The coronavirus disease 2019 (COVID‑19) outbreak, which has caused >46 millions confirmed infections and >1.2 million coronavirus related deaths, is one of the most devastating worldwide crises in ...recent years. Infection with COVID‑19 results in a fever, dry cough, general fatigue, respiratory symptoms, diarrhoea and a sore throat, similar to those of acute respiratory distress syndrome. The causative agent of COVID‑19, SARS‑CoV‑2, is a novel coronavirus strain. To date, remdesivir has been granted emergency use authorization for use in the management of infection. Additionally, several efficient diagnostic tools are being actively developed, and novel drugs and vaccines are being evaluated for their efficacy as therapeutic agents against COVID‑19, or in the prevention of infection. The present review highlights the prevalent clinical manifestations of COVID‑19, characterizes the SARS‑CoV‑2 viral genome sequence and life cycle, highlights the optimal methods for preventing viral transmission, and discusses possible molecular pharmacological mechanisms and approaches in the development of anti‑SARS‑CoV‑2 therapeutic agents. In addition, the use of traditional Chinese medicines for management of COVID‑19 is discussed. It is expected that novel anti‑viral agents, vaccines or an effective combination therapy for treatment/management of SARS‑CoV‑2 infection and spread therapy will be developed and implemented in 2021, and we would like to extend our best regards to the frontline health workers across the world in their fight against COVID‑19.
Alzheimer's disease (AD) is a neurodegenerative disorder causing 70% of dementia cases. However, the mechanism of disease development is still elusive. Despite the availability of a wide range of ...biological data, a comprehensive understanding of AD's mechanism from machine learning (ML) is so far unrealized, majorly due to the lack of needed data density. To harness the AD mechanism's knowledge from the expression profiles of postmortem prefrontal cortex samples of 310 AD and 157 controls, we used seven predictive operators or combinations of RapidMiner Studio operators to establish predictive models from the input matrix and to assign a weight to each attribute. Besides, conventional fold-change methods were also applied as controls. The identified genes were further submitted to enrichment analysis for KEGG pathways. The average accuracy of ML models ranges from 86.30% to 91.22%. The overlap ratio of the identified genes between ML and conventional methods ranges from 19.7% to 21.3%. ML exclusively identified oxidative phosphorylation genes in the AD pathway. Our results highlighted the deficiency of oxidative phosphorylation in AD and suggest that ML should be considered as complementary to the conventional fold-change methods in transcriptome studies.
Cisplatin resistance is a major clinical problem in the clinical management of oral squamous cell carcinoma (OSCC) patients. Resveratrol is a natural phytoestrogen with antitumor activities. Whether ...resveratrol can overcome cisplatin resistance and prevent metastasis in OSCC cells is not known. In this study, we first examined the anti‐metastatic capacity of resveratrol and then explored the underlying mechanisms using a cisplatin‐resistant human OSCC cell line (CAR). The results demonstrated that at a non‐toxic dose range (25 to 75 µM), 24‐hr treatment of resveratrol was able to suppress the migration and invasion capacities of CAR cells dose dependently. Interestingly, 50 µM resveratrol treatment could significantly down‐regulate the expression of the phosphorylated forms of ERK and p‐38, in addition to those of MMP‐2 and MMP‐9. At the same time, the expression levels of phosphorylated ERK together with those unphosphorylated forms of ERK, p38, and JNK were all insignificantly altered. In conclusion, the signaling cascade for resveratrol's suppression of cisplatin‐resistant human oral cancer CAR cells was revealed and summarized. Also the rapid effectiveness in suppressing metastatic behaviors of drug‐resistant oral cancer cells of non‐toxic resveratrol might extend its application to the drug‐resistant oral cancer treatment in the near future.
Practical applications
Based on the evidence we provided in the study, we have proposed a model recording the possible pathway for resveratrol inhibiting the metastasis of cisplatin‐resistant oral cancer cells. We suppose this signaling pathway may work in other cancer cell lines, and can be helpful in full understanding of the drug‐resistance
The current study provides the drug reposition evidence for resveratrol can inhibit the metastasis behaviors of cisplatin‐resistant oral cancer cells. This novel application is beneficial in not only clinical therapy for the oral cancer patients but also in translational medical science achievements.
Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely ...unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.
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•AMPKα facilitates TCA cycle by maintaining PDH complex activity•AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex•Activation of AMPKα-PDHA axis promotes tumor lung metastasis•AMPKα-PDHA axis predicts poor metastasis-free survival in breast cancer patients
Cai et al. demonstrate that phosphorylation of the catalytic subunit PDHA on Ser295 and S314 by AMPKα is essential for the maintenance of pyruvate dehydrogenase complex activity and TCA cycle. Activation of AMPKα-PDHA axis predicts poor metastasis-free survival in breast cancer patients and facilitates tumor lung metastasis.
