum creatinine, blood urea nitrogen, serum albumin, kidney weight ratio, and histopathology. These parameters were tested on rats and divided into the following four groups: normal group, negative control group that administered cisplatin with doses amount of 7 mg/kg body weight (BW) intraperitoneally, nanocurcumin group (cisplatin + nanocurcumin) and curcumin group (cisplatin + curcumin). The agents were administered at a dose of 100 mg/kg BW every day in 9 days before cisplatin administration. The sample of blood serum and kidneys organ were taken 48h after cisplatin administration. Results: The negative control group showed a significant increase in serum creatinine, blood urea nitrogen, and kidney weight ratio, whereas it showed a significant decrease in serum albumin. The administration of sample agents showed a significant decrease in serum creatinine, blood urea nitrogen, and kidney weight ratio and an increase in the albumin level as compared to negative control group. Conclusion: Nanocurcumin showed significant improvement in kidneys more than curcumin. In contrast, histopathological examination verified the necrosis in negative control group, suggesting the renoprotection effect of nanocurcumin against nephrotoxicity on cisplatin-induced rats.

Cisplatin has been used for decades for the treatment of ovarian cancer. However, despite its potent anticancer effect, cisplatin’s efficacy as a single agent was inadequate in patients with advanced stage. Curcumin has been shown to sensitize cisplatin activity in several cancer models. However, the low bioavailability of curcumin has limited its anticancer potential. Hence, nano-formulation of curcumin was developed to increase its therapeutic efficacy in ovarian cancer. The objective of this study was to investigate the mechanism of curcumin nanoparticles given in combination with cisplatin in rat ovarian carcinoma induced by dimethylbenz(a)anthracene (DMBA). The administration of cisplatin and nanocurcumin resulted in a significant reduction in ovarian tumor volume and weight. Furthermore, there were reduction in expressions of Ki67, TGF-β, PI3K, and Akt phosphorylation. Co-treatment of cisplatin and nanocurcumin also reduced JAK expression, STAT3 phosphorylation, and reduced IL-6 concentrations. Altogether, nanocurcumin, given as a co-treatment with cisplatin has therapeutic potential in ovarian cancer models by inhibiting proliferation through downregulation of PI3K/Akt and JAK/STAT3 signaling pathways.

[This corrects the article DOI: 10.1371/journal.pone.0240020.].

BackgroundAdverse 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.MethodsEligible 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).ResultsA 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.ConclusionHIV 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.

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.

Breast cancer stem cells (BCSCs) express high levels of the anti-apoptotic protein, survivin. This study aimed to discover a natural active compound with anti-cancer properties that targeted survivin in human breast cancer stem cells. From the seven examined compounds, andrographolide was selected as a lead compound through in silico molecular docking with survivin, caspase-9, and caspase-3. We found that the affinity between andrographolide and survivin is higher than that with caspase-9 and caspase-3. Human CD24-/CD44+ BCSCs were treated with andrographolide in vitro for 24 hours. The cytotoxic effect of andrographolide on BCSCs was compared to that on human mesenchymal stem cells (MSCs). The expression of survivin, caspase-9, and caspase-3 mRNA was analyzed using qRT-PCR, while Thr34-phosphorylated survivin and total survivin levels were determined using ELISA and Immunoblotting assay. Annexin-V/PI flow cytometry assays were performed to evaluate the apoptotic activity of andrographolide. Our results demonstrate that the CC50 of andrographolide in BCSCs was 0.32mM, whereas there was no cytotoxic effect in MSCs. Moreover, andrographolide decreased survivin and Thr34-phosphorylated survivin, thus inhibiting survivin activation and increasing survivin mRNA in BCSCs. The apoptotic activity of andrographolide was revealed by the increase of caspase-3 mRNA and protein, as well as the increase in both the early and late phases of apoptosis. In conclusion, andrographolide can be considered an anti-cancer compound that targets BCSCs due to its molecular interactions with survivin, caspase-9, and caspase-3, which induce apoptosis. We suggest that the binding of andrographolide to survivin is a critical aspect of the effect of andrographolide.

