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Background: This meta-analysis aimed to determine the incidence and overall risk of major adverse cardiovascular events (MACEs) related to immune checkpoint inhibitors (ICIs)., Methods: We systematically searched all cohort studies, including the available MACE data in cancer patients receiving ICIs, in PubMed, Embase, and the Cochrane Library, from their inception to September 5, 2023. The primary outcome was the incidence of MACEs associated with ICI exposure, and the secondary outcome was the overall risk of MACEs associated with ICI exposure versus non-ICI exposure controls. Risk ratios with 95% confidence intervals were used in the random- or fixed-effects models., Results: Overall, 26 cohort studies met the inclusion criteria, involving 109,883 cancer patients. In the median follow-up period ranging from 3.3 to 55.2 months, the incidence of MACEs associated with ICI exposure was 8.22%, ranging from 0.55% to 3.98%, among the nine MACEs, including myocarditis, tachyarrhythmia, pericarditis, pericardial effusions, cardiovascular death, myocardial infarction, heart failure, stroke, and conduction disorder. The incidence of MACE associated with non-ICI exposure was 3.84%, ranging from 0.81% to 4.72%. The risks of all-grade MACEs and pericardial effusions were significantly higher in the ICI group than in the non-ICI controls. ICI treatment, age, male sex, and prior radiation therapy were significantly associated with MACEs., Conclusion: The risk of MACEs during ICI treatment in patients with cancer is more common than is currently recognized. ICI use is closely associated with an increased risk of MACEs. Patients at risk were older, male, and had a history of radiation therapy., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

NLR family member X1 (NLRX1) is an important member of the NOD-like receptor (NLR) family and plays unique roles in immune system regulation. Patients with hepatitis B virus (HBV) infection are more likely to have the NLRX1 mutation p.Arg707Cys than healthy individuals. It has been reported that NLRX1 increases the infection rate of HBV in HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). However, the role of NLRX1 mutation (p.Arg707Cys) in hepatitis remains unclear. We constructed Huh7 cells that stably overexpressed NTCP, using LV003 lentivirus. First, wild-type (WT) and mutant (MT) NLRX1 overexpression plasmids were constructed. The MT plasmid contained a point mutation at position 707 of the WT overexpression plasmid. Then, Huh7-NTCP cells were transfected with the WT or MT NLRX1 overexpression plasmid, and subsequent NLRX1 expression was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. HBV RNA levels were determined using RT-qPCR. HBsAg and HBcAg levels were confirmed immunohistochemically. Interferon alpha (IFN-α), interleukin 6 (IL-6), and type I interferon beta (IFN-β) levels were determined using enzyme-linked immunosorbent assay kits. p-p65, p-interferon regulatory factor (IRF) 3, and p-IRF7 expression levels were examined using western blot. The interaction of NLRX1 and retinoic acid-inducible gene (RIG)-1/mitochondrial antiviral signaling (MAVS) protein was confirmed by coimmunoprecipitation. The interaction of NLRX1 with IFN-α, IL-6, or IFN-β was analyzed by dual luciferase reporter gene assay. The levels of HBV RNA, HBsAg, and HBcAg in infected cells transfected with the WT NLRX1 or MT NLRX1 expression plasmid were higher than those in the untransfected control group; and these levels were lower in the cells transfected with MT NLRX1 than in those transfected with WT NLRX1. The levels of IFN-α, IFN-β, IL-6, p-p65, p-IRF3, and p-IRF7 were lower in cells transfected with WT NLRX1 or MT NLRX1 than in control cells. The levels of IFN-β, p-p65, p-IRF3, and p-IRF7 were higher in cells transfected with MT NLRX1 than in those transfected with WT NLRX1. Moreover, NLRX1 competitively inhibited RIG1 binding to MAVS, but the mutation in MT NLRX1 reduced this inhibitory effect. In addition, NLRX1 decreased the promoter activity of IFN-α, IFN-β, and IL-6. Our findings revealed that NLRX1 is a regulatory factor that inhibits the anti-HBV ability of hepatocytes and that the mutation p.Arg707Cys in NLRX1 suppresses HBV infection and activates the IFN/nuclear factor κB pathway., (© 2024. The Author(s).)

