The Indonesian Biomedical Journal (Prodia Education and Research Institute)
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Curcumin Analogs PGV-1 and CCA-1.1 Induce Cell Cycle Arrest in Human Hepatocellular Carcinoma Cells with Overexpressed MYCN
Get PDFBACKGROUND: Liver cancer is the third leading mortality in cancer. Curcumin shows effective anticancer potency against various cancer including liver cancer. The synthesized curcumin analog compounds Pentagamavunone-1 (PGV-1) and Chemoprevention Curcumin Analog-1.1 (CCA-1.1) have been well studied in breast, leukemia, and colon cancer cells with better potency than curcumin itself, yet their cytotoxic activities were not known in liver cancer cells. Thus, this study was conducted to elevate the anticancer effect of these curcumin analogs against hepatocellular carcinoma (HCC) cells in vitro, specifically in MYCN-expressing cells, based on its cellular physiology.METHODS: JHH-7 cells were used as the HCC cell model with high expression of MYCN. The viability of the cells was observed using trypan blue exclusion method while cell cycle profile and intracellular reactive oxygen species (ROS) levels were quantified by means of flow cytometry. Chromosomal staining with Hoechst was applied to determine the cell cycle arrest phase, whilst X-gal staining was used to assess the cellular senescence activity.RESULTS: The result of current study presented that the growth inhibitory activity of PGV-1 as well as CCA-1.1 in JHH-7 cells was associated with the cell cycle arrest and cellular senescence. Both curcumin analogs PGV-1 and CCA-1.1 ultimately induced mitotic arrest (p<0.001) better than curcumin. Moreover, PGV-1 and CCA-1.1 similarly increased the senescent cells that partly mediated through ROS elevation. The transcription level of MYCN was not altered upon treatment with curcumin and its analogs in JHH-7 cells, suggesting that molecular mechanism of the inhibitory effect was independent from MYCN signaling.CONCLUSION: Taken together, these observations revealed that both PGV-1 and CCA-1.1 potentially serve as multi-targeted curcumin-based compounds and lead to promising anti-hepatocellular cancer agents.KEYWORDS: Curcumin analogs, hepatocellular carcinoma, mitotic arrest, MYC
Bax mRNA Expression as A Potential Biomarker of Placental Apoptosis in Early-onset Preeclampsia
Get PDFBACKGROUND: Early-onset preeclampsia is characterized by higher oxidative stress and apoptosis level than late-onset one. Studies comparing the expression of the Bcl-2 family protein in early and late-onset preeclampsia are still lacking and show inconclusive evidence. This study aimed to compare the expression of Bax and Bcl-2 messenger RNA (mRNA) as a biomarker of placental apoptosis between early-onset and late-onset preeclampsia.METHODS: A cross-sectional study was conducted using formalin-fixed, paraffin-embedded preeclamptic placental samples and dividing them into early-onset and late-onset preeclampsia groups. Bax and Bcl-2 mRNA expressions were assessed using the quantitative real-time polymerase chain reaction method. Apoptosis was assessed through DNA fragmentation examination by the ligation-mediated real-time polymerase chain reaction method.RESULTS: Thirty early-onset and 30 late-onset preeclamptic placental samples were included. The mean fold change Bax mRNA in early-onset was higher than in late-onset preeclampsia (6.02±3.59 vs. 2.82±1.97; p=0.00). The mean fold change Bcl-2 mRNA early-onset was not different from late-onset preeclampsia (31.20±17.94 vs. 31.01±27.60; p=0.98). The mean DNA fragmentation cycle threshold in early-onset preeclampsia was lower than in late-onset preeclampsia (28.07±0.64 vs. 30.63±0.96; p=0.00). A weak negative correlation exists between fold change Bax mRNA and DNA fragmentation cycle threshold (r=-0.30; p=0.02).CONCLUSION: Bax mRNA showed significant correlation in DNA fragmentation compared to Bcl-2 mRNA; hence, might show more role in apoptotic pathway. Early-onset preeclampsia has higher Bax mRNA relative expression and apoptosis than late-onset preeclampsia. Therefore, Bax mRNA can be potential biomarker in early-onset preeclampsia.KEYWORDS: mRNA, Bax, Bcl-2, apoptosis, DNA fragmentation, early-onset, preeclampsi