Background. Atopic dermatitis or eczema is one of the most common dermatologic problems, especially in children. Several studies have hypothesized that alteration of gut-colonizing microbes might have induced and conditioned the development of the disease. Thus, modulation of microbial diversity and abundance might help alleviate symptoms and conditions for patients. Given the ability of commensal and symbiotic microorganisms in modulating the immune system, probiotics administration has been studied in previous research in the management of eczema. However, until today, there are conflicting results between studies making inconclusive recommendations towards probiotics supplementation in the management of atopic dermatitis. This case-based review was done to assess and evaluate the therapeutic efficacy of probiotics supplementation in the management of eczema in children. Method. An electronic database search was conducted in PubMed-NCBI, Cochrane, EBSCO, ProQuest, and SCOPUS in March 2020. Individual studies and reviews were then gathered for screening using predetermined inclusion and exclusion criteria. The included studies were then critically appraised for their validity and importance. Result. A total of 5 studies, all of which were RCTs, were included in this review. Out of all the studies included, 4 showed no clinically significant improvements in using probiotics in the management of eczema in children as they did not pass the minimal clinically important difference (MCID) of eczema severity as determined by SCORAD (SCORing Atopic Dermatitis). Conclusion. Supplementation of probiotics in the management of eczema in children does not show a clinically relevant difference vs. standard treatment in reducing eczema severity.

The decreasing of sensitivity or resistance to tamoxifen occured after long-term treatment in breast cancer. One of the major factor in tamoxifen resistance is over expression of efflux transporter P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Curcumin has known as inhibitor of P-gp and BCRP. The addition of curcumin to the tamoxifen resistant cells is expected to increase the sensitivity of breast cancer cells to tamoxifen. This study aim to know the effect of curcumin in increasing the cell sensitivity to tamoxifen through inhibition of P-gp and BCRP transporter efflux. MCF-7 breast cancer cell line was induced with tamoxifen 1 µM for 10 passage (MCF-7(T)), then cell viability and mRNA expression of P-gp and BCRP were analyzed. To the MCF-7(T) cells, curcumin was given at of 5/10/20 µM with or without tamoxifen for 5 days and cell viability and mRNA expression of P-gp and BCRP were analyzed on day 5th. As positive control, verapamil 50 µM was used as P-gp inhibitor, ritonavir 15 µM and nelfinavir 15 µM were used as BCRP inhibitor. The results showed that MCF-7(T) cells sensitivity to tamoxifen decreased with 11.8 times, the cell viability increased 10.82 fold and mRNA expression of P-gp and BCRP increased 4.04 fold. Then after administration of curcumin with or without tamoxifen for 5 days, the cell viability and the mRNA expression of P-gp and BCRP decreased. As conclusion, curcumin increased the sensitivity of MCF-7(T) to tamoxifen characterized by the decreasing of cell viability and mRNA expression of P-gp and BCRP. However, the administration of combination of curcumin with tamoxifen was more potent than just curcumin. The increased sensitivity was estimated at least partly through the inhibition of P-gp and BCRP mRNA expression by curcumin

Chronic myeloid leukemia (CML) is a clonal haemopoietic stem cell disorders with reciprocal translocation in chromosome 9 (ch9) and 22 (ch22) which cause the fusion of Break cluster region-Abelson murine leukemia (BCR-ABL) oncogene. This fusion will activate tyrosine kinase. Imatinib mesylate is the first tyrosine kinase inhibitor (TKI), which could change the prognosis of CML patients. However, there is a resistance to TKI’s, and based on transcriptomic study, increase expression of gen signal transducer and activator of transcription (STAT) 5A and runt-related transcription factor 3 (RUNX3) can cause resistance to TKI’s. The STAT5 protein, which in normal myeloid cells being activated by cytokine, in CML patients was activated even without cytokines. STAT5 refer to STAT5A and STAT5B, however they have might have different role in hematopoietic stem cells or in CML cells. This review summarizes the role of STAT5 in tyrosine kinase inhibitor resistance in CML patients.