The growing global interest in preventing and controlling fires in high-rise buildings reflects the increasing significance of this issue today. This research aims to establish an early warning framework for fire risk in high-rise buildings. Firstly, considering the importance of a scientific indicator system for the application of the model, this study combines the event analysis method with the building design fire code to identify 11 key risk factors that have a far-reaching impact on the prevention of fires in high-rise buildings. Based on identifying the risk factors, a high-rise building fire risk warning tree is also established, which scientifically solves the problem of the indicator system of the warning object. Subsequently, in response to the various complex issues arising from the uncertainty of fire occurrence in high-rise buildings, this study adopts the unascertained method to model the fire risk of high-rise buildings for early warning. In addition, the developed methodology was empirically validated through case studies and analyses of empirical data on fire risks in nine representative high-rise buildings. The results of the unascertained method were also compared with the results of the K-means method, from which it was concluded that the unascertained method can predict building fires more accurately. The research results provide a reliable decision support system for fire disaster prevention and control in high-rise buildings., (© 2024. The Author(s).)

Parkinson's disease (PD) is a prevalent and advancing age-related neurodegenerative disorder, distinguished by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Iron regional deposit in SNpc is a significant pathological characteristic of PD. Brain iron homeostasis is precisely regulated by iron metabolism related proteins, whereas disorder of these proteins can damage neurons and glial cells in the brain. Additionally, growing studies have reported iron metabolism related proteins are involved in the ferroptosis progression in PD. However, the effect of these proteins in the ferroptosis of PD has not been systematically summarized. This review focuses on the roles of iron metabolism related proteins in the ferroptosis of PD. Finally, we put forward the iron early diagnosis according to the observation of iron deposits in the brain and showed the recent advances in iron chelation therapy in PD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In Parkinson's disease (PD), exogenous ghrelin protects dopaminergic neurons through its receptor, growth hormone secretagogue receptor (GHSR). However, in contrast to the strikingly low levels of ghrelin, GHSR is highly expressed in the substantia nigra (SN). What role does GHSR play in dopaminergic neurons is unknown. In this study, using GHSR knockout mice (Ghsr -/- mice) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model, we found that GHSR deletion aggravated dopaminergic neurons degeneration, and the expression and activity of GHSR were significantly reduced in PD. Furthermore, we explored the potential mechanism that GHSR deficiency aggregated PD-related neurodegeneration. We showed that DEPTOR, a subunit of mTORC1, was overexpressed in Ghsr -/- mice, positively regulating autophagy and enhancing autophagy initiation. The expression of lysosomal markers was abnormal, implying lysosomal dysfunction. As a result, the damaged mitochondria could not be effectively eliminated, which ultimately exacerbated the injury of nigral dopaminergic neurons. In particular, we demonstrated that DEPTOR could be transcriptionally regulated by KLF4. Specific knockdown of KLF4 in dopaminergic neurons effectively alleviated neurodegeneration in Ghsr -/- mice. In summary, our results suggested that endogenous GHSR deletion-compromised autophagy by impairing lysosomal function, is a key contributor to PD, which provided ideas for therapeutic approaches involving the manipulation of GHSR., Competing Interests: Declaration of competing interest The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in the misregulation of iron metabolism and subsequent neurodegeneration. However, growing evidence showed that the levels of IRP2 were increased in the substantia nigra (SN) in MPTP-induced PD mice. To further clarify the role of increased IRP2 in PD, we developed IRP2-overexpressed mice by microinjecting AAV-Ireb2 in the SN. These mice showed decreased motor ability, abnormal gait and anxiety. Iron deposits induced by increased TFR1 and dopaminergic neuronal loss were observed in the SN. When these mice were treated with MPTP, exacerbated dyskinesia and dopaminergic neuronal loss were observed. In addition, TP53 was post-transcriptionally upregulated by IRP2 binding to the iron regulated element (IRE) in its 3' untranslated region. This resulted in increased lipid peroxidation levels and induced ferroptosis through the SLC7A11-ALOX12 pathway, which was independent of GPX4. This study revealed that IRP2 homeostasis in the SN was critical for PD progression and clarified the molecular mechanism of ferroptosis caused by IRP2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: To investigate the effectiveness of the intervention with critical value management and push short messaging service (SMS), and to determine improvement in the referral rate of patients with positive hepatitis C antibody (anti-HCV)., Methods: No intervention was done for patients with positive anti-HCV screening results from 1 January 2015 to 31 October 2021. Patients with positive anti-HCV results at our hospital from 1 November 2021 to 31 July 2022 were informed vide critical value management and push SMS. For inpatients, a competent physician was requested to liaise with the infectious disease physician for consultation, and patients seen in the OPD (outpatient department) were asked to visit the liver disease clinic. The Chi-square correlation test, one-sided two-ratio test and linear regression were used to test the relationship between intervention and referral rate., Results: A total of 638,308 cases were tested for anti-hepatitis C virus (HCV) in our hospital and 5983 of them were positive. 51.8% of the referred patients were aged 18-59 years and 10.8% were aged ≥75 years. The result of Chi-square correlation test between intervention and referral was p  = .0000, p  < .05. One-sided two-ratio test was performed for statistics of pre-intervention referral rate ( p 1) and post-intervention referral rate ( p 2). Normal approximation and Fisher's exact test for the results obtained were 0.000, p  < .05, and the alternative hypothesis p 1 -  p 2  < 0 was accepted. The linear regression equation was referral = 0.1396 × intervention + 0.3743, and the result model p  = 8.79e - 09, p  < .05. The model was significant, and the coefficient of intervention was 0.1396., Conclusions: The interventions of critical value management and push SMS were correlated with the referral rate of patients with positive anti-HCV.