MMP-9 and TIMP-1 Promote Extracellular Matrix Remodeling in the Formation of Ovarian Endometrioma: in vitro Study on Chicken Chorioallantoic Membrane
Get PDFBACKGROUND: The invasion of endometrial tissue in the peritoneal layers is an important precursor to the formation of endometriosis. However, the mechanisms of the initial development of endometrioma remain unclear. This study aimed to explore the correlation between matrix metalloproteinase (MMP)-9 activity and tissue inhibitors of metalloproteinase (TIMP)-1 expression in the initial development of endometriosis through the invasion process of endometrial lesions in extracellular matrix (ECM) remodeling.METHODS: A total of 30 samples of endometrioma tissue were obtained from 24 women with endometriosis and examined at Dr. Sardjito General Hospital, Yogyakarta, Indonesia. The tissue was then implanted into a chicken chorioallantoic membrane (CAM) for five days to examine its invasion ability. The invasion scores were assessed using hematoxylin-eosin staining. MMP-9 activity and TIMP-1 expression were analyzed using gelatin zymography and western blot, respectively. The correlations between MMP-9 activity and TIMP-1 expressions with the invasion scores were analyzed using Spearman correlation tests with significance set as p<0.05.RESULTS: The results showed that there was a strong positive correlation between MMP-9 activity and invasion scores of endometriomas tissue (r=0.656; p=0.000). Meanwhile, expression levels of TIMP-1 had a weak negative correlation with the increase of invasion scores of endometrioma (r=-0.388; p=0.034). These results indicate the involvement of MMP-9 and TIMP-1 in the initial development of endometriosis during the ECM remodeling.CONCLUSION: MMP-9 activity and TIMP-1 expression were correlated with the invasion score of endometrioma tissue. This study provides evidence for understanding the mechanisms involved in ECM remodeling in the early process of endometriosis.KEYWORDS: endometrioma, extracellular matrix remodeling, MMP-9, TIMP-1
Mesenchymal Stem Cell Therapy for Ischemic Stroke in Animal Model: A Systematic Review
Get PDFBACKGROUND: Stroke is one of many leading causes of death and disability worldwide. Despite decades of research, treatment for stroke recovery is still inadequate. Recently, mesenchymal stem cell (MSC) therapy is considered as one of the potential treatments for stroke due to their capabilities to repair or regenerate damaged tissues, as well as immunomodulators in inflammatory conditions. Many pre-clinical and clinical trials have shown MSC therapy feasibility, safety, and efficacy in treating stroke. However, evidence regarding the optimal treatment plan and factors that can improve stem cell functional outcomes in treating stroke needs to be further explored. Therefore, a systematic review was conducted.METHODS: Recent literatures from 2015-2022 regarding stem cell therapies, specifically MSC on ischemic stroke, were collected from two reliable databases: PubMed and PubMed Central. Collected literatures were properly applied to inclusion-exclusion criteria and appraised critically. Keyword strategies on databases were employed, including both medical subject headings (MeSH).RESULTS: Five literatures from 726 were identified and used for systematic review. All animal model in the literatures were prepared to have middle cerebral artery occlusion. All studies indicated that MSC therapy is a safe and reliable procedure despite the variety of transplantation routes. No report of toxicity, rejection reaction, nor infection on MSC treated groups.CONCLUSION: Stem cell sources, dosages, and delivery routes could be resourceful for future translational studies to ensure the safety and efficacy of MSC therapy for ischemic stroke.KEYWORDS: ischemic stroke, mesenchymal stem cells, regenerative medicine, immunomodulato
