Search

Background: Fibrosis is a core pathological factor of ligamentum flavum hypertrophy (LFH) resulting in degenerative lumbar spinal stenosis. Autophagy plays a vital role in multi-organ fibrosis. However, autophagy has not been reported to be involved in the pathogenesis of LFH., Methods: The LFH microarray data set GSE113212, derived from Gene Expression Omnibus, was analyzed to obtain differentially expressed genes (DEGs). Potential autophagy-related genes (ARGs) were obtained with the human autophagy regulator database. Functional analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were conducted to elucidate the underlying biological pathways of autophagy regulating LFH. Protein-protein interaction (PPI) network analyses was used to obtain hub ARGs. Using transmission electron microscopy, quantitative RT-PCR, Western blotting, and immunohistochemistry, we identified six hub ARGs in clinical specimens and bipedal standing (BS) mouse model., Results: A total of 70 potential differentially expressed ARGs were screened, including 50 up-regulated and 20 down-regulated genes. According to GO enrichment and KEGG analyses, differentially expressed ARGs were mainly enriched in autophagy-related enrichment terms and signaling pathways related to autophagy. GSEA and GSVA results revealed the potential mechanisms by demonstrating the signaling pathways and biological processes closely related to LFH. Based on PPI network analysis, 14 hub ARGs were identified. Using transmission electron microscopy, we observed the autophagy process in LF tissues for the first time. Quantitative RT-PCR, Western blotting, and immunohistochemistry results indicated that the mRNA and protein expression levels of FN1, TGFβ1, NGF, and HMOX1 significantly higher both in human and mouse with LFH, while the mRNA and protein expression levels of CAT and SIRT1 were significantly decreased., Conclusion: Based on bioinformatics analysis and further experimental validation in clinical specimens and the BS mouse model, six potential ARGs including FN1 , TGFβ1 , NGF , HMOX1 , CAT , and SIRT1 were found to participate in the fibrosis process of LFH through autophagy and play an essential role in its molecular mechanism. These potential genes may serve as specific therapeutic molecular targets in the treatment of LFH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Fei, Chen, Chen, Lai, Tan, Yu, Xiang, Dong, Zhang, Wang and Zhang.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused recurring and major outbreaks in multiple human populations around the world. The plethora of clinical presentations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been described extensively, of which olfactory dysfunction (OD) was established as an important and common extrapulmonary manifestation of COVID-19 infection. The aim of this protocol is to conduct a systematic review and meta-analysis on peer-reviewed articles which described clinical data of OD in COVID-19 patients., Methods: This research protocol has been prospectively registered with the Prospective Register of Systematic Reviews (PROSPERO; CRD42020196202). CINAHL, ClinicalTrials.gov, Cochrane Central, EMBASE, MEDLINE and PubMed, as well as Chinese medical databases China National Knowledge Infrastructure (CNKI), VIP and WANFANG, will be searched using keywords including 'COVID-19', 'coronavirus disease', '2019-nCoV', 'SARS-CoV-2', 'novel coronavirus', 'anosmia', 'hyposmia', 'loss of smell', and 'olfactory dysfunction'. Systematic review and meta-analysis will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. Articles will be screened according to pre-specified inclusion and exclusion criteria to extract studies that include new clinical data investigating the effect of COVID-19 on olfactory dysfunction. Included articles will be reviewed in full; data including patient demographics, clinical characteristics of COVID-19-related OD, methods of olfactory assessment and relevant clinical outcomes will be extracted. Statistical analyses will be performed using the Comprehensive Meta-Analysis version 3., Discussion: This systematic review and meta-analysis protocol will aim to collate and synthesise all available clinical evidence regarding COVID-19-related OD as an important neurosensory dysfunction of COVID-19 infection. A comprehensive search strategy and screening process will be conducted to incorporate broad clinical data for robust statistical analyses and representation. The outcome of the systematic review and meta-analysis will aim to improve our understanding of the symptomatology and clinical characteristics of COVID-19-related OD and identify knowledge gaps in its disease process, which will guide future research in this specific neurosensory defect., Systematic Review Registration: PROSPERO registration number: CRD42020196202.

