The Indonesian Biomedical Journal (Prodia Education and Research Institute)
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B Cell-Activating Factor (BAFF) and Ubiquitin Enzyme A20 as Functional Proteins in Targeted Therapy on Patients with Systemic Lupus Erythematosus
Get PDFBACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation. The pathogenesis of SLE involves key proteins, including B cell-activating factor (BAFF) and the ubiquitin enzyme A20, both serving as negative regulators of inflammation and contributing to B cell homeostasis. In this review, focused on interventions directed at BAFF and the A20 enzyme, utilizing monoclonal antibodies either independently or in conjunction with conventional therapy for SLE patients.METHODS: A literature search was conducted on the PubMed platform by combining various terms, including "B-cells activating factor", "TNFAIP3 protein (human)", "therapeutics" or "drug therapy", and "lupus erythematosus, systemic" (limited to the last 10 years). From total of 104 articles discovered in thr search, the total number of articles collected after being filtered was 27 articles.RESULTS: Clinical development and evaluation have been conducted regarding the use of appropriate therapy for SLE patients. Selective BAFF inhibitor has been tested in clinical trials as a blocking agent in BAFF receptor (BAFF-R) and signaling nuclear factor-kappaB (NF-κB) by A20 bindings to inhibit the activation of autoreactive B cells. Just like other antimonoclonal therapies, BAFF and the A20 enzyme can be used as therapeutic targets with a single use or combined with the standard therapy in patients with SLE. In addition, the use of BAFF and A20 also shown to have safe side effects in patients with SLE. CONCLUSION: BAFF protein and A20 enzyme present promising therapeutic targets for managing autoimmune diseases like SLE. Therapeutic interventions can be administered individually or in conjunction with standard treatments. KEYWORDS: systemic lupus erythematosus, therapeutic targets, BAFF, A2
The Increase in CD14+CD16+ Monocytes is Correlated with Cardiovascular Disease Risk Marker in Type 2 Diabetes
Get PDFBACKGROUND: Type 2 Diabetes (T2D) impairs the innate immune system including monocytes. Monocytes are divided into two subgroups depending on the expression of cluster of differentiation (CD)14 and CD16 receptors, namely CD14+CD16- and CD14+CD16+. CD14+CD16+ are proinflammatory monocytes and develop into M1 type macrophages, which contribute to foam cell production, a risk factor for cardiovascular disease (CVD). Therefore, it is important to determine the influence of T2D conditions on changes in monocyte subsets and whether these changes correlate with CVD risk markers.METHODS: Peripheral blood mononuclear cell (PBMC) was obtained from 10 T2D subjects and 10 healthy donors. Subsequently, PBMC was incubated for 24 hours with and without 10 mL lipopolysaccharide. Flow cytometry was used to evaluate CD14 and CD16 expression, while multiplex immunoassays were applied to measure interleukin (IL)-1b and IL-10 concentrations in supernatants.RESULTS: In T2D, the percentage of CD14+CD16+ monocytes increased (p=0.07), and an increase in CD14+CD16+ monocytes more than 6.8% was linked with CVD risk markers (r=10.146, p=0.002). Meanwhile, inflammatory mediators released by monocytes shown an increase in IL-1b (p=0.041) but not in IL-10 (p=0.082) in T2D subjects. Fasting blood glucose levels were also found to be substantially linked with an increase in CD14+CD16+ monocytes (r=0.530, p=0.016).CONCLUSION: T2D patients had a higher percentage of CD14+CD16+ monocytes and IL-1b levels than healthy donors. An increase in CD14+CD16+ monocytes above 6.8% associated with CVD risk markers in T2D patients.KEYWORDS: type 2 diabetes, monocytes, CD14, CD16, cardiovaskular disease risk marke