Background Digoxin has long been prescribed in children with heart failure, but its efficacy has not been evaluated. A previous study at the Department of Child Health, Dr. Cipto Mangunkusumo Hospital revealed that plasma digoxin levels, following a maintenance dose of 15 μg/kg/d, were sub-therapeutic. Regarding its narrow margin of safety, the trend is to use digoxin in even lower dose. Thus, the drug’s impact on cardiac performance need to be evaluated. Objective To evaluate whether a lower maintenance dose of digoxin (10 μg/kg/d) is sufficient to achieve a therapeutic level and to assess for possible correlations between plasma digoxin level and left ventricular ejection fraction (LVEF) as well as fractional shortening (LVFS). Methods A cross-sectional study was conducted on 20 pediatric heart failure patients at the Department of Child Health, Dr. Cipto Mangunkusumo Hospital, Jakarta, from January to May 2012. Plasma digoxin levels were measured by ELISA method after one month or more of treatment; LVEF and LVFS were measured by echocardiography. Correlations between plasma digoxin level and LVEF or LVFS were analyzed by Spearman’s correlation test. The LVEF before and after digoxin treatment were compared by paired T-test. Results Thirteen out of 20 patients had plasma digoxin levels within therapeutic range (0.5-1.5 ng/mL; 95%CI 0.599 to 0.898) and 7 had sub-therapeutic levels (

Latar belakang. Fomula berbasis isolat protein kedelai banyak digunakan untuk anak-anak dengan alergi susu sapi di Indonesia. Namun, diperlukan penelitian untuk mendapatkan gambaran penerimaan orangtua dan toleransi saluran cerna pada penggunaan formula isolat protein kedelai. Tujuan. Pertama, menentukan penerimaan orangtua terhadap pemberian suatu isolat protein kedelai pada bayi yang diduga mengalami alergi terhadap protein susu sapi. Kedua, mengetahui toleransi saluran cerna pada pemberian susu formula tersebut. Metode. Suatu studi pasca-pemasaran, prospektif, multisenter yang dilakukan di Jakarta, Bandung, Surabaya, Yogyakarta, Solo, dan Denpasar sejak September 2011 sampai April 2012. Subyek berusia antara 6 bulan hingga 1 tahun dengan gejala dugaan alergi terhadap protein susu sapi yang diberikan formula isolat protein kedelai dan diamati selama 4 minggu. Luaran yang diharapkan adalah penerimaan orangtua terhadap pemberian formula isolat protein kedelai dan toleransi saluran cerna terhadap pemberian isolat protein kedelai. Hasil. Diteliti 534 subyek yang dapat dianalisis selama periode penelitian. Mayoritas orangtua (84%) merasa puas dengan formula isolat protein kedelai, 83% orangtua berencana untuk melanjutkan pemberian susu formula karena berkurang (31,5%) dan hilangnya gejala yang diduga akibat alergi susu sapi (32,4%). Gejala klinis yang diduga akibat alergi terhadap protein susu sapi menurun pada setiap kunjungan berikutnya. Tidak ada efek samping serius yang dilaporkan selama periode penelitian. Kesimpulan. Penelitian ini menemukan tingkat penerimaan orangtua dan toleransi saluran cerna yang baik terhadap pemberian formula isolat protein kedelai kepada bayi dengan gejala sugestif alergi terhadap protein susu sapi. Formula isolat protein kedelai cukup aman dijadikan sebagai formula alternatif pengganti pada anak dengan alergi susu sapi.