Diabetic patients are highly vulnerable to hypoxic injury, which is associated with hypoxia induced BNIP3 expression that subsequently activate apoptosis. Our previous research show that ...Tetramethylpyrazine (TMP), a food flavoring agent, represses the hypoxia induced BNIP3 expression attenuate myocardial apoptosis. In this study, we evaluate the effect of TMP to provide protection against hypoxia aggravated high-glucose associated cellular apoptosis.
The cytoprotective effect of TMP against high glucose induced cellular damages was determined on embryo derived H9c2 cardiomyoblast cells that were subjected to 5% hypoxia for 24 h and subjected to different duration of 33 mM high glucose challenge. Further, the involvement of HIF-1α and BNIP3 in cellular damage and the mechanism of protection of TMP were determined by overexpression and silencing HIF-1α and BNIP3 protein expression.
The results show that hypoxic effects on cell viability aggravates with high glucose challenge and this augmentative effect is mediated through BNIP3 in H9c2 cardiomyoblast cells. However, TMP administration effectively reversed the augmented HIF-1α levels and BNIP3 elevation. TMP improved the survival of H9c2 cells and effectively suppressed apoptosis in H9c2 cells. Further comparison on the effects of TMP on H9c2 cells challenged with high glucose and those challenged with hypoxia show that TMP precisely regulated the hypoxic intensified apoptotic effects in high-glucose condition.
The results clearly show that flavoring agent-TMP attenuates cytotoxicity amplified by hypoxia challenge in high glucose condition by destabilizing HIF-1α.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Melanoma is a malignant tumor with aggressive behavior. Vemurafenib, a BRAF inhibitor, is clinically used in melanoma, but resistance to melanoma cytotoxic therapies is associated with BRAF ...mutations. Curcumin can effectively inhibit numerous types of cancers. However, there are no reports regarding the correlation between curcumin and vemurafenib‐resistant melanoma cells. In this study, vemurafenib‐resistant A375.S2 (A375.S2/VR) cells were established, and the functional mechanism of the epidermal growth factor receptor (EGFR), serine–threonine kinase (AKT), and the extracellular signal‐regulated kinase (ERK) signaling induced by curcumin was investigated in A375.S2/VR cells in vitro. Our results indicated that A375.S2/VR cells had a higher IC50 concentration of vemurafenib than the parental A375.S2 cells. Moreover, curcumin reduced the viability and confluence of A375.S2/VR cells. Curcumin triggered apoptosis via reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential (ΔΨm), and intrinsic signaling (caspase‐9/‐3‐dependent) pathways in A375.S2/VR cells. Curcumin‐induced apoptosis was also mediated by the EGFR signaling pathway. Combination treatment with curcumin and gefitinib (an EGFR inhibitor) synergistically potentiated the inhibitory effect of cell viability in A375.S2/VR cells. The present study provides new insights into the therapy of vemurafenib‐resistant melanoma and suggests that curcumin might be an encouraging therapeutic candidate for its drug‐resistant treatment.
We conducted the first genome‐wide association study (GWAS) of prostate cancer (PCa) in Taiwan with 1844 cases and 80,709 controls. Thirteen independent single‐nucleotide polymorphisms (SNPs) reached ...genome‐wide significance (p < 5 × 10−8). Among these, three were distinct from previously identified loci: rs76072851 in CORO2B gene (15q23), odds ratio (OR) = 1.54, 95% confidence interval (CI), 1.36–1.76, p = 5.30 × 10−11; rs7837051, near two long noncoding RNA (lncRNA) genes, PRNCR1 and PCAT2 (8q24.21), OR = 1.41 (95% CI, 1.31–1.51), p = 8.77 × 10−21; and rs56339048, near an lncRNA gene, CASC8 (8q24.21), OR = 1.25 (95% CI, 1.16–1.35), p = 2.14 × 10−8. We refined the lead SNPs for two previously identified SNPs in Taiwanese: rs13255059 (near CASC8), p = 9.02 × 10−43, and rs1456315 (inside PRNCR1), p = 4.33 × 10−42. We confirmed 35 out of 49 GWAS‐identified East Asian PCa susceptibility SNPs. In addition, we identified two SNPs more specific to Taiwanese than East Asians: rs34295433 in LAMC1 (1q25.3) and rs6853490 in PDLIM5 (4q22.3). A weighted genetic risk score (GRS) was developed using the 40 validated SNPs and the area under the receiver‐operating characteristic curve for the GRS to predict PCa was 0.67 (95% CI, 0.63–0.71). These identified SNPs provide valuable insights into the molecular mechanisms of prostate carcinogenesis in Taiwan and underscore the significant role of genetic susceptibility in regional differences in PCa incidence.