The Regulation of SPRY4 Intronic Transcript 1 (SPRY4-IT1) on KIT Signaling and Imatinib Resistance of Gastrointestinal Stromal Tumor (GIST) Cells
Get PDFBACKGROUND: SPRY4 intronic transcript 1 (SPRY4-IT1), is a long non-coding RNA coded by the intron of SPRY4. SPRY4 is highly expressed in gastrointestinal stromal tumor (GIST) and inhibits the tumorigenesis of GIST, but whether SPRY4-IT1 regulates the tumorigenesis of GIST or not remains unclear. Therefore, in this study, the regulation of SPRY4-IT1 expression and its role in GIST will be investigated.METHODS: GIST-T1 cells, and Ba/F3 cells which express KIT proto-oncogene (KIT) and SPRY4-IT1 were used as cell models. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to examine mRNA expression, while the protein expression and signal transduction were examined by western blot. The association between SPRY4-IT1 and KIT was examined by pull down of KIT and PCR. Cell proliferation, survival, and cell cycle progression were examined by cell counting kit-8 (CCK8) and flow cytometry.RESULTS: KIT mutants increased the expression of SPRY4-IT1 in GIST. SPRY4-IT1 bound to KIT, also enhanced the activation and expression of both wild-type KIT and primary KIT mutants, therefore increasing the activation of downstream signaling proteins AKT and ERK of KIT, GIST cell survival, and proliferation. In addition, SPRY4-IT1 reduced the sensitivity of wild-type KIT, or primary KIT mutants to the first-line targeted therapeutic drug of GIST, imatinib, which can inhibit KIT activation. Gaining drug-resistant secondary KIT mutants might be one of the main reasons of GIST recurrence after targeted therapy. Similar to wild-type KIT and primary KIT mutants, the activation and expression of secondary KIT mutants and their resistance to imatinib were also increased by SPRY4-IT1.CONCLUSION: The results indicated positive feedback between SPRY4-IT1 and wild-type KIT, primary KIT mutants or secondary KIT mutants, and the upregulation of AKT and ERK activation by SPRY4-IT1 in GIST cells, providing a new insight in the KIT signaling regulation in GIST, and the resistance of GIST to targeted therapy.KEYWORDS: SPRY4-IT1, KIT, GIST, SPRY4, signalin
Mesenchymal Stem Cell–derived Extracellular Vesicles: An Emerging Therapeutic Strategy for Diabetic Wound Healing
Get PDFOne of the most serious side effects of diabetes is diabetic foot ulceration (DFU). It is a severe and extremely morbid illness that has been linked to higher mortality on its own. The development of effective wound therapeutics in the future may be influenced by our current and developing understanding of wound pathophysiology. By reestablishing cellular functioning, small extracellular vesicles (sEVs), a crucial medium for intercellular communications, exhibit encouraging therapeutic potential in the treatment of DFU. Mesenchymal stem cell (MSC) derived exosomes and engineered extracellular vesicles (EVs) have the potential to aid in the healing of wounds. Along with encouraging the growth and stimulation of endothelial cells, keratinocytes, and fibroblasts, they also have immunomodulatory and anti-inflammatory properties. They help prevent damaged cells from dying, revitalize senescent cells, and boost angiogenesis. MSC-EVs can be a safe, effective and ethical therapy for DFU by increasing M2 macrophages polarization, improving the proliferation, reducing scar, and improving angiogenesis.KEYWORDS: mesenchymal stem cell, extracellular vesicle, diabetic wound, wound healin
Diabetes Risk Allele of Transcription Factor 7-like 2 (TCF7L2) Polymorphisms is Associated with Higher Glucagon-like Peptide 1 (GLP1) and Lower Insulin Secretion
