Profibrotic Inflammatory Cytokines and Growth Factors Are Predicted as the Key Targets of Uncaria gambir (Hunter) Roxb. in Keloids: An Epistatic and Molecular Simulation Approach.

Keloid is characterized as the fibrotic tissue resulting from the increase of fibroblast activity. Uncaria gambir (Hunter) Roxb. possesses bioactive compounds that have potential as antifibrotic agents, while the mechanism of action in keloid has not yet been elucidated. The aim of this study was to investigate the interaction of gambir bioactive compounds with keloid target proteins using an epistatic and molecular simulation approach. The known bioactive compounds of gambir targets and keloid-related protein targets were screened using databases. The network was constructed and analyzed to obtain the core protein targets. The targets were enriched to describe the Gene Ontology (GO) and pathway related to the proteins. Eleven targets were defined as the main targets of gambir bioactive compounds related to keloid disease. Gambiriin C, Isogambirine, and Procyanidin B1 were identified as the most promising compounds with the highest binding energy to transforming growth factor beta 1 (TGFß1), AKT serine/threonine kinase 1 (AKT1), and matrix metallopeptidase 1 (MMP1) as the target proteins. GO enrichment and pathway analysis found that gambir bioactive compounds may act on keloid-related target proteins to regulate cell proliferation, migration, transcription, and signal transduction activity via profibrotic cytokine and growth factor signaling pathways. This study provides a reference for potential targets, compounds, and pathways to explain the mechanism of gambir against keloid.

Phytochemical Profile, Antioxidant, Enzyme Inhibition, Acute Toxicity, In Silico Molecular Docking and Dynamic Analysis of Apis Mellifera Propolis as Antidiabetic Supplement.

This study aims to identify the phytochemical profile of Apis mellifera propolis and explore the potential of its anti-diabetic activity through inhibition of α-amylase (α-AE), α-glucosidase(α-GE), as well as novel antidiabetic compounds of propolis. Apis mellifera propolis extract (AMPE) exhibited elevated polyphenol 33.26±0.17 (mg GAE/g) and flavonoid (15.45±0.13 mg RE/g). It also indicated moderate strong antioxidant activity (IC50 793.09±1.94 µg/ml). This study found that AMPE displayed promising α-AE and α-GE inhibition through in vitro study. Based on LC-MS/MS screening, 18 unique AMPE compounds were identified, with majorly belonging to anthraquinone and flavonoid compounds. Furthermore, in silico study determined that 8 compounds of AMPE exhibited strong binding to α-AE that specifically interacted with its catalytic residue of ASP197. Moreover, 2 compounds exhibit potential inhibition of α-GE, by interacting with crucial amino acids of ARG315, ASP352, and ASP69. Finally, we suggested that 2,7-Dihydroxy-1-(p-hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene and 3(3-(3,4-Dihydroxybenzyl)-7-hydroxychroman-4-one as novel inhibitors of α-AE and α-GE. Notably, these compounds were initially discovered from Apis mellifera propolis in this study. The molecular dynamic analysis confirmed their stable binding with both enzymes over 100 ns simulations. The in vivo acute toxicity assay reveals AMPE as a practically non-toxic product with an LD50 value of 16,050 mg/kg. Therefore, this propolis may serve as a promising natural product for diabetes mellitus treatment.

Acute and Subchronic Toxicological Study of the Cocktail Extract from Curcuma xanthorrhiza Roxb, Phyllanthus niruri L. and Morinda citrifolia L.

Curcuma xanthorrhiza Roxb, Phyllanthus niruri L., and Morinda citrifolia L. are Indonesian medicinal herbs used empirically as traditional therapeutics for maintaining health. The cocktail extract of these three plants (CECPM) had been developed and demonstrated immunostimulant activity in rats. This study aimed to evaluate the acute and subchronic toxicity of CECPM in vivo. The acute toxicity assay was conducted by orally administering a range dose of CECPM (313, 625, 1250, 2500, or 5000 mg/kg body weight (bw) on female mice once and then evaluating the toxic symptom every day for 14 days later. The chronic toxicity test was carried out by giving various doses of CECPM (600, 800, and 1000 mg/kg·bw) to female and male rats orally continuously for 90 consecutive days. The signs of toxicities were evaluated at the 90- and 28 days postadministration. The acute oral toxicity assays showed that there was no toxic syndrome and mortality found during the period of the experiment. The lethal dose level (LD50) of CECPM was more than 5000 g/kg, which was categorized as practically non-toxic. Meanwhile, in the sub-chronic toxicity study, some parameters tested at 90 days postadministration and after 28 days of withdrawal, such as the body weight, relative organ weight, food intake, hematological and biochemical blood parameters, and also histopathological examination of five primary tissues (heart, liver, kidney, spleen, and lung) revealed no abnormalities. There was no-observed adverse effect level (NOAEL) for the present study of CECPM 1000 mg/kg·bw of the rat. Therefore, it is concluded that the orally administered CECPM was relatively nontoxic during acute and subchronic toxicology studies.