Solar-driven photocatalytic CO 2 reduction into CH 4 with H 2 O is considered to be a promising way to alleviate the energy crisis and greenhouse effect. However, current CO 2 photoreduction technologies tend to overlook the role of photooxidation half reaction as well as the effect of the protons produced by water oxidation on CH 4 generation, resulting in low CO 2 conversion efficiency and poor CH 4 selectivity. In the present study, a series of chloride-modified Bi 2 WO 6 nanosheets were constructed in view of chloride-assisted photocatalytic water oxidation. The results show that the CH 4 yield of the synthesized sample can be enhanced up to about 10 times compared to that with no Cl - modification. Besides, the selectivity of CH 4 can be regulated by the loading amount of chloride, varying from 51.29% for Bi 2 WO 6 to 94.98% for the maximum. The increase of product yield is attributed to chloride modification, which not only changed the morphology of the catalyst, but also modified the pathway of water oxidation. Further studies on intermediate products and the density functional theory calculation confirm that the Cl - ions on Bi 2 WO 6 nanosheets not only promote H 2 O oxidation, but also lower the energy barrier for intermediate *CHO generation, thus facilitating CH 4 production. The results gained herein may provide some illuminating insights into the design of a highly selective photocatalyst for efficient CO 2 reduction.

Background: Nephrotoxicity, especially acute kidney injury (AKI), is the main dose-limiting toxicity of cisplatin. Although recent studies showed that curcumin prevented cisplatin-induced AKI effectively, further studies to understand the mechanism are required. Methods: We established an AKI mouse model. Male C57BL/6 mice were assigned to three groups: saline group (control), cisplatin group (CP), and curcumin + cisplatin group (CP + Cur). The CP group received a single intraperitoneal (i.p.) injection of cisplatin, while the control group received saline. The CP + Cur group received i.p. curcumin three days before cisplatin injection and curcumin administered for another three days until the day before euthanization. Renal injury was assessed by serological and histological analysis. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the phosphatase and tensin homolog (PTEN), and microRNA (miR)-181a expression in the renal tissues. Bioinformatics prediction and western blotting methods validated the targets of miR-181a in vitro . Results: Curcumin treatment alleviated cisplatin-induced nephrotoxicity as validated by the blood urea nitrogen (BUN) values, and histological analysis of kidneys. At the molecular level, curcumin treatment decreased miR-181a expression level, which was induced by cisplatin and restored the in vivo expression of PTEN, which was suppressed by cisplatin. We verified the direct regulation of PTEN by miR-181a in cultured human embryonic kidney 293T cells. Conclusions: We showed the involvement of miR-181a/PTEN axis in the renoprotective effect of curcumin against cisplatin-induced AKI, and provide new evidence on the ability of curcumin to alleviate cisplatin-induced nephrotoxicity.

Ovarian cancer is a highly lethal malignancy in the female reproductive system. Platinum drugs, represented by cisplatin, are the first-line chemotherapeutic agents for treatment of various malignancies including ovarian cancer, but drug resistance leads to chemotherapy failure. MicroRNAs emerged as promising molecules in reversal of cisplatin resistance. MiR-186 was reported to be downregulated in the cisplatin-resistant ovarian cell lines and miR-186 expression increased cisplatin sensitivity. However, we found the bidirectional regulatory effects of miR-186 on cisplatin sensitivity for the first time that overexpression of miR-186 at low concentration increased the cisplatin sensitivity of ovarian cancer cells A2780/DDP, while high concentration of miR-186 decreased the cisplatin sensitivity. The survival assay in other types of cancer cell lines verified the bidirectional regulatory function of miR-186 on cisplatin sensitivity in dose and cell type dependent manners. MiR-186 suppressed the protein levels of PTEN and PIK3R3 dose-dependently, which are opposite regulatory molecules of the oncogenic AKT pathway. MiR-186 also enhanced the protein levels of apoptotic gene APAF1 dose-dependently. We proposed the final effects of PTEN and APAF1 outweighed PIK3R3 when miR-186 at low concentration so as to increase the cisplatin sensitivity of ovarian cancer cells, while the final effects of PIK3R3 outweighed PTEN and APAF1 when miR-186 at high concentration so as to decrease the cisplatin sensitivity. We concluded the outcome of regulation of these opposite functional molecules contributed to the bidirectional regulatory effects of miR-186 in ovarian cancer cisplatin sensitivity. It deserves more attentions when developing therapeutic strategies based on the bidirectional functional miRNAs., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Although many persons with severe dementia (PWSDs) are cared for at home by their family caregivers, few studies have assessed end of life (EOL) care experiences of PWSDs. We present the protocol for the PISCES study (Panel study Investigating Status of Cognitively impaired Elderly in Singapore) which aims to describe the clinical course, health care utilization, and expenditures for community-dwelling PWSDs; and perceived burden, coping, resilience, anticipatory and prolonged grief among their caregivers. This ongoing multi-center prospective longitudinal study is recruiting primary informal caregivers of 250 PWSDs from major restructured public hospitals, community hospitals, home care foundations, and hospices in Singapore. Caregivers are surveyed every four months for two years or until the PWSD passes away and then at eight weeks and six months post-death to assess the bereavement of the caregiver. Survey questionnaires included validated tools to assess PWSDs' quality of life, suffering, behaviors, functional status, resource utilization; and caregiver's satisfaction with care, awareness of prognosis, care preferences, resilience, coping, perceived burden, distress, positive aspects of caregiving, anticipatory grief, and bereavement adjustment. We also conduct qualitative in-depth interviews with a sub-sample of caregivers. The survey data is being linked with medical and billing records of PWSDs. The study has been approved by an ethics board. Results from the study will be disseminated through publications and presentations targeting researchers, policy makers and clinicians interested in understanding and improving EOL care for PWSDs and their caregivers.

