Chemoresistance to 5-fluorouracil (5-FU) is a significant challenge in treating colorectal cancer (CRC). Novel combined regimens to thwart chemoresistance are therefore urgently needed. Herein, we demonstrated that the combination of Avenanthramide A (AVN A) and 5-FU has significant therapeutic advantages against CRC. Mechanistically, AVN A directly binds to the S198 site of the histone lysine demethylase KDM4C to promote its degradation, which subsequently fosters H3K9me3 occupancy on the MIR17HG promoter to block its transcription and derepress Bim expression. AVN A enhanced the therapeutic efficacy of 5-FU via impairing the KDM4C/MIR17HG/GSK-3β negative feedback loop. Importantly, the clinical correlation of the KDM4C/MIR17HG/Bim signaling axis with 5-FU response was validated in the refractory CRC patients. We provide evidence for the enhanced effectiveness of 5-FU when combined with AVN A in chemoresistant xenografts, CRC organoids, and Apc ^Min/+ mouse model. Additionally, AVN A mitigated the systemic adverse effects of 5-FU. Overall, our findings demonstrate that combinatorial therapy with AVN A and 5-FU represents an appealing opportunity and highlights KDM4C/MIR17HG/GSK-3β negative feedback loop which confers therapeutically exploitable vulnerability to chemo-refractory CRC patients.

Objective:To systematically review the severe risk in common chronic diseases and coronavirus disease 2019 (COVID-19) cases.Methods:PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, China Biology Medicine disc, medRxiv, SSRN and ChinaXiv were searched for clinical and epidemiological studies that reported chronic diseases in patients with COVID-19. Only studies of severe COVID-19 in comparison with non-severe controls were included. The prevalence rates of chronic diseases including chronic obstructive pulmonary disease (COPD), diabetes mellitus, hypertension, malignant tumor, cardiovascular diseases, cerebrovascular disease, chronic kidney disease, and chronic liver disease were estimated. Pooled odds ratio ( OR) with 95% confidence interval ( CI) between patients with severe COVID-19 and non-severe groups were calculated. R 3.6.3 software was used for meta-analysis. Results:The search yielded 2 455 articles. A total of 19 eligible comparative studies with 4 792 patients were included in a quantitative analysis. Meta-analysis showed that there was a proportion of 55.0% (95% CI 40.0%-80.0%) male among patients with COVID-19, and the overall pooled prevalence of any chronic diseases in COVID-19 cases was 30.4% (95% CI 24.0%-37.0%). The most prevalent comorbidity was hypertension (16.9%(95% CI 14.0%-20.0%)), followed by diabetes mellitus (8.3%(95% CI 8.0%-9.0%)). The proportion of male patients with severe COVID-19 was higher than that of male patients with non-severe COVID-19 (64.4% vs 52.8%, OR=1.49, 95% CI 1.08-2.05, Z=4.63, P<0.01). The prevalence rates of COPD, cerebrovascular disease, diabetes mellitus, chronic kidney disease, hypertension, cardiovascular diseases and malignant tumor in severe COVID-19 patients were higher than those of non-severe patients ( OR=5.77, 95% CI 3.80-8.74; OR=4.47, 95% CI 2.71-7.38; OR=3.55, 95% CI 2.86-4.40; OR=3.05, 95% CI=1.76-5.28; OR=2.82, 95% CI=1.96-3.97; OR=2.39, 95% CI=1.77-3.23; OR=2.15, 95% CI 1.27-3.66, respectively, Z=8.37, 6.01, 11.60, 4.20, 5.46, 5.71, 3.12, all P<0.01). There was no significant difference in the prevalence of chronic liver disease between severe and non-severe patients ( OR=1.35, 95% CI 0.84-2.17, P=0.11). Conclusion:COVID-19 patients with chronic diseases have higher risk of developing severe disease, and the ORs from high to low are COPD, cerebrovascular disease, diabetes mellitus, chronic kidney disease, hypertension, cardiovascular diseases and malignant tumor.