Andrographis paniculata (Burm. f.) Nees extract ameliorates insulin resistance in the insulin-resistant HepG2 cells via GLUT2/IRS-1 pathway.

Hyperglycaemia is one condition related to inflammation leading to insulin signalling impairment. This study was conducted to investigate the insulin sensitivity improvement of Sambiloto (Andrographis paniculata (Burm. f.)) Nees extract in insulin resistance-induced HepG2 (IR-HepG2) cells by stimulating insulin sensitivities and inhibiting inflammatory response. Sambiloto extract at 2 µg/mL revealed glucose uptake stimulation and up-regulating GLUT-2 and IRS-1 gene expression, and inhibited pro-inflammatory cytokine IL-6 gene expression in IR-HepG2 cells. Phytochemical analysis showed that the total phenolic level and andrografolide content of Sambiloto extract were 2.91 ± 0.04% and 1.95%, respectively. This result indicated that Sambiloto extract ameliorated insulin resistance in high glucose-induced IR-HepG2 cells via modulating the IRS-1/GLUT-2 pathway due to IL-6 inhibition. These findings suggested that Sambiloto extract had potency as an anti-inflammatory and insulin-resistance improvement in IR-HepG2 cells.

An examination of Indonesian teachers' and students' perception and level of digital citizenship.

Despite the advanced development of technology has played a critical role in promoting a global community for people around the globe, it has been paid little attention in the literature that explores teachers' and students' readiness to become part of the digital citizenship particularly in the Indonesian education context. It is thus the objective of the present study to examine Indonesian teachers' and students' perception and their level of digital citizenship. Using a non-probability sampling technique, a total of 157 participants participated in the survey, including 39 teachers and 118 students. Many participants were from vocational-secondary schools (N = 58) and non-vocational secondary schools (N = 99). However, after a screening process, of 157 datasets, only 98 data were used for the quantitative data analysis using the Rasch modelling. Rasch modelling method was used for the quantitative data analysis. The findings of the current study revealed that teachers and students had a high-level level of digital citizenship. The teacher and student participants also had a positive view digital citizenship. However, although teachers and students perceived that the internet had helped them develop an understanding of political and social issues, they were reported to have fewer political activities online. They were reluctant to discuss political and social issues in the online community. Findings also showed that the participants' political activity was statistically different in reference to their age, although teachers and students were shown to have a similar level of digital citizenship. Recommendations were thus offered based on the findings.

Developing an integrated model of Islamic social finance: toward an effective governance framework.

This study proposed an integrated model of Islamic Social Finance (ISF) to accelerate the transformation of the poor toward prosperity. This is a qualitative and quantitative approach using grounded theory and the Average Weighted Index (AWI). The integration model of Islamic social finance is implemented through 4 ER (Economic Rescue, Economic Recovery, Economic Reinforcement, and Economic Resilience) by integrating Islamic social finance instruments in a joint project scheme. The additional finding of the empirical investigation shows that integrated Islamic social finance is 12% more effective in enriching the poor than the non-integrated program. This study emphasizes the significance of integrating Islamic social finance in accelerating the well-being of the poor community.

Integrating sustainable Islamic social finance: An Analytical Network Process using the Benefit Opportunity Cost Risk (ANP BOCR) framework: The case of Indonesia.