AvrA Salmonella Increases TLR4/NF-κB/β-catenin/TGF-β Expressions of Colorectal Cancer Mice Model
Get PDFBACKGROUND: Colorectal cancer (CRC) is reported as the third most frequently diagnosed cancer worldwide. Salmonella infection plays a role in developing this cancer, which is chronically related to the avirulence protein A (AvrA) effector protein produced by the bacteria. This study was conducted to point out the effect of AvrA Salmonella on the occurrence of CRC through the regulation of TLR4/NF-κB/β-catenin/TGF-β expressions in the azoxymethane (AOM)/dextran sodium sulfate (DSS) CRC model.METHODS: A randomized control group post-test-only study was conducted using male Balb/c mice with 30-gram body weight (10-12 weeks), which were divided into three groups, namely the negative control (normal mice without any treatment), positive control (AOM/DSS-treated mice), treatment 1 (T1) (AOM/DSS-treated mice + AvrA Salmonella) groups. Colon tissue was collected and then prepared for immunohistochemistry staining using TLR4, β-catenin, NF-κB, TGF-β, and Ki67 antibodies, whereas apoptotic cells were stained using TUNEL assay.RESULTS: The expressions of TLR4, β-catenin, NF-κB, TGF-β, Ki67, and apoptosis percentage indicated significant differences among the three groups, which statistically showed p<0.05 in all observed parameters. The mean of all parameters was far more significant in the T1 group than in the negative and positive control groups.CONCLUSION: The findings revealed that AvrA Salmonella could increase the expressions of TLR4, β-catenin, NF-κB, TGF-β, and Ki67 and decrease the apoptotic percentage. Thus, AvrA Salmonella influences CRC tumorigenesis through TLR4/NF-κB/β-catenin/TGF-β and is suggested as a potential target in future preventive and curative management for CRC.KEYWORDS: AvrA Salmonella, carcinogenesis, colorectal cancer
Presence of blaCTXM-1, blaCTXM-9, and blaTEM-1 Genes in Extended-spectrum β-lactamase-producing Escherichia coli Isolates from Hospital Wastewater
Get PDFBACKGROUND: Extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) are selectively proliferated in the human gut, excreted through feces, and deposited through wastewater lines, with hospital wastewater acting as a major reservoir of antibiotic resistance genes and resistant bacteria, thus pose adverse effects to human health. This study aimed to determine the presence of blaCTXM-1, blaCTXM-9, blaTEM-1, and blaSHV-1 genes in ESBL-EC in wastewater from selected hospitals in Manila and Quezon City, the Philippines.METHODS: Influent and effluent in twelve hospital wastewater treatment plants were collected, screened for cefotaxime-resistant E. coli, and examined for the ESBL production through phenotypic characterization using conventional bacterial identification, disk diffusion method, and VITEK® 2 Compact system and genotypic identification of ESBL-EC blaCTXM-1, blaCTXM-9, blaTEM-1, blaSHV-1 genes using multiplex polymerase chain reaction (PCR).RESULTS: Conventional bacterial identification methods and the VITEK® 2 Compact system results showed that both influent and effluent samples were positive for ESBL-EC at 33.3% and 16.7%, respectively. Multiplex PCR results revealed that various E. coli isolates were of ESBL-EC blaCTXM-1, blaCTXM-9, and blaTEM-1 genes. Multi-drug resistance was observed among all ESBL-EC isolates with resistance being highest against ampicillin, cefuroxime, ceftazidime, ceftriaxone, cefepime, piperacillin, and aztreonam.CONCLUSION: As the study revealed the presence of ESBL-producing bacteria, efforts must be made to ensure the prudent antimicrobial use with possible emphasis on antibiotic rotation accompanied by intensified infection prevention and control in hospital settings.KEYWORDS: antimicrobial resistance, beta-lactams, blaCTXM, blaTEM, extended-spectrum beta-lactamase, E. coli, hospital wastewate