As an important imaging method for long-range satellite targets, inverse synthetic aperture ladar (ISAL) has the characteristics of high-resolution imaging and competitive detectability. Since the working wavelength of the ISAL is comparable to the micro-vibrations generated by mechanical moving components of satellites, which will cause image defocusing, motion compensation is of great significance. In this paper, an autofocus algorithm is proposed for estimating and compensating the phase error relating to both translational and rotational micro-vibrations. Comparing with non-parametric algorithms like phase gradient autofocus and parametric algorithms like contrast-based autofocus and entropy-based autofocus, the proposed one, which is based on two prominent points, is especially effective for the rotational phase error oscillating numbers of cycles. Simulations and experiments are conducted to validate the feasibility of the proposed algorithm.

Gastrointestinal (GI) motility disorder is caused by excessive autophagy of the interstitial cells of Cajal (ICC). Chaihu Shugan Powder (CSP) is a traditional Chinese medicine with therapeutic benefits in GI motility disorders; however, the underlying mechanism of its therapeutic effect in GI disorders, especially autophagy of ICC, remains unclear. Thus, this study investigated the effects of CSP-contained serum on glutamate-induced autophagy in rat gastric ICC, exploring its underlying mechanism. In vitro cultured rat stomach ICC were identified by fluorescence microscopy and then stimulated with glutamate (5 mmol/L) for 3 h to establish the autophagy model. These cells were then treated with 10% CSP-containing serum or the autophagy inhibitor 3-methyladenine (3-MA; 5 mmol/L) for 24 h. The control group was cultured with only 10% serum containing physiological saline. The viability of ICC was measured by the CCK-8 assay. The ultrastructure and autophagosomes of ICC were observed using transmission electron microscopy. LC3 expression was detected by immunofluorescence, and LC3, Beclin1, Bcl2, and PI3KC3 expression was detected by western blot analysis. Transmission electron microscopy showed abundant endoplasmic reticulum, mitochondria, and other organelles in the control group, whereas the cells in the autophagy model control group had clear autophagic vacuoles, which were not apparent in both CSP and 3-MA groups. ICC viability was significantly increased by CSP and 3-MA interventions (P < 0.01), accompanied by a decrease in LC3 fluorescence (P < 0.01). Moreover, the expression levels of LC3II/I, Beclin1, and PI3KC3 were significantly decreased (all P < 0.01) with CSP and 3-MA treatment, while Bcl2 expression level was higher than that of the model group (P < 0.01). Thus, CSP can reduce autophagic damage by enhancing Bcl2 expression and downregulating the expression of LC3, Beclin1, and PI3KC3 to protect ICC. These results highlight the potential of CSP in the treatment of GI motility disorders.