Background: DLBS1033 is a bioactive protein fraction extracted from Lumbricus rubellus, with fibrinogenolytic, fibrinolytic and anti-aggregation activities reported in an in vitro study. Plasma half-life is an important parameter to calculate its dose. This study was conducted to evaluate the biological half-life of DLBS1033 by measuring serial plasmin-antiplasmin (PAP) complex. PAP complex is a stable and inactive compound as a result of fibrinolysis process. Methods: this was an open-label clinical trial in healthy adult subjects. Subjects were divided into two groups to receive single dose drugs (received 3 x 490 mg) or repeated administration until steady state conditions (3 x 490 mg/day for 3 days). Blood samples for PAP complex measurement were collected at time 0 (before drug administration for single dose group), then at 0.5, 1, 1.5, 2, 3, 6, 8, 10, 12, and 24 hours after drug administration. Safety parameters used in this study were creatinine, prothrombin time (PT), activated partial thromboplastin time (aPTT), SGOT, and SGPT. Results: the biological half-life of DLBS1033 was calculated based on the mean of PAP complex concentration on each time sampling. In single dose group, the highest mean of PAP complex concentration was reached before drug administration. Our result showed that the activity of DLBS1033 could not be determined after single dose administration. In steady state condition, the PAP complex concentration increase in 2 hours after last drug administration. The biological half-life of DLBS1033 was 8.6 hours. There were no significant safety findings on all laboratory parameters and no serious adverse events. Conclusion: it is concluded that the fibrinolytic effects of DLBS1033 can be measured in steady state condition. The biological half-life of DLBS1033 in steady state condition was 8.6 hours. There were no serious adverse events on two groups of subjects.

Liver fibrosis is characterized by excessive accumulation of extracellular matrix in chronic liver injury. Alcohol-induced fibrosis may develop into cirrhosis, one of the major causes of liver disease mortality. Previous studies have shown that alpha mangostin can decrease ratio of pSmad/Smad and pAkt/Akt in TGF-β-induced liver fibrosis model in vitro. Further investigation of the mechanism of action of alpha mangostin in liver fibrosis model still needs to be done. The present study aimed to analyze the mechanism of action of alpha mangostin on acetaldehyde induced liver fibrosis model on TGF-β and ERK 1/2 pathways. Immortalized HSCs, LX-2 cells, were incubated with acetaldehyde, acetaldehyde with alpha mangostin (10 and 20 μM), or alpha mangostin only (10 μM). Sorafenib 10 μM was used as positive control. LX-2 viability was counted using trypan blue exclusion method. The effect of alpha mangostin on hepatic stellate cells proliferation and activation markers and its possible mechanism of action via TGF-β and ERK1/2 were studied. Acetaldehyde was shown to increase proliferation and expression of profibrogenic and migration markers on HSC, while alpha mangostin treatment resulted in a reduced proliferation and migration of HSC and decreased Ki-67 and pERK 1/2 expressions. These findings were followed with decreased expressions and concentrations of TGF-β; decreased expression of Col1A1, TIMP1, and TIMP3; increased expression of MnSOD and GPx; and reduction in intracellular reactive oxygen species. These effects were shown to be dose dependent. Therefore, we conclude that alpha mangostin inhibits hepatic stellate cells proliferation and activation through TGF-β and ERK 1/2 pathways.

Phaleria macrocarpa is one of the Indonesian herbal plants which has been shown to have a hepatoprotective effect. This study was conducted to evaluate the protective effect of water extract of mahkota dewa (Phaleria macrocarpa) in liver fibrosis and to elucidate its mechanism of action. Male Sprague-Dawley rats were treated with carbon tetrachloride (CCl4) for 8 weeks to induce liver fibrosis. Rats were randomly divided into 6 groups (n=5), i.e., control group, CCl4 group, CCl4 + NAC group, CCl4 + various doses of water extract of Phaleria macrocarpa (50, 100, and 150 mg/kg body weight). Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), liver histopathology, malondialdehyde (MDA), ratio GSH/GSSG, Tumor Necrosis Factor- (TNF-) α, and Transforming Growth Factor- (TGF-) β1 were analyzed. This study demonstrated that water extract of Phaleria macrocarpa and NAC significantly protected CCl4-induced liver injury as demonstrated by reduced AST, ALT, ALP, and fibrosis percentage compared with the CCl4-only group. In addition, water extract of Phaleria macrocarpa and NAC significantly reduced the levels of MDA, TNF-α, and TGF-β1 as well as increasing the ratio of GSH/GSSG. Water extract of Phaleria macrocarpa prevents CCl4-induced fibrosis in rats. The prevention of liver fibrosis was at least in part through its antioxidant and anti-inflammatory activities and through its capacity to inhibit hepatic stellate cells (HSC) activation by reducing fibrogenic cytokine TGF-β1.