Achatina fulica Mucus Ameliorates UVB-induced Human Dermal Fibroblast Photoaging via the TGF-β/Smad Pathway
Get PDFBACKGROUND: Ultraviolet B (UVB) induces skin photoaging by reducing collagen deposition via impairment of the TGF-β/Smad signaling pathway. Achatina fulica mucus (AFM) is a native medicine acting as vehicle of anti-aging ingredients. The present investigation examined the effect of AFM on UVB-induced fibroblast photoaging by assessing TGF-β, Smad3, and Smad7 mRNA expressions.METHODS: AFM was extracted from A. fulica using electrical shock and freeze-dried into a powder. Normal human dermal fibroblast (NHDF) cultures were irradiated with/without 100 mJ/cm2 UVB and treated with/without 10% platelet-rich plasma or different concentrations of AFM: 3.9 μg/mL in AF3 group; 15.625 μg/mL in AF15 group, and 62.5 μg/mL in AF62 group. The mRNA expressions of TGF-β, Smad3, and Smad7 in NHDF were evaluated by quantitative polymerase chain reaction.RESULTS: TGF-β mRNA expressions in the AF3 (0.85±0.01), AF15 (0.94±0.02) and AF62 (1.64±0.03) groups were significantly higher (p<0.05) compared with that in the UVB group (0.55±0.04). Moreover, Smad3 expressions in the AF3 (1.42±0.25), AF15 (1.89±0.13), and AF62 (2.50±0.31) groups were significantly higher (p<0.05) compared with that in the UVB group (0.57±0.08). Furthermore, Smad7 expressions in the AF3 (1.57±0.18), AF15 (0.87±0.03), and AF62 (0.25±0.09) groups were significantly lower (p<0.05) than that in the UVB group (2.57±0.06).CONCLUSION: AFM ameliorates UVB-induced fibroblast photoaging by upregulating the TGF-β/Smad3 expressions and downregulating Smad7 expression.KEYWORDS: Achatina fulica, TGF-β, Smad, collagen, UVB, fibroblast, photoagin
Losartan Has a Comparable Effect to Human Recombinant ACE2 in Reducing Interleukin-6 (IL-6) Levels on Human Adipocytes Exposed to SARS-CoV-2 Spike Protein
Get PDFBACKGROUND: High angiotensin-converting enzyme 2 (ACE2) expression in adipocyte cells facilitates the initiation of SARS-CoV-2 infection and triggers a cytokine storm. This finding suggests that obesity is an independent risk factor for the severity of the symptoms caused by COVID-19. The use of cardiovascular medications that focus on ACE2, such as angiotensin II receptor blockers, remains controversial, and their effects on inflammatory cytokine production and ACE2 expression in cells, especially adipocytes, remain inconsistent.METHODS: The human adipocytes were isolated from obese donor subcutaneous adipose tissue and infected with the subunit S1 spike protein from SARS-Cov-2. The adipocytes were later treated with either hrsACE2 or losartan. The levels of ACE2 and inflammatory cytokines interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were measured using enzyme linked immunosorbent assay (ELISA). ACE2 and S1 spike protein binding assays were also performed. RESULTS: ACE2, IL-6, and TNF-α levels were significantly increased in human adipocyte cells infected with SARS-Cov-2 but not IL-1β. There was a statistically significant positive correlation between ACE2 and IL-6 (r=0.878, p<0.001). Administration of losartan and hrsACE2 was shown to reduce ACE2 levels and its binding to the SARS-CoV-2 S1 spike protein, and IL-6 levels were statistically significant, but had no significant effect on IL-1β or TNF-α levels.CONCLUSION: This study shows that the administration of losartan in COVID-19 may not be harmful, but instead has a protective effect similar to that of hrsACE2 in preventing a cytokine storm, especially IL-6.KEYWORDS: obesity, SARS-CoV-2, losartan, IL-6, ACE
Increased hs-CRP and Sepsis Influence the Occurrence of Thrombocytopenia in Severe and Critically Ill COVID-19 Patients Receiving Anticoagulants