Aims: Atherosclerosis is the most common cause of cardiovascular disease, such as myocardial infarction and stroke. Previous study revealed that microRNA (miR)-134 promotes lipid accumulation and proinflammatory cytokine secretion through angiopoietin-like 4 (ANGPTL4)/lipid lipoprotein (LPL) signaling in THP-1 macrophages., Methods: ApoE KO male mice on a C57BL/6 background were fed a high-fat/high-cholesterol Western diet, from 8 to 16 weeks of age. Mice were divided into four groups, and received a tail vein injection of miR-134 agomir, miR-134 antagomir, or one of the corresponding controls, respectively, once every 2 weeks after starting the Western diet. After 8 weeks we measured aortic atherosclerosis, LPL Activity, mRNA and protein levels of ANGPTL4 and LPL, LPL/ low-density lipoprotein receptor related protein 1 Complex Formation, proinflammatory cytokine secretion and lipid levels., Results: Despite this finding, the influence of miR-134 on atherosclerosis in vivo remains to be determined. Using the well-characterized mouse atherosclerosis model of apolipoprotein E knockout, we found that systemic delivery of miR-134 agomir markedly enhanced the atherosclerotic lesion size, together with a significant increase in proinflammatory cytokine secretion and peritoneal macrophages lipid contents. Moreover, overexpression of miR-134 decreased ANGPTL4 expression but increased LPL expression and activity in both aortic tissues and peritoneal macrophages, which was accompanied by increased formation of LPL/low-density lipoprotein receptor-related protein 1 complexes in peritoneal macrophages. However, an opposite effect was observed in response to miR-134 antagomir., Conclusions: These findings suggest that miR-134 accelerates atherogenesis by promoting lipid accumulation and proinflammatory cytokine secretion via the ANGPTL4/LPL pathway. Therefore, targeting miR-134 may offer a promising strategy for the prevention and treatment of atherosclerotic cardiovascular disease.

Arctiin, an important lignan compound in Fructus Arctii, has been reported to possess various kinds of bioactivities. Previous studies on the pharmacokinetic of arctiin after oral administration showed that it had a rapid absorption phase followed by a sharp but lasting disappearance. To gain deep insight into the action mechanism of arctiin, the excretion and metabolism of arctiin in vivo should be further studied. In this paper, three metabolites were isolated and identified in rat feces as (-)-enterolactone (M-1), (-)-arctigenin (M-2) and [(2R,3R)-2-(3'-hydroxybenzyl)-3-(3″,4″-dimethoxybenzyl)-butyrolactone] (M-3). Based on the structures of three metabolites, possible metabolic pathways of arctiin in rats are proposed. At the same time, the cumulative excretion rate of arctiin and its metabolites in rat urine and feces were determined, indicating that arctiin was excreted 19.84% in urine and 1.80% in feces, respectively, enterolactone, the most main metabolite, was excreted 35.80% in feces. These results provide very important information for understanding the metabolism and excretion of arctiin in vivo and speculating its action mechanism, they can provide useful information and reference for further metabolic investigations on arctiin in humans., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To determine the plasma protein binding rate of arctiin and arctigenin., Method: The ultrafiltration combined with HPLC was employed to determine the plasma protein binding rate of arctiin and arctigenin as well as rat plasma and healthy human plasma proteins., Result: The plasma protein binding rate of arctiin with rat plasma at the concentrations of 64. 29, 32.14, 16.07 mg x L(-1) were (71.2 +/- 2.0)%, (73.4 +/- 0.61)%, (78.2 +/- 1.9)%, respectively; while the plasma protein binding rate of arctiin with healthy human plasma at the above concentrations were (64.8 +/- 3.1)%, (64.5 +/- 2.5)%, (77.5 +/- 1.7)%, respectively. The plasma protein binding rate of arctigenin with rat plasma at the concentrations of 77.42, 38.71, 19.36 mg x L(-1) were (96.7 +/- 0.41)%, (96.8 +/- 1.6)%, (97.3 +/- 0.46)%, respectively; while the plasma protein binding rate of arctigenin with normal human plasma at the above concentrations were (94.7 +/- 3.1)%, (96.8 +/- 1.6)%, (97.9 +/- 1.3)%, respectively., Conclusion: The binding rate of arctiin with rat plasma protein was moderate, which is slightly higher than the binding rate of arctiin with healthy human plasma protein. The plasma protein binding rates of arctigenin with both rat plasma and healthy human plasma are very high.