Apolipoprotein D (ApoD), a lipocalin transporter of small hydrophobic molecules, plays an essential role in several neurodegenerative diseases. It was reported that increased immunostaining for ApoD of glial cells surrounding dopaminergic (DAergic) neurons was observed in the brains of Parkinson's disease (PD) patients. Although preliminary findings supported the role of ApoD in neuroprotection, its derivation and effects on the degeneration of nigral DAergic neurons are largely unknown. In the present study, we observed that ApoD levels released from astrocytes were increased in PD models both in vivo and in vitro. When co-cultured with astrocytes, due to the increased release of astrocytic ApoD, the survival rate of primary cultured ventral midbrain (VM) neurons was significantly increased with 1-methyl-4-phenylpyridillium ion (MPP + ) treatment. Increased levels of TAp73 and its phosphorylation at Tyr99 in astrocytes were required for the increased ApoD levels and its release. Conditional knockdown of TAp73 in the nigral astrocytes in vivo could aggravate the neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD mice. Our findings reported that astrocyte-derived ApoD was essential for DAergic neuronal survival in PD models, might provide new therapeutic targets for PD., (© 2024. The Author(s).)

α-Synuclein (α-Syn) is closely related to the pathogenesis of Parkinson's disease (PD). Under pathological conditions, the conformation of α-syn changes and different forms of α-syn lead to neurotoxicity. According to Braak stages, α-syn can propagate in different brain regions, inducing neurodegeneration and corresponding clinical manifestations through abnormal aggregation of Lewy bodies (LBs) and lewy axons in different types of neurons in PD. So far, PD lacks early diagnosis biomarkers, and treatments are mainly targeted at some clinical symptoms. There is no effective therapy to delay the progression of PD. This review first summarized the role of α-syn in physiological and pathological states, and the relationship between α-syn and PD. Then, we focused on the origin, secretion, aggregation, propagation and degradation of α-syn as well as the important regulatory factors in these processes systematically. Finally, we reviewed some potential drug candidates for alleviating the abnormal aggregation of α-syn in order to provide valuable targets for the treatment of PD to cope with the occurrence and progression of this disease., Competing Interests: Declaration of Competing Interest The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Type 2 diabetes mellitus is a chronic metabolic disease characterized by insulin resistance, with high morbidity and mortality worldwide. Due to the tightly intertwined connection between the insulin resistance pathway and the PI3K/AKT signaling pathway, regulating the PI3K/AKT pathway and its associated targets is essential for hypoglycemia and the prevention of type 2 diabetes mellitus. In recent years, metabolites isolated from traditional Chinese medicine has received more attention and acceptance for its superior bioactivity, high safety, and fewer side effects. Meanwhile, numerous in vivo and in vitro studies have revealed that the metabolites present in traditional Chinese medicine possess better bioactivities in regulating the balance of glucose metabolism, ameliorating insulin resistance, and preventing type 2 diabetes mellitus via the PI3K/AKT signaling pathway. In this article, we reviewed the literature related to the metabolites of traditional Chinese medicine improving IR and possessing therapeutic potential for type 2 diabetes mellitus by targeting the PI3K/AKT signaling pathway, focusing on the hypoglycemic mechanism of the metabolites of traditional Chinese medicine in type 2 diabetes mellitus and elaborating on the significant role of the PI3K/AKT signaling pathway in type 2 diabetes mellitus. In order to provide reference for clinical prevention and treatment of type 2 diabetes mellitus., 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 © 2024 Feng, Ren, Zhang, Yang, Jiao, Li and Jiang.)

