Kaohsiung Journal of Medical Sciences最新文献

Frailty is the incremental accumulation of minute defects that progressively impair health and performance. Frailty is commonly observed in older adults; however, secondary frailty may also occur in patients with metabolic disorders or major organ failure. In addition to physical frailty, several distinct types of frailty have been identified, including oral, cognitive, and social frailty, each of which is of practical importance. This nomenclature suggests that detailed descriptions of frailty can potentially advance relevant researches. In this narrative review, we first summarize the clinical value and plausible biological origin of frailty, as well as how to appropriately assess it using physical frailty phenotypes and frailty indexes. In the second part, we discuss the issue of vascular tissue as a relatively underappreciated organ whose pathologies contribute to the development of physical frailty. Moreover, when vascular tissue undergoes degeneration, it exhibits vulnerability to subtle injuries and manifests a unique phenotype amenable to clinical assessment prior to or accompanying physical frailty development. Finally, we propose that vascular frailty, based on an extensive set of experimental and clinical evidence, can be considered a new frailty type that requires our attention. We also outline potential methods for the operationalization of vascular frailty. Further studies are required to validate our claim and sharpen the spectrum of this degenerative phenotype.

Friend leukemia integration 1 (FLI1) is an ETS transcription factor family member. Here, we identified cg11017065 as the most hyper-methylated cytosine and guanine (CpG) in colorectal cancer (CRC), which belongs to the FLI1 gene. Moreover, integrated bioinformatics prediction and analysis of our cohort showed that FLI1 expression was downregulated and DNA methylation was elevated in CRC. Bioinformatics prediction also indicated that patients overexpressing FLI1 had higher survival rates than those with low FLI1 expression. CRC cells with ectopic expression of FLI1 had reduced invasion, migration, cloning ability and increased apoptosis. Furthermore, DNA-methyltransferase 3b (DNMT3b) was found to be significantly overexpressed in CRC, and low DNMT3b expression predicted a prolonged survival. DNMT3b bound to the FLI1 promoter. Inhibition of DNMT3b increased FLI1 expression and inhibited the malignant phenotype of CRC cells. Inhibition of FLI1 reversed the phenotypic modulation by DNMT3b depletion in vitro and in vivo. In conclusion, our data indicate that DNMT3b potentiates CRC cell proliferation, migration, and invasion through downregulating FLI1.

Resveratrol (RSV) has been shown to have a neuroprotective effect in various central nervous system disorders, although the role of RSV in diabetes-induced cognitive dysfunction is still not fully elucidated. Here, we investigated whether RSV improved diabetes-related cognitive dysfunction in vivo and in vitro. We induced a rat diabetic model with a high-fat and high-sucrose diet followed by intraperitoneal injection of streptozotocin and a diabetic neuron cell model by stimulation with high levels of glucose. We observed that RSV improved impairment in spatial learning and memory in the Morris water maze test (MWM) and novel object recognition test (ORT) in diabetic rats. RSV reversed the reduced miR-146a-5p and upregulated thioredoxin-interacting protein (TXNIP) and inhibited the diabetes-induced increase in interleukin (IL)-1β and tumor necrosis factor (TNF)-α levels in vivo and in vitro. RSV also inhibited diabetes-induced endoplasmic reticulum stress (ESR) by reducing ESR-related protein expression in vivo and in vitro. Moreover, inhibition of miR-146a-5p partially abolished the protective effects of RSV in HG-treated primary neurons. Additionally, we used starBase to predict that miR-146a-5p interacts with TXNIP, which we then verified using a luciferase reporter gene assay. We further observed that miR-146a-5p regulates the mRNA and protein expression of TXNIP in vitro, indicating that the miR-146a-5p/TXNIP axis is involved in the regulation of cognitive dysfunction in a rat diabetic model. Collectively, these results demonstrate that RSV plays a neuroprotective role in diabetes-associated cognitive dysfunction at least in part through regulation of the miR-146a-5p/TXNIP axis.