Resveratrol is known to be an effective chemo-preventive phytochemical against multiple tumor cells. However, the increasing drug resistance avoids the cancer treatment in oral cavity cancer. In this ...study, we investigated the oral antitumor activity of resveratrol and its mechanism in cisplatin-resistant human oral cancer CAR cells. Our results demonstrated that resveratrol had an extremely low toxicity in normal oral cells and provoked autophagic cell death to form acidic vesicular organelles (AVOs) and autophagic vacuoles in CAR cells by acridine orange (AO) and monodansylcadaverine (MDC) staining. Either DNA fragmentation or DNA condensation occurred in resveratrol-triggered CAR cell apoptosis. These inhibitors of PI3K class III (3-MA) and AMP-activated protein kinase (AMPK) (compound c) suppressed the autophagic vesicle formation, LC3-II protein levels and autophagy induced by resveratrol. The pan-caspase inhibitor Z-VAD-FMK attenuated resveratrol-triggered cleaved caspase-9, cleaved caspase-3 and cell apoptosis. Resveratrol also enhanced phosphorylation of AMPK and regulated autophagy- and pro-apoptosis-related signals in resveratrol-treated CAR cells. Importantly, resveratrol also stimulated the autophagic mRNA gene expression, including Atg5, Atg12, Beclin-1 and LC3-II in CAR cells. Overall, our findings indicate that resveratrol is likely to induce autophagic and apoptotic death in drug-resistant oral cancer cells and might become a new approach for oral cancer treatment in the near future.
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•Plumbagin does not affect the cell viability of human EPCs.•Plumbagin suppresses VEGF-promoted EPC migration and tube formation.•Plumbagin reduces VEGF-induced promotion of PLC, Akt ...and ERK activation.•Plumbagin inhibits VEGF-induced promotion of NF-κB and HIF-1 activation in EPCs.•Plumbagin suppress EPC expression and angiogenesis in vivo.
Plumbagin, a naturally occurring naphthoquinone component isolated from the root of Plumbago zeylanica, reduces angiogenesis in human umbilical vein endothelial cells; whether plumbagin also has anti-angiogenic activity in human endothelial progenitor cells (EPCs) has remained unclear. Importantly, the recruitment of bone marrow-derived EPCs promotes physiological and pathological neovascularization. In this study, plumbagin inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation of human EPCs, without cytotoxic effects. We also found that plumbagin inhibited angiogenesis via the phospholipase C (PLC), Akt, extracellular-signal-regulated kinase (ERK), nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)-1 signaling pathways. In an EPC Matrigel plug assay, plumbagin significantly diminished microvessel formation and EPC-specific marker expression. Our report is the first to reveal that plumbagin reduces EPC-related angiogenesis both in vitro and in vivo. Further evaluations of plumbagin are warranted, to determine its antitumor activity and other angiogenesis-related disorders.
Problem
Preeclampsia, a multifaceted condition during pregnancy characterized by hypertension and organ dysfunction, poses significant risks to both maternal and fetal health. This study aims to ...investigate the bidirectional causal relationship between peripheral immune cell phenotypes and preeclampsia using a two‐sample Mendelian randomization (MR) approach.
Method of study
Genetic data from two sizable cohorts were utilized: 3757 individuals from Sardinia, providing information on 731 immune traits, and 200 929 Finnish adult females, encompassing 6663 preeclampsia cases. Single‐nucleotide polymorphisms served as instrumental variables. The MR analyses employed the inverse variance‐weighted (IVW) method as the primary tool, supplemented by MR‐Egger, weighted median, and weighted mode methods to enhance reliability and address potential heterogeneity and horizontal pleiotropy.
Results
Among the 731 immune cell phenotypes studied, 18 displayed a suggestive positive association (IVW p < .05) with heightened preeclampsia risk, while 20 exhibited a suggestive negative association linked to reduced risk. Following false discovery rate (FDR) adjustment, four immune phenotypes showed significant associations with decreased preeclampsia risk: CD27 on CD24+ CD27+ B cells (B‐cell panel) (odds ratio OR = 0.927, PFDR = 0.061), CD33+ HLA DR+ CD14− absolute count (OR = 0.963, PFDR = 0.061), CD80 on plasmacytoid dendritic cells (OR = 0.923, PFDR = 0.061); and CD80 on CD62L+ plasmacytoid dendritic cells (OR = 0.923, PFDR = 0.061). In the reverse‐direction MR analysis, no significant causal effects of preeclampsia on immune cell phenotypes were observed.
Conclusions
This study provides quantifiable evidence linking specific immune cell phenotypes to the risk of developing preeclampsia. This novel understanding of the immunological aspects underlying preeclampsia's pathogenesis could lead to innovative therapeutic strategies centered on immune modulation.
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