Background: The skin is the largest organ in the human body, not only resisting the invasion of harmful substances, but also preventing the loss of moisture and nutrients. Maintaining skin homeostasis is a prerequisite for the proper functioning of the body. Any damage to the skin can lead to a decrease in local homeostasis, such as ultraviolet radiation, seasonal changes, and air pollution, which can damage the skin tissue and affect the function of the skin barrier., Objective: This article reviews the maintenance mechanism and influencing factors of skin homeostasis and the symptoms of homeostasis imbalance., Methods: We searched for articles published between 1990 and 2022 in English and Chinese using PubMed, Web of Science, CNKI, and other databases in the subject area of dermatology, using the following search terms in various combinations: "skin homeostasis," "skin barrier," and "unstable skin." Based on our results, we further refined our search criteria to include a series of common skin problems caused by the destruction of skin homeostasis and its treatments. Limitations include the lack of research on dermatological and cosmetic problems triggered by the disruption of skin homeostasis., Results: This study describes the neuroendocrine-immune system, skin barrier structure, and skin metabolic system that maintain skin homeostasis. In addition, we discuss several common symptoms that occur when skin homeostasis is out of balance, such as dryness, redness, acne, sensitivity, and aging, and explain the mechanism of these symptoms., Conclusion: This article provides an update and review for students and practitioners, and provides a theoretical basis for the development of skin care products for the maintenance and repair of skin homeostasis., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: The oxidative stress hypothesis is challenging the dominant position of amyloid-β (Aβ) in the field of understanding the mechanisms of Alzheimer's disease (AD), a complicated and untreatable neurodegenerative disease., Objective: The goal of the present study was to uncover the oxidative stress mechanisms causing AD, as well as the potential therapeutic targets and neuroprotective drugs against oxidative stress mechanisms., Methods: In this study, a systematic workflow combining pharmacological experiments and computational prediction was proposed. 222 drugs and natural products were collected first and then tested on SH-SY5Y cells to obtain phenotypic screening data on neuroprotection. The preliminary screening data were integrated with drug-target interactions (DTIs) and multi-scale biomedical data, which were analyzed with statistical tests and gene set enrichment analysis. A polypharmacology network was further constructed for investigation., Results: 340 DTIs were matched in multiple databases, and 222 cell viability ratios were calculated for experimental compounds. We identified significant potential therapeutic targets based on oxidative stress mechanisms for AD, including NR3C1, SHBG, ESR1, PGR, and AVPR1A, which might be closely related to neuroprotective effects and pathogenesis. 50% of the top 14 enriched pathways were found to correlate with AD, such as arachidonic acid metabolism and neuroactive ligand-receptor interaction. Several approved drugs in this research were also found to exert neuroprotective effects against oxidative stress mechanisms, including beclometasone, methylprednisolone, and conivaptan., Conclusion: Our results indicated that NR3C1, SHBG, ESR1, PGR, and AVPR1A were promising therapeutic targets and several drugs may be repurposed from the perspective of oxidative stress and AD.