The utilization of Islamic social finance instruments is far behind what is expected. To realize its full potential, Islamic social finance instruments must be integrated. This study examined solutions and priority strategies for integrating sustainable Islamic social finance that could be implemented in the short and long term using the Benefit, Opportunity, Cost, and Risk (BOCR) framework, which includes six aspects: Governance, sustainable financing, institutional aspect, human resources, regulations, and supporting technology. This qualitative research employed the Analytic Network Process (ANP) method using the benefit, opportunity, cost, and risk analysis. The data were obtained mainly through focus group discussions and in-depth interviews with respondents among academics, practitioners, associations, regulators, and community leaders. The respondents were selected for their expertise and experience in the selected topic. The data were processed using the Microsoft Excel and Super Decision software. There are several findings worth considering from the analysis. First, the highest priority in integrating Islamic social finance aspects are human resources (0.97), regulation (0.86), and technology (0.76). Second, based on the short- and long-term analysis, financial integration through sustainable financing (0.01 and 1.44, respectively) and improving human resource quality through certification and training (0.01 and 1.56, respectively) is a priority solution and strategy to integrate sustainable Islamic social finance. Meanwhile, according to expert judgments, integrating national data (0.24) and optimizing technology use (0.18) are priority solutions and strategies. The findings emphasize the critical role of improving human resource quality to utilize technology, with experts identifying a national data integration as the most critical solution. As a result, relevant stakeholders are concerned about technology management training for Islamic philanthropic managers, with the goal of maximizing the potential of technology's growing role and adoption.

Lagerstroemia ovalifolia Exerts Anti- Inflammatory Effects in Mice of LPSInduced ALI via Downregulating of MAPK and NF-κB Activation.

Lagerstroemia ovalifolia Teijsm. & Binn. (LO) (crape myrtle) has reportedly been used as traditional herbal medicine (THM) in Java, Indonesia. Our previous study revealed that the LO leaf extract (LOLE) exerted anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Based on this finding, the current study aimed to evaluate the protective effects of LOLE in a mouse model of LPS-induced acute lung injury (ALI). The results showed that treatment with LPS enhanced the inflammatory cell influx into the lungs and increased the number of macrophages and the secretion of the inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) of mice. However, these effects were notably abrogated with LOLE pretreatment. Furthermore, the increase of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1) expression in the lung tissues of mice with ALI was also reversed by LOLE. In addition, LOLE significantly suppressed the LPS-induced activation of the MAPK/NF-κB signaling pathway and led to heme oxygenase-1 (HO-1) induction in the lungs. Additionally, in vitro experiments showed that LOLE enhanced the expression of HO-1 in RAW264.7 macrophages. The aforementioned findings collectively indicate that LOLE exerts an ameliorative effect on inflammatory response in the airway of ALI mice.

Antioxidant and Anti-Inflammatory Effects of Bischofia javanica (Blume) Leaf Methanol Extracts through the Regulation of Nrf2 and TAK1.

Bischofia javanica (Blume) has been traditionally used to treat inflammatory diseases such as tonsillitis and ulcers throughout Asia, including China, Indonesia, and the Philippines: however, the molecular mechanisms by which B. javanica exerts its antioxidant and anti-inflammatory properties remain largely unknown. In this study, we analyzed the antioxidant and anti-inflammatory mechanisms of methanol extracts of B. javanica leaves (MBJ) in vitro and in vivo. MBJ decreased nitric oxide (NO) production and the expression of pro-inflammatory cytokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α, in lipopolysaccharide (LPS)-treated RAW 264.7 cells. The observed suppression of inflammatory responses by MBJ was correlated with an inhibition of the nuclear factor-κB (NF-κB) and the mitogen-activated protein kinase (MAPK) pathways. Additionally, MBJ induced nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that upregulates the expression of anti-inflammatory and antioxidant genes. Furthermore, MBJ exhibited antioxidant and anti-inflammatory effects in an acute hepatitis mouse model. In conclusion, our results confirm the medicinal properties of B. javanica, and therefore MBJ could be applied to improve inflammatory and redox imbalances in different types of pathologies.

The Cytotoxic, Apoptotic Induction, and Cell Cycle Arrest Activities of Solanum nigrum L. Ethanolic Extract on MCF-7 Human Breast Cancer Cell.

