Macroautophagy/autophagyis a lysosomal-regulated degradation process that participates incellular stress and then promotes cell survival or triggers celldeath. Ferroptosis was initially described as anautophagy-independent, iron-regulated, nonapoptotic cell death.However, recent studies have revealed that autophagy is positivelyassociated with sensitivity to ferroptosis. Nonetheless, themolecular mechanisms by which these two types of regulated cell death(RCD) modulate each other remain largely unclear. Here, we screened85 deubiquitinating enzymes (DUBs) and found that overexpression ofUSP13 (ubiquitin specific peptidase 13) could significantlyupregulate NFE2L2/NRF2 (NFE2 like bZIP transcription factor 2)protein levels. In addition, in 39 cases of KRAS-mutated lungadenocarcinoma (LUAD), we found that approximately 76% of USP13overexpression is positively correlated with NFE2L2 overexpression.USP13 interacts with and catalyzes the deubiquitination of thetranscription factor NFE2L2. Additionally, USP13 depletion promotesan autophagy-to-ferroptosis switch invitro andin xenograft tumor mouse models, through the activation of theNFE2L2-SQSTM1/p62 (sequestosome 1)-KEAP1 axis in KRAS mutant cellsand tumor tissues. Hence, targeting USP13 effectively switchedautophagy-to-ferroptosis, thereby inhibiting KRAS (KRASproto-oncogene, GTPase) mutant LUAD, suggesting the therapeuticpromise of combining autophagy and ferroptosis in the KRAS-mutantLUAD.
Abstract Circadian rhythm dysfunction is primary symptom of depression and is closely related to depression onset. The role of the lateral habenula (LHb) of the thalamus in the pathogenesis of depression has been a research topic of great interest. The neuronal activity of this structure has circadian characteristics, which are related to the regulation of circadian rhythms. However, in depression model of rats, the role of clock genes in the LHb has not been assessed. To address this gap, we used a clomipramine (CLI) injection‐induced depression model in rats to assess the daily expression of rhythmic genes in the LHb and depression‐like behavior in rats at multiple time points. In determining the role of the Per2 gene in the development of depression‐like behavior in the LHb, we found that the expression of this clock gene differed in a circadian manner. Per2 expression was also significantly decreased in CLI‐treated rats in late afternoon (17:00) and in the middle of the night (1:00). Furthermore, silencing Per2 in the LHb of normal rats induced depression‐like behavior at night, suggesting that Per2 may play an important role in the pathogenesis of depression. Collectively, these results indicate that decreased Per2 expression in the LHb may be related to increased depression‐like behavior at night in depression model of rats.
Abstract Objective A thorough examination of the available approaches is crucial to comprehensively understand the variance among the alignment strategies employed in total knee arthroplasty (TKA). In this study, we assessed the functional outcomes during the perioperative and postoperative periods of TKA in patients using generic instruments with varus knee to compare the mechanical alignment (MA) and kinematic alignment (KA) procedures. Methods A total of 127 patients from the First Affiliated Hospital of Wannan Medical College who had undergone unilateral TKA between November 2019 and April 2021 were included. The patients with varus knee deformity were categorized into two groups [type I ( n = 64) and type IV ( n = 63)] based on the modified coronal plane alignment of the knee (mCPAK) classification. The type I and IV groups were further subdivided into MA ( n = 30 and n = 32) and KA subgroups ( n = 34 and n = 21), respectively. The clinical information collected included sex, surgical side, age, body mass index, and perioperative data [including operation time, intraoperative blood loss, length of hospital stay, and the American Society of Anesthesiologists (ASA) classification]. All patients were monitored for 12 months post-surgery to evaluate the recovery of knee joint function. During this period, the Knee Disability and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR) and the active range of motion (AROM) and visual analog scale (VAS) pain scores were compared at different time points, i.e., before the operation and 6 weeks, 6 months, and 12 months post-operation. Additionally, the patients’ subjective experiences were assessed at 6 and 12 months post-surgery using Forgotten Joint Score Knee (FJS-12 Knee), while complications were recorded throughout the monitoring period. Results No significant variances were observed in ASA classification, operation duration, blood loss volume during surgery, and hospital stay length between the patients who underwent KA TKA and those who received MA TKA ( P > 0.05). During the initial 6 weeks post-operation, the KA group exhibited a significantly reduced average VAS pain score ( P < 0.05), with no such differences at 6 months and 1 year after the surgery ( P > 0.05). Furthermore, the KA group had significantly higher scores on the KOOS JR at 6 weeks, 6 months, and 1 year following the surgery ( P < 0.05). Moreover, the AROM score of the KA group significantly improved only at 6 weeks after the surgery ( P < 0.05); however, no prominent differences were found at 6 months and 1 year after the operation ( P > 0.05). The KA cohort also exhibited a significant increase in FJS-12 Knee at 1 year following the operation ( P < 0.05), whereas no such difference was detected at 6 months following the surgery ( P > 0.05). Thus, compared to the MA method, the KA procedure provided pain relief and improved active motion range within 6 weeks after the surgery in patients undergoing TKA. Further, the KOOS JR exhibited significant increases at 6 weeks, 6 months, and 1 year while the FJS-12 Knee demonstrated a significant increase at 1 year after the KA TKA procedure. Conclusion Therefore, our study results suggest that the KA approach can be considered in patients using generic instruments with varus alignment of the knee, particularly those with mCPAK type I and IV varus knees, to help improve patient satisfaction.