Introduction: Chronic heart failure (CHF), as the final stage of the progression of many cardiovascular disorders, is one of the main causes of hospitalization and death in the elderly and has a substantial impact on patients' quality of life (QOL). Exercise-based cardiac rehabilitation (CR) has been shown to considerably enhance QOL and prognosis. Given the barriers to center-based CR faced by most developing countries in the form of expensive instruments, the development of home-based CR is necessary. Tai Chi, as an instrument-free exercise, has been shown to be successful in treating elderly CHF individuals. Fu Yang, as one of the academic concept of Traditional Chinese Medicine (TCM), believes that the fundamental pathogenesis of CHF is the gradual decline of Yang, and emphasizes the restoration of Yang physiological function in the treatment process. Therefore, we develope a home-based Tai Chi exercise rehabilitation program called Fu Yang Tai Chi (FYTC) for elderly CHF patients by combining the Fu Yang Theory of TCM with the CR theory. The objective of this study is to evaluate the effectiveness, acceptability, and safety of the program., Methods and Analysis: We suggest conducting a parallel randomized controlled clinical trial with open label. Eighty CHF elderly participants will be randomly assigned in a 1:1 ratio to the FYTC rehabilitation program group or the moderate-intensity aerobic walking control group. Eligible participants will engage in either three sessions weekly of FYTC or walking exercise for 12 weeks. The primary outcome is the relative change in 6 min walk distance (6MWD). The secondary outcomes are the plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), QOL, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDd), self-rating anxiety scale (SAS) and depression scale (SDS), exercise skills, and noninvasive hemodynamic monitoring. Throughout the trial, adverse events will be recorded for safety evaluation. Researchers who are blinded to the treatment allocation will analyze the data., Ethics and Dissemination: This research was authorized by the Guang'anmen Hospital Ethics Committee of the Chinese Academy of Medical Sciences (2022-141-KY). Our findings will be shared online and in academic conferences as well as in peer-reviewed journals., Trial Registration Number: ChiCTR2200063511., 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., (© 2023 Jiao, Meng, He, Li, Xu, Cui, Lou, Li, Ma, Sun, Wu and Li.)

Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D 2 R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D 2 R heterodimers in nigral dopaminergic neurons in Parkinson's disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D 2 R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP + or MPTP treatment. Application of QNP (10 μM) alone significantly increased the viability of MPP + -treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D 2 R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D 2 R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin., (© 2023. The Author(s).)

OTUD5 (OTU Deubiquitinase 5) is a functional cysteine protease with deubiquitinase activity and is a member of the ovarian tumor protease (OTU) family. OTUD5 is involved in the deubiquitination of many key proteins in various cellular signaling pathways and plays an important role in maintaining normal human development and physiological functions. Its dysfunction can affect physiological processes, such as immunity and DNA damage repair, and it can even lead to tumors, inflammatory diseases and genetic disorders. Therefore, the regulation of OTUD5 activity and expression has become a hot topic of research. A comprehensive understanding of the regulatory mechanisms of OTUD5 and its use as a therapeutic target for diseases is of great value. Herein, we review the physiological processes and molecular mechanisms of OTUD5 regulation, outline the specific regulatory processes of OTUD5 activity and expression, and link OTUD5 to diseases from the perspective of studies on signaling pathways, molecular interactions, DNA damage repair and immune regulation, thus providing a theoretical basis for future studies.

OTU domain-containing protein 3 (OTUD3) knockout mice exhibited loss of nigral dopaminergic neurons and Parkinsonian symptoms. However, the underlying mechanisms are largely unknown. In this study, we observed that the inositol-requiring enzyme 1α (IRE1α)-induced endoplasmic reticulum (ER) stress was involved in this process. We found that the ER thickness and the expression of protein disulphide isomerase (PDI) were increased, and the apoptosis level was elevated in the dopaminergic neurons of OTUD3 knockout mice. These phenomena were ameliorated by ER stress inhibitor tauroursodeoxycholic acid (TUDCA) treatment. The ratio of p-IRE1α/IRE1α, and the expression of X-box binding protein 1-spliced (XBP1s) were remarkably increased after OTUD3 knockdown, which was inhibited by IRE1α inhibitor STF-083010 treatment. Moreover, OTUD3 regulated the ubiquitination level of Fortilin through binding with the OTU domain. OTUD3 knockdown resulted in a decrease in the interaction ability of IRE1α with Fortilin and finally enhanced the activity of IRE1α. Taken together, we revealed that OTUD3 knockout-induced injury of dopaminergic neurons might be caused by activating IRE1α signaling in ER stress. These findings demonstrated that OTUD3 played a critical role in dopaminergic neuron neurodegeneration, which provided new evidence for the multiple and tissue-dependent functions of OTUD3.

As a member of the TRIM (tripartite motif) protein family, TRIM56 can function as an E3 ubiquitin ligase. In addition, TRIM56 has been shown to possess deubiquitinase activity and the ability to bind RNA. This adds to the complexity of the regulatory mechanism of TRIM56. TRIM56 was initially found to be able to regulate the innate immune response. In recent years, its role in direct antiviral and tumor development has also attracted the interest of researchers, but there is no systematic review on TRIM56. Here, we first summarize the structural features and expression of TRIM56. Then, we review the functions of TRIM56 in TLR and cGAS-STING pathways of innate immune response, the mechanisms and structural specificity of TRIM56 against different types of viruses, and the dual roles of TRIM56 in tumorigenesis. Finally, we discuss the future research directions regarding TRIM56.