Get PDFBACKGROUND: Despites its benefits, as one of COVID-19 principal treatments, anticoagulant raises a significant concern regarding the anticoagulant-related thrombocytopenia. However, up to date, there is lack of study examining anticoagulantinduced thrombocytopenia during COVID-19, hence this study was conducted to determine the factors inducing anticoagulant-induced thrombocytopenia in COVID-19 patients.METHODS: An observational cross-sectional study of 106 anticoagulant-treated COVID-19 subjects was conducted. Blood serum was drawn from subjects, then platelets, prothrombin time (PT), activated partial thromboplastin (aPPT), international ratio (INR), D-dimer, ferritin, fibrinogen, and high-sensitivity C-reactive protein (hs-CRP), were measured. For thrombocytopenia risk assessment, the 4T score was calculated. To assess the risk of thrombocytopenia. Statistical analysis using Chi-square and Mann-Whitney U test were performed and followed by multivariate analysis to examine the correlation among the thrombocytopenia risk factors.RESULTS: Significant differences were identified in the length of stay (LOS) (p=0.04), disease severity (p=0.021), sepsis (p=0.006), hs-CRP (p=0.003), and mortality rate (p=0.028) between thrombocytopenia and nonthrombocytopenia groups. A multivariate analysis through linear and logistic regression disclosed an increase in hs-CRP (OR=-0.29; p=0.045) and sepsis (OR=4.32; p=0.03) that precipitate the thrombocytopenia events.CONCLUSION: In severe and critically ill COVID-19 patients, the occurrence of thrombocytopenia was followed by an increase in inflammatory parameters such as D-dimer, fibrinogen, ferritin, hs-CRP and prolonged coagulation. The increase in hs-CRP and sepsis may raise the risk of thrombocytopenia, especially in severe and crtically ill cases of COVID-19.KEYWORDS: COVID-19, anticoagulant, thrombocytopenia, inflammation, infectious diseas
Preoperative Level of Insulin-Like Growth Factor Binding Protein 2 Predicts The Suboptimal Outcome After Primary Debulking Surgery in Patients with Advance Ovarian Cancer
Get PDFBACKGROUND: The need for clinically useful biomarkers which can predict the surgical outcome after primary debulking surgery (PDS) in patients with advance ovarian cancer (AOC) is really important. Insulin-like growth factor-binding protein 2 (IGFBP2) is the main binding protein expressed by ovarian cancer cells, which plays a prominent role in promoting proliferation, driving invasion, and suppressing apoptosis. This study was conducted to assess the performance of IGFBP2 in predicting the surgical outcome after PDS in patients with AOC.METHODS: Twenty-four subjects with AOC (Stage IIIc/IV) who underwent PDS were recruited consecutively. Clinicopathologic data were obtained from subjects' medical records. Blood samples were withdrawn form each subject and preoperative level of IGFBP2 were measured using enzyme-linked immunosorbent assay (ELISA). Multivariate analysis was employed to test the performance of multiple predictors of surgical outcome.RESULTS: Eighteen patients (75%) had suboptimal outcome after PDS. Mean IGFBP2 level was significantly higher in the suboptimal group (1157.5±359.9 ng/mL vs. 679.1±504.5 ng/mL, p=0.018). In bivariate model, higher preoperative level of IGFBP2 predict the suboptimal outcome with good accuracy (AUC: 0.796, sensitivity: 83.3%, specificity: 83.3%, p=0.033, optimal threshold level 870 ng/mL). Higher IGFBP2 level was associated with higher risk of suboptimal outcome, although IGFBP2 was not an independent risk factor (adjusted OR: 5.0, 95% CI: 0.43-57.9, p=0.198).CONCLUSION: IGFBP2 is a novel and promising biomarker for surgical outcome prediction following PDS in AOC patients. Since it is predictive for suboptimal outcome, patients with higher preoperative level of IGFBP2 needs more thorough preoperative evaluation as well as meticulous surgical technique to optimize the surgical outcome.KEYWORDS: IGFBP2, advance ovarian cancer, PDS, surgical outcome, predicto