Tumor-associated macrophages (TAMs) and M2 macrophage polarization have been documented for their implication in various malignancies, but their implication in liver cancer remains to be determined. This study is intended to explore the effect of S100A9 regulated TAMs and macrophage polarization in liver cancer progression. THP-1 cells were induced to differentiate into M1 and M2 macrophages, which were then cultured in liver cancer cell conditioned culture medium before the M1 and M2 macrophages were identified by measuring biomarkers using real-time polymerase chain reaction. The differential expressed genes in macrophages in Gene Expression Omnibus (GEO) databases were screened. S100A9 overexpression and knockdown plasmid were transfected into macrophages to determine the effect of S100A9 on M2 macrophage polarization of TAMs and on proliferation ability of liver cancer cells. The proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) abilities of liver cancer co-cultured with TAMs. M1 and M2 macrophages were successfully induced and liver cancer cell conditioned culture medium can increase polarization of macrophages into M2 macrophages, in which elevated expression of S100A9 was detected. Data in GEO database showed that tumor microenvironment (TME) upregulated S1000A9 expression. Suppression on S1000A9 can significantly suppress M2 macrophage polarization. TAM can provide the necessary microenvironment for liver cancer cells, HepG2 and MHCC97H by increasing cell proliferation, migration, and invasion ability, while suppression on S1000A9 can reverse this expression pattern. Suppression on S100A9 expression can regulate M2 macrophage polarization of TAMs to suppress the progression of liver cancer.

Dexmedetomidine (DEX), a common anesthetic, has significant effects on the biological features of cancer cells. Although numerous studies have been published on the impact of DEX on the biological characteristics of GC cells, the mechanism remains unknown. This study aimed to explore the effect of DEX on the biological properties of GC cells. DEX suppressed the viability and increased the apoptosis of GC cells in vitro and inhibited tumor growth in vivo. Besides, DEX raised the levels of reactive oxygen species (ROS) and iron, but decreased the levels of glutathione (GSH), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) in GC cells, which were abolished by Ferrostatin-1 (the inhibitor of ferroptosis) treatment. In addition, the level of circ0008035 and E2F7 were downregulated, but miR-302a level was upregulated in DEX-treated GC cells. Circ0008035 increased the expression of E2F2 by acting as a sponge for miR-302a. Circ0008035 inhibited DEX-induced ferroptotic cell death in GC cells, which was reversed by miR-302a overexpression or E2F7 reduction. Taken together, DEX mediated ferroptotic cell death in GC through regulating the circ0008035/miR-302a/E2F7 axis, suggesting a feasible therapy option for GC.

Previous studies about renal protection of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes mellitus (T2DM) patients with heart failure (HF) on diuretics were still limited. The goal of the study is to survey the efficacy of SGLT2i to reduce all-cause mortality and renal impairments in patients with T2DM and HF using diuretics. The retrospective cohort study was analyzed from Kaohsiung Medical University Hospital Research Database (KMUHRD) in Taiwan. Adults with T2DM and HF using any diuretics at least 28 days during 2016-2018 were enrolled and then divided into the SGLT2i group and the non-SGLT2i group. Propensity score matching was used to balance baseline characteristics between the two groups. The primary outcome was all-cause mortality. Secondary outcomes contained dialysis occurrence, renal progression, and acute kidney injury (AKI). After 1:1 matching, there were 183 patients in each group respectively. When compared with the non-SGLT2i group, the SGLT2i group had significantly lower all-cause mortality (hazard ratios [HR]: 0.49, 95% CI 0.29-0.83, p = 0.008) and reduction of renal progression (HR: 0.30, 95% CI 0.12-0.75, p = 0.010). SGLT2i showed the trend to decrease dialysis occurrence (HR: 0.83, 95% CI 0.20-3.47, p = 0.797) and an increase in AKI (HR: 1.38, 95% CI 0.67-2.87, p = 0.383) but without significance. SGLT2 inhibitors were associated with reduced all-cause mortality and less renal progression with significance in T2DM patients with HF on diuretics.