Acupuncture Points ; Acupuncture Therapy ; Adult ; Ankle ; Cognitive Therapy ; Female ; Humans ; Intestine, Large ; physiopathology ; Middle Aged ; Rectal Diseases ; physiopathology ; psychology ; therapy ; Treatment Outcome ; Wrist

OBJECTIVETo investigate the effects of rapamycin and 3-methyladenine on autophagy impairment, oxidative stress and premature senescence induced by high-glucose in primarily cultured rat mesangial cells.

METHODSRat glomerular mesangial cells (GMCs) were isolated and cultured in normal glucose, high glucose, high glucose with 3-methyladenine (3-MA), or high glucose with rapamycin. At 24 h, 72 h and 10 days of culture, the cells were examined for expression levels of autophagy markers LC3 and p62/SQSTM1, malondialdehyde (MDA) and protein carbonyl, β-galactosidase (SA-β-gal) activity and heterochromatin foci (SAHF).

RESULTSCompared with those of normal cell culture, the cells exposed to high glucose for 72 h and 10 days showed down-regulated LC3 expression, up-regulated p62/SQSTM1 expression, elevated MDA and protein carbonyl levels, and increased SAHF formation and percentage of SA-β-gal-positive cells. These changes were reversed in GMCs exposed to high glucose and rapamycin for 72 h and 10 days, but exacerbated in cells incubated with 3-MA.

CONCLUSIONHigh glucose can suppress autophagic function of rat GMCs to result in oxidative damage and cell senescence. Rapamycin can attenuate autophagy impairment, oxidative damage and senescence induced by high glucose, whereas 3-MA can further aggravate high glucose-induced cell injuries in rat GMCs.

Animals ; Autophagy ; drug effects ; Cells, Cultured ; Cellular Senescence ; drug effects ; Glomerular Mesangium ; cytology ; Glucose ; adverse effects ; Male ; Mesangial Cells ; cytology ; drug effects ; metabolism ; Oxidative Stress ; drug effects ; Rats ; Rats, Sprague-Dawley ; Sirolimus ; pharmacology

AIM: To study the effects of over-expression of tricarboxylic acid cycle intermediates transporter NaDC3 (high affinity sodium-dependent dicarboxylate transporter) on energy metabolism and ROS generation in human renal tubular cells. METHODS: Recombinant retrovirus vector containing NaDC3 gene was constructed and used for infecting human renal tubular epithelial cell HKC. Control vector containing Neo gene was also constructed and infected cells. Liquid scintillation method was used to determine the level of [~3H]-succinate (as a transport substrate of NaDC3) in the cells. Clark electrode method and reverse phase HPLC were used to detect oxygen consumption and ATP content intracellularly, respectively. Mitochondrial membrane potential and reactive oxygen species (ROS) content in HKC were determined with laser confocal microscope after treatment with fluorescent probe JC-1 and CM-H_2DCFDA, respectively. RESULTS: Western blotting analysis showed that the expression of NaDC3 protein in uninfected- and control vector-infected cells was at lower level. After infection with recombinant NaDC3 vector, expression level of NaDC3 protein in HKC cells was increased markedly. Transport assay revealed that the level of [~3H]-succinate in NaDC3-infected cells was noticeably increased. Oxygen consumption and ATP content in NaDC3-infected HKC were significantly higher than those in uninfected- and control vector-infected cells. Laser confocal analysis revealed that mitochondrial membrane potential and ROS level in NaDC3-infected HKC were increased, compared with uninfected- and control vector-infected cells. CONCLUSION: Over-expression of NaDC3 accelerates the speed rate of energy metabolism and increases intracellular ROS generation by transporting an overdose of tricarboxylic acid cycle intermediates in human renal tubular epithelial cells.

Objective:To assess the value of spiral CT in diagnosis and treatment of chronic otitis media.Methods:The spiral CT findings of 74 cases including 93 ears proved by operation and pathology were studied.Results:The lesions such as the disruption of the ossicular chain showed in spiral CT or three-dimensional image were in accord with those seen in the operation,the accuracy was 95.7%,the disruption of the ossicular chain and bony erosion in the tympanic cavity and antrum were severe in the typeⅢ chronic otitis media.Conclusion:Spiral CT is helpful to diagnose and definite the chronic otitis media,three-dimensional image can provide valuable information for surgery.