Methylprednisolone is an effective drug in the treatment of autoimmune disease, such as multiple sclerosis (MS), due to long-acting anti-inflammatory, antiallergic and immunosuppressant. Previous studies have noted the importance of myeloid-derived suppressor cells (MDSC) in MS progression. However, it is still not known whether methylprednisolone could influence the ratio and function of MDSC during MS treatment. In the current study, we found an increased ratio of MDSC at the onset of EAE in mice model; but methylprednisolone pulse therapy (MPPT) did not alter the percentage and suppressive function of MDSC during disease attenuation. However, the percentage of G-MDSC in PBMC significantly increased in patients with MS. Surprisingly, relapsing MS patients showed a significant increase in both M-MDSC and G-MDSC after MPPT. The disease remission positively correlated expansion of MDSC and expression of arginase-1. Additionally, MPPT reduced the expression of inhibitory glucocorticoid (GCs) receptor β subunit on MDSC while elevating serum levels of immune regulatory S100A8/A9 heterodimer. Thus, MDSC dynamics and function in mouse EAE differ from those in human MS during MPPT. Our study suggested that GCs treatment may help relieve the acute phase of MS by expanding MDSC through up-regulating of GR signalling and S100A8/A9 heterodimers.
Dihydromyricetin (DHM) is a traditional plant-extracted flavonoid with some health benefits. This study aimed to metabolically engineer the strains for DHM bioproduction. Two strains of BK-11 and BQ-21 were integrated with flavonoid 3-hydroxylase (F3H) or both F3H and flavonoid 3′-hydroxylase (F3′H). The resulting strains have expressed the enzymes of GmCPR and SlF3′5′H, and then, the promoters of INO1p and TDH1p were used to enhance further the DHM production from naringenin in Saccharomyces cerevisiae. Through multiple-copy integration, 709.6 mg/L DHM was obtained by adding 2.5 g/L naringenin in a 5 L bioreactor, implying that the synergistic effect between F3′H and flavonoid 3′5′-hydroxylase is likely to promote the DHM production. An yield of 246.4 mg/L DHM was obtained from glucose by deleting genes for branch pathways and integrating PhCHS, MsCHI, Pc4CL, and FjTAL. To our knowledge, this is the highest production reported for the de novo biosynthesis of DHM.
China's Xuan Wei County in Yunnan Province have the world's highest incidence of lung cancer in nonsmoking women-20 times higher than the rest of China. Previous studies showed, this high lung cancer incidence may be associated with the silica particles embedded in the production combustion from the C1 coal. The aim of this study is to separate the silica particles from production combustion from the C1 bituminous coal in Xuan Wei County of Yunnan Province, and study in vitro toxicity of naturally occurring silica particles on BEAS-2B.①Separating the silica particles from combustion products of C1 bituminous coal by physical method, observing the morphology by Scanning Electron Microscope, analysis elements by SEM-EDX, observed the single particle morphology by Transmission Electron Microscope, analyed its particle size distribution by Laser particle size analyzer, the surface area of silica particles were determined by BET nitrogen adsorption analysis; ②Cell viability of the experimental group (silica; naturally occurring), control group (silica; industrial produced and crystalline silica) was detected by assay used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, and the reactive oxygen species (ROS), lactate dehydrogenase (LDH) were determined after 24 h-72 h exposed to these particles.①The physical method can separate silica particles from production combustion from the C1 bituminous coal, which have different size, and from 30 nm to 120 nm particles accounted for 86.8%, different morphology, irregular surface area and containing trace of aluminum, calcium and iron and other elements; ②Under the same concentration, the experiment group have higher toxicity on BEAS-2B than control groups.Physical method can separate silica particles from production combustion from the C1 bituminous coal and not change the original morphology and containing trace; ②Naturally occurring silica nanoparticles have irregular morphology, surface area, and containing complex trace elements may has greater toxicity than the silica nanoparticle of industrial produced and crystalline silica.
To identify differentially expressed microRNAs (miRNAs) related to lung adenocarcinoma in Xuanwei region and predict their target genes and related signaling pathways based on bioinformatic analysis.High-throughput microarray assay was performed to detect miRNA expression profiles in 34 paired human lung adenocarcinoma and adjacent normal tissues (including 24 cases in Xuanwei region and 10 in other regions). Gene ontology and KEGG pathway analyses were used to predict the target genes and the regulatory signaling pathways.Thirty-four miRNAs were differentially expressed in lung adenocarcinoma tissues in cases in Xuanwei region as compared with cases in other regions, including 23 upregulated and 11 downregulated miRNAs. The predicted target genes included GF, RTK, SOS, IRS1, BCAP, CYTOKINSR, ECM, ITGB, FAK and Gbeta;Y involving the PI3K/Alt, WNT and MAPK pathways.The specific microRNA expression profiles of lung adenocarcinoma in cases found in Xuanwei region allow for a better understanding of the pathogenesis of lung adenocarcinoma in Xuanwei. The predicted target genes may involve the PI3K/Alt, WNT and MAPK pathways.
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