Laryngeal cancer is a usual malignant tumor of the head and neck. The role and mechanism of deubiquitinase USP21 in laryngeal cancer are still unclear. We aimed to explore whether USP21 affected laryngeal cancer progress through deubiquitinating AURKA. USP21 and AURKA levels were evaluated by qRT-PCR and Western blot. Kaplan-Meier analysis was conducted by survival package. MTT was performed to detect cell proliferation. The wound healing assay was applied to evaluate cell migration. Transwell was used to measure cell invasion. Co-IP and GST-pull down determined the interaction between USP21 and AURKA. In addition, AURKA ubiquitination levels were analyzed. USP21 was signally elevated in laryngeal cancer tissues and cells. USP21 level in clinical stages III-IV was higher than that in clinical stages I-II, and high levels of USP21 were highly correlated with poor prognosis in laryngeal cancer. USP21 inhibition suppressed AMC-HN-8 and TU686 cell proliferation, migration and invasion. Co-IP and GST-pull down confirmed the interaction between USP21 and AURKA. Knockdown of USP21 markedly increased the ubiquitination level of AURKA, and USP21 restored AURKA activity through deubiquitination. In addition, overexpression of AURKA reversed the effects of USP21 knockdown on cell growth, migration, and invasion. USP21 stabilized AURKA through deubiquitination to promote laryngeal cancer progression.

Insulin receptor substrate 1 and 2 (IRS1/2) have been found involved in many cancers development and their inhibitors exert significant tumor-suppressive effects. Here, we tried to explore the function of NT157, an IGF1R-IRS1/2 inhibitor, in ovarian cancer. We treated ovarian cancer cells with varying doses of NT157. The MTT assay was employed to evaluate cell proliferation and colony formation assay was used for detecting colony-forming ability. TUNEL assay was adopted to test cell apoptosis. Cell invasion was checked by the Transwell assay. The expression of apoptosis-related proteins, autophagy markers, IRS1/2, and PI3K/AKT/mTOR pathway was compared by Western blot, immunofluorescence, or qRT-PCR. As indicated by the data, NT157 abated the viability, proliferation, and induced autophagy of ovarian cancer cells. Overexpressing IRS1/2 attenuated the tumor-suppressive effect of NT157 and heightened the PI3K/AKT/mTOR pathway activation. Inhibition of the PI3K/AKT/mTOR pathway enhanced the tumor-suppressive effect of NT157 and facilitated NT157-mediated autophagy. However, the autophagy inhibitor 3-MA partly reversed NT-157-mediated antitumor effects. In conclusion, this study disclosed that NT157 suppressed the malignant phenotypes of ovarian cancer cells by inducing autophagy and hampering the expression of IRS1/2 and PI3K/AKT/mTOR pathway.

As one kind of novel noncoding RNA, circular RNAs (circRNAs) are involved in different biological processes. Although growing evidences have supported the important role of circRNAs in renal diseases, the mechanism remains unclear in neonatal acute kidney injury (AKI). High-throughput sequencing analysis was used to investigate the expression of circRNAs between hypoxia-induced AKI neonates and controls. Bioinformatics analysis was conducted to predict the function of differentially expressed circRNAs. Finally, the differentially expressed circRNAs were screened and determined by quantitative real-time PCR (qPCR). (1) A total of 296 differentially expressed circRNAs were identified (Fold change >2 and p < 0.05). Of them, 184 circRNAs were markedly upregulated, and 112 were significantly downregulated in the AKI group. (2) The pathway analysis showed that ubiquitin-mediated proteolysis, renal cell carcinoma, Jak-STAT, and HIF-1 signaling pathways participated in AKI. (3) Top five upregulated and five downregulated circRNAs with higher fold changes were selected for qPCR validation. Hsa_circ_0008898 (Fold Change = 5.48, p = 0.0376) and hsa_circ_0005519 (Fold Change = 4.65, p = 0.0071) were significantly upregulated, while hsa_circ_0132279 (Fold Change = -4.47, p = 0.0008), hsa_circ_0112327 (Fold Change = -4.26, p = 0.0048), and hsa_circ_0017647 (Fold Change = -4.15, p = 0.0313) were significantly downregulated in asphyxia-induced AKI group compared with the control group. This study could contribute to future research on neonatal AKI and facilitate the identification of novel therapeutic targets.