Get PDFBACKGROUND: The most influential susceptible gene associated with diabetes, transcription factor 7-like 2 (TCF7L2), has been observed in diverse populations. TCF7L2 influences type 2 diabetes risk through glucagon-like peptide 1 (GLP1) production. The presence of risk allele of TCF7L2 leads to the alteration of gene expression in pancreatic beta cells; however, how the mechanism is related with GLP1 remains unclear. This study was conducted to explore the variations of GLP1 increment and insulin secretion between individuals with and without diabetes risk allele of single nucleotide polymorphisms (SNPs) in TCF7L2.METHODS: A cross-sectional analytic study was conducted involving individuals subjects who harbored known variants of SNPs in the TCF7L2: heterozygote or mutant of rs12255372 (GT or TT), rs7903146 (CT or TT), rs10885406 (AG or GG); as well as control subjects with wild type of rs12255372 (GG), rs7903146 (CC), and rs10885406 (AA). Anthropometric parameters, blood glucose, insulin, and GLP1 were measured; and homeostasis model assessment-beta cell (HOMA-%B) index was calculated.RESULTS: The GLP1 increment response was higher in subjects carrying the diabetes risk allele (0.34±0.80 ng/mL) than those with the wild type (-0.04±0.57 ng/mL) (p=0.041). The HOMA-%B was reduced in subjects carrying the diabetes risk allele (71.64±24.72) than those with the wild type (103.23±68.00) (p=0.011). Among individuals carrying the diabetes risk allele, the likelihood of GLP1 increment with high response was twice as high (p=0.007), while the occurrence of low HOMA-%B was 1.47 more frequent (p=0.011).CONCLUSION: TCF7L2 polymorphisms were associated with the GLP1 increment response and reduced HOMA-%B, which might be potentially contributing to GLP1 resistance in patients with diabetes risk factors.KEYWORDS: diabetes risk, TCF7L2, GLP1, HOMA-%
Serum DNase1, sTNFR1 and sTNFR2 as Risk Factors for Lupus Nephritis in Systemic Lupus Erythematosus Patients
Get PDFBACKGROUND: Early detection and management of lupus nephritis (LN) in systemic lupus erythematosus (SLE) are essential to prevent irreversible kidney damage and improve patient outcomes; therefore, identifying reliable biomarkers to predict LN is paramount. However, there are still relatively few studies examining the potential biomarkers for LN in SLE patients. This study was conducted to investigate serum deoxyribonuclease I (DNase), soluble tumor necrosing factor 1 (sTNFR1) and soluble tumor necrosing factor 2 (sTNFR2) as a risk factor for LN in SLE patients.METHODS: A case-control study involving SLE patients aged 20-60 years was conducted. Blood was withdrawn from each subject for the measurement of serum level of DNase1, sTNFR1, and sTNFR2 that was performed using enzyme-linked immunoassay (ELISA) methods. Data was then analyzed using Chi-Square test and logistic regression tests.RESULTS: A total of 22 patients with LN and 22 without LN were included. The cut-off value for DNase1, sTNFR1, and sTNFR2 were 5.05 ng/mL, 6.52 ng/mL, and 7.02 ng/mL, respectively. The risk factors of LN in SLE patients were the low level of serum DNase1 (aOR=6.64; 95%CI: 1.25-35.29; p=0.026), low level of serum sTNFR1 (aOR=8.12; 95% CI: 1.56-42.10; p=0.013), and low level of serum sTNFR2 (aOR=5.57; 95%CI: 1.03-30.11; p=0.046).CONCLUSION: Serum DNase1 lower than 5.05 ng/mL, sTNFR1 lower than 6.52 ng/mL, and sTNFR2 lower than 7.02 ng/mL were risk factors for lupus nephritis in SLE patients. Hence, serum DNase1, sTNFR1 and sTNFR2 could be used as risk factors predictors for LN in SLE patients.KEYWORDS: DNase1, sTNFR1, sTNFR2, SLE, lupus nephriti
Differential Effects of Anthracycline-based Neoadjuvant Chemotherapy on Stromal and Intratumoral FOXP3+ Tumor-Infiltrating Lymphocytes in Invasive Breast Cancer of No Special Type