OBJECTIVE: The purpose of this research was to evaluate the cytotoxic, cell cycle arrest, and apoptotic induction activities of the fruit of S. nigrum L. ethanolic-70% extract against MCF-7 human breast cancer cell. METHODS: S. nigrum L. ripe fruit was blended and macerated with ethanol 70% and the filtrate was evaporated. The semisolid extract was then analyzed phytochemically. Cytotoxic analysis was performed using MCF-7 cancer and Vero normal cell by MTT method and followed by apoptotic and cell cycle arrest analysis using flow cytometry. RESULTS: The phytochemical analysis resulted that extract contained total phenolic and flavonoid compounds with the level of 1.545±0.080% and 0.212±0.002%, respectively. Glycitin was the highest level of isoflavone compound, namely, 375.0844 mg/100 g extract. The cytotoxic evaluation revealed that the extract exhibited a selectively toxic effect between cancer and normal cell. The extract inhibited MCF-7 proliferation with IC50 value about 40.77±4.86 µg/mL and conversely toward Vero cell at lower cytotoxic activity with an IC50 value of 298.96±27.28 µg/mL. Evaluation of MCF-7 cell cycles demonstrated that the extract arrested the cell cycle in the S phase and continued to the G2/M phase at the half of the IC50 value. The extract induced apoptotic of MCF-7 cell about 43.31% in which this activity was nearly the same with doxorubicin as a positive control (59.14%). However, solamargine was predicted as the most active anticancer compounds by a molecular docking study so that it was suggested to measure the level of this compound. CONCLUSION: It can be concluded that the fruit of S. nigrum L. ethanolic-70% extract demonstrated cytotoxic activity toward MCF-7 breast cancer cell and nontoxic on Vero normal cell. Solamargine was predicted as the most active anticancer compound. This extract had an opportunity to be developed as a potential anticancer agent to overcome breast cancer diseases.

Role of Hypoxia Inducible Factor-1 Alpha (HIF-1α) in Cytoglobin Expression and Fibroblast Proliferation of Keloids.

BACKGROUND: Keloids are characterized by an overabundance of collagen deposition due to elevated activity and proliferation of fibroblasts, which lead to hypoxic conditions. Adaptation to these conditions is regulated by the transcription factor hypoxia inducible factor-1α (HIF-1α). Cytoglobin (Cygb), a reactive oxygen species scavenger, is a target gene of HIF-1α. In our previous study, we showed that Cygb expression in keloid tissue was correlated with HIF-1α expression. However, whether HIF-1α regulates Cygb expression and the proliferation of keloid fibroblasts remained unclear. Therefore, this study aimed to determine the role of HIF-1α in Cygb expression and fibroblast proliferation of keloids. METHODS: This was an in vitro study using a primary culture of keloid fibroblasts in which ibuprofen was used to inhibit HIF-1α expression. The expression of HIF-1α and Cygb mRNA were analyzed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) methods, and their protein levels were analyzed using an enzyme-linked immunosorbent assay (ELISA). Fibroblast proliferation was analyzed using a Trypan blue exclusion assay. RESULTS: Inhibition of HIF-1α by ibuprofen decreased Cygb mRNA expression but not in all the samples, followed by a decrease in the protein level of Cygb. There was a positive correlation between the HIF-1α protein and Cygb mRNA, probably due to the regulation of Cygb by HIF-1α at the mRNA level, but not the protein level. The proliferation of keloid fibroblasts was significantly decreased and positively correlated with the HIF-1α protein. CONCLUSION: HIF-1α regulates Cygb expression and fibroblast proliferation in keloids.

Metabolic Interplay between Tumour Cells and Cancer-Associated Fibroblasts (CAFs) under Hypoxia versus Normoxia.

The growth of tumour cells is closely related to cancer-associated fibroblasts (CAFs) present within their microenvironment. CAFs, the most abundant cells in tumour stroma, secrete growth factors that play pivotal roles in tumour cell proliferation, metabolism, angiogenesis and metastasis. Tumour cells adapt to rapid environmental changes from normoxia to hypoxia through metabolic interplay with CAFs. In this mini review, we discuss the role of lactate dehydrogenases (LDHs) and monocarboxylate transporters (MCTs) on the metabolic interplay between tumour cells and CAFs under hypoxia compared to normoxia. The LDHs catalyse the interchange of lactate and pyruvate, whereas MCTs facilitate the influx and efflux of monocarboxylates, especially lactate and pyruvate. To sum up, tumour cells switch their metabolic state between glycolysis and oxidative phosphorylation through metabolic interplay with CAFs, which exhibit the Warburg effect under hypoxia and reverse Warburg effect under normoxia.