Tamoxifen is the first line drug used in the treatment of estrogen receptor-positive (ER+) breast cancer. The development of multidrug resistance (MDR) to tamoxifen remains a major challenge in the treatment of cancer. One of the mechanisms related to MDR is decrease of drug influx via overexpression of drug efflux transporters such as P-glycoprotein (P-gp/MDR1), multidrug resistance associated protein (MRP), or BCRP (breast cancer resistance protein). We aimed to investigate whether the sensitivity of tamoxifen to the cells is maintained through the short period and whether the expressions of several drug efflux transporters have been upregulated. We exposed MCF7 breast cancer cells with tamoxifen 1 μM for 10 passages (MCF7 (T)). The result showed that MCF7 began to lose their sensitivity to tamoxifen from the second passage. MCF7 (T) also showed a significant increase in all transporters examined compared with MCF7 parent cells. The result also showed a significant increase of CC50 in MCF7 (T) compared to that in MCF7 (97.54 μM and 3.04 μM, resp.). In conclusion, we suggest that the expression of several drug efflux transporters such as P-glycoprotein, MRP2, and BCRP might be used and further studied as a marker in the development of tamoxifen resistance.

Diabetic nephropathy (DN) lowered quality of life and shortened life expectancy amongst those affected. Evidence indicates interaction between advanced glycation end products (AGEs), activated protein kinase C (PKC) and angiotensin II exacerbate the progression of DN. Inhibitors of angiotensin-converting enzyme (ACEIs), renin angiotensin aldosterone system (RAAS), AGEs, and PKC have been tested for slowing down the progression of DN. The exact molecular drug targets that lead to the amelioration of renal injury in DN are not well understood. This review summarizes the potential therapeutic targets, based on putative mechanism in the progression of the disease.

Background: Cell culture techniques have many advantages for investigation of drug transport to target organ like liver. HepG2 and Huh-7 are two cell lines available from hepatoma that can be used as a model for hepatic drug transport. The present study is aimed to analyze the expression level of several drug transporter genes in two hepatoma cell lines, HepG2 and Huh-7 and their response to inhibitors. Materials and Methods: This is an in vitro study using HepG2 and Huh-7 cells. The expression level of the following drug transporter genes was quantified: P-glycoprotein/multidrug resistance protein 1, Organic Anionic Transporter Protein 1B1 (OATP1B1) and Organic Cationic Transporter-1 (OCT1). Ribonucleic acid was extracted from the cells using Tripure isolation reagent, then gene expression level of the transporters is quantified using Applied Biosystems quantitative reverse transcriptase polymerase chain reaction. Verapamil (P-glycoprotein inhibitor), nelfinavir (OATP1B1 inhibitor), quinidine (OCT1 inhibitor) were used to differentiate the inhibitory properties of these agents to the transporter expressions in HepG2 and Huh-7 cells. Results: Huh-7 shows a higher level of P-glycoprotein, OATP1B1 and OCT1 expressions compared with those of HepG2. Verapamil reduces the expressions of P-glycoprotein in HepG2 and Huh-7; nelfinavir reduces the expression of OATP1B1 in HepG2 and Huh-7; while quinidine reduces the OCT1 gene expressions in HepG2, but not in Huh-7 cells. Conclusion: This study indicates that HepG2 might be a more suitable in vitro model than Huh-7 to study drug transport in hepatocytes involving drug transporters.