Get PDFBACKGROUND: Neoadjuvant chemotherapy (NAC) plays a crucial role in the management of invasive breast cancer with no special type (IBC-NST), with the immune system's response to cancer heavily relying on the dynamics between tumor-infiltrating lymphocytes (TILs) and cancer cells. In this study, the differential effects of anthracycline-based NAC on stromal and intratumoral foxhead box P3 (FOXP3+) TILs expressions were specifically examined.METHODS: In this cross-sectional study, 32 IBC-NST samples were evaluated for pre- and post-NAC FOXP3+ TIL expression as well as the changes of FOXP3+ TIL expression. Comprehensive data collection regarding subjects' age, tumor size, grade, lymphovascular invasion, regional lymph node metastasis, and receptor status were conducted. Immunohistochemistry was utilized to quantify FOXP3+ TILs. The stromal, intratumoral and total FOXP3+ TILs expression were then analyzed.RESULTS: Significant reductions in FOXP3+ TIL expression post-NAC were observed, with stromal FOXP3+ TILs showing a median decrease of 3.6 units in subjetcs aged ≥50 years (p=0.013) and a median decrease of 13.2 units in subjects with tumors ≥5 cm after NAC (p=0.006). In contrast, intratumoral FOXP3+ TILs remained relatively stable, with minor changes. The total FOXP3+ TIL expression, combining stromal and intratumoral components, was significantly decreased with a median of 13.0 units decreased to 5.3 units (p<0.001).CONCLUSION: This study highlights the significant reduction in stromal FOXP3+ TIL expression after NAC treatment in IBC-NST subjects, in contrast to the relatively stable intratumoral FOXP3+ TILs. Understanding these differences may guide future therapeutic strategies and improve treatment outcomes for IBC-NST.KEYWORDS: biomarkers, chemotherapy, FOXP3, prognostic, response, lymphocyte
Effects of SGLT2-inhibitor on The Expression of MicroRNA-21, Transforming Growth Factor-β1, and Matrix Metalloproteinase-2 in The Process of Cardiac Fibrosis in Hyperglycemic Model Rats
Get PDFBACKGROUND: Sodium glucose co-transporter-2 inhibitor (SGLT2-i), a new oral antidiabetic drug, has been recommended for its morbidity and mortality benefits in patients with heart failure. This study aimed to determine the effect of acute SGLT2-i therapy on the relative ratio expression of microRNA-21 (miR-21), transforming growth factor-β1 (TGF-β1), and matrix metalloproteinase-2 (MMP-2) in the process of cardiac fibrosis in the hyperglycemia Wistar rat models compared to biguanide (metformin) therapy.METHODS: We used Streptozotocin (STZ) to induce hyperglycemia in Wistar rats (n=31), randomly divided into four groups: negative control (NC, n=4), positive control (PC, n=10), hyperglycemia plus metformin (M, n=8), and hyperglycemia plus empagliflozin (E, n=9). After seven weeks, the rats were sacrificed and the heart tissue was taken for microRNA and messenger RNA (mRNA) extraction, followed by reverse transcription quantitative real time polymerase chain reaction (RT-qPCR) examination. The data was analyzed using One-way ANOVA.RESULTS: Results showed a decreasing trend in the gene expression relative ratio of miR-21 (1.0 vs. 1.9; p=0.079) and TGF-β1 (0.9 vs. 3.2; p=0.145), but a significant increase in MMP-2 gene expression (1.3 vs. 0.7; p=0.002) in the SGLT2-i (empagliflozin) vs. biguanide (metformin) groups.CONCLUSION: Empagliflozin administration may play a significant role in preventing the occurrence of cardiac fibrosis in hyperglycemia.KEYWORDS: sodium glucose co-transporter-2 inhibitor, microRNA-21, transforming growth factor-β1, matrix metalloproteinase-2, cardiac fibrosi
Lower Plasma β-Amyloid 1-42 Levels in Amnestic Mild Cognitive Impairment Compared to Healthy Individuals
Get PDFBACKGROUND: Amnestic mild cognitive impairment (aMCI) is strongly associated with an increased risk of progression to Alzheimer’s disease (AD). In AD, cerebrospinal fluid (CSF) β-Amyloid 1-42 levels are known to decrease, a pattern which is also observed in aMCI. While in AD, apolipoprotein E (ApoE) ε4 allele is known to be a genetic risk factor, the role of ApoE ε4 allele in modulating plasma β-Amyloid 1-42 levels in aMCI remains unclear. Therefore, this study was performed to evaluate plasma β-Amyloid 1-42 levels in aMCI patients compared to cognitively healthy individuals and investigate its association with ApoE ε4 allele.METHODS: A cross-sectional study involving 57 aMCI and 54 cognitively healthy control (HC) subjects was performed. Blood samples were taken from subjects from both groups for measurement of the plasma β-Amyloid 1-42 and ApoE ε4 allele. The plasma levels of β-Amyloid 1-42 were measured using an enzyme-linked immunosorbent assay (ELISA) methods, while the ApoE ε4 allele genotyping was conducted using polymerase chain reaction (PCR) techniques.RESULTS: Plasma β-Amyloid 1-42 in individuals with aMCI (23.9 pg/mL) was significantly lower than that in HC (25.3 pg/mL) with cut-off value of 24.6 pg/mL (AUC: 70.8%; 95% CI: 61.1–80.5%; p<0.001) sensitivity of 64.8%, and specificity of 71.9%. There was no significant association between plasma β-Amyloid 1-42 and the ApoE ε4 allele. However, plasma β-Amyloid 1-42 in ε4 carriers were lower than in ε4 non-carriers.CONCLUSION: Lower plasma β-Amyloid 1-42 levels were observed in aMCI patients compared to cognitively healthy individuals, suggesting its potential as a biomarker for identifying aMCI.KEYWORDS: blood biomarkers, amyloid beta peptides, amnestic mild cognitive impairment (aMCI
Stenochlaena palustris Ethanol Extract Decreases Viability and Induces G1-Phase Cell Cycle Arrest in HSC-3 Tongue Cancer Cells via p21 and p27
Get PDFBACKGROUND: Oral squamous cell carcinoma (OSCC) of the tongue is an aggressive cancer with a poor prognosis due to its resistance to standard treatments. Stenochlaena palustris, a medicinal fern containing bioactive compounds, has shown potential anticancer properties. However, there is a lack of studies addressing the effects of S. palustris ethanol extract (SPEE) on tongue cancer. This study examined the effects of SPEE on the cell viability and cell cycle of human squamous cell carcinoma (HSC)-3 tongue cancer cells.METHODS: SPEE was prepared with the maceration method. HSC-3 cells were treated with SPEE at concentrations of 100, 500, and 1000 µg/mL for 24 and 48 hours. Cell viability was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle analysis was performed using flow cytometer. Immunoblotting was used to measure amount of cell cycle regulators, protein 21 (p21) and protein 27 (p27).RESULTS: SPEE treatment led to a significant decrease in HSC-3 viable cells in a concentration- and time-dependent manner, with the most pronounced effect at higher concentration and prolonged treatment time. There was a slightly increase in the percentage of cells in the Sub-G1 phase in SPEE-treated group, meanwhile there was a significant increase in the percentage of cells in the G1-phase. Increased amount of p21 and p27 were observed in SPEE-treated group.CONCLUSION: SPEE significantly inhibited HSC-3 cell proliferation in a concentration- and time-dependent manner, primarily by inducing G1-phase cell cycle arrest through the upregulation of p21 and p27. Taken together, SPEE could be a potential anti-cancer agent for tongue cancer cell. KEYWORDS: Stenochlaena palustris, tongue cancer, cytotoxic, cell cycle arrest, HSC-3 cells, p21, p2