Nitric oxide (NO) is a crucial factor in regulating neuronal development. However, certain effects of NO are complex under different physiological conditions. In this study, we used differentiated neural stem cells (NSCs), which contained neural progenitor cells, neurons, astrocytes, and oligodendrocytes, to observe the physiological effects of sodium nitroprusside (SNP) on the early developmental stage of the nervous system. After SNP treatment for 24 h, the results showed that SNP at 100 μM, 200 μM, 300 μM, and 400 μM concentrations resulted in reduced cell viability and increased cleaved caspase 3 levels, while no significant changes were found at 50 μM. There were no effects on neuronal differentiation in the SNP-treated groups. The phosphorylation of p38 was also significantly upregulated with SNP concentrations of 100 μM, 200 μM, 300 μM, and 400 μM, with no changes for 50 μM concentration in comparison with the control. We also observed that the levels of phosphorylation increased with the increasing concentration of SNP. To further explore the possible role of p38 in SNP-regulated survival of differentiated NSCs, SB202190, the antagonist of p38 mitogen-activated protein kinase, at a concentration of 10 mM, was pretreated for 30 min, and the ratio of phosphorylated p38 was found to be decreased after treatment with SNP. Survival and cell viability increased in the SB202190 and SNP co-treated group. Taken together, our results suggested that p38 is involved in the cell survival of NSCs, regulated by NO.

Fermented organic fertilizers made from pig manure contaminated with antibiotics are widely used in fruit tree production. However, their effects on the residual antibiotics and the spread of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) in apple orchards are still largely unknown. In the present study, we detected 100 ARGs and 10 MGEs that were transferred from pig manure to an apple orchard. Compared with the original pig manure, significantly greater concentrations of tetracycline, chlortetracycline, oxytetracycline, sulfadiazine, and salfamethyldiazine were observed in anaerobic fermentation residues of the pig manure. The total relative abundance levels of ARGs on the apple pericarp surface, in the orchard soil treated with biogas slurry, and in the orchard soil treated with biogas residue were 122.5, 5.2, 1.4 times higher than those in pristine soil, respectively, which were primarily attributed to the increase in the relative abundance of some ARG subtypes, including blaCTX-M, blaTEM, ermC, sul2, tetO, vgaB, and vgb. Long-term biogas slurry and biogas residue applications to orchard soil enriched bioaccumulation of 10 ARGs and 1 MGEs on the apple pericarp surface with 67.98 the highest factor. This research indicates that the application of anaerobic fermentation residues of pig manure promoted the spread of ARGs in the soil and fruits and increased the level of ARG pollution in the orchard. Results of this study highlight the importance of assessing the ecological safety of organic fertilizers from the perspective of ARGs and indicate that efforts should be devoted to further reducing ARG levels in pig manure before its application to farmland., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Therapeutic strategies based on neural stem cells (NSCs) transplantation bring new hope for neural degenerative disorders, while the biological behaviors of NSCs after being grafted that were affected by the host tissue are still largely unknown. In this study, we engrafted NSCs that were isolated from a rat embryonic cerebral cortex onto organotypic brain slices to examine the interaction between grafts and the host tissue both in normal and pathological conditions, including oxygen-glucose deprivation (OGD) and traumatic injury. Our data showed that the survival and differentiation of NSCs were strongly influenced by the microenvironment of the host tissue. Enhanced neuronal differentiation was observed in normal conditions, while significantly more glial differentiation was observed in injured brain slices. The process growth of grafted NSCs was guided by the cytoarchitecture of host brain slices and showed the distinct difference between the cerebral cortex, corpus callosum and striatum. These findings provided a powerful resource for unraveling how the host environment determines the fate of grafted NSCs, and raise the prospect of NSCs transplantation therapy for neurological diseases.

Inositol-requiring enzyme 1 α (IRE1α) is a type I transmembrane protein that resides in the endoplasmic reticulum (ER). IRE1α, which is the primary sensor of ER stress, has been proven to maintain intracellular protein homeostasis by activating X-box binding protein 1 (XBP1). Further studies have revealed novel physiological functions of the IRE1α, such as its roles in mRNA and protein degradation, inflammation, immunity, cell proliferation and cell death. Therefore, the function of IRE1α is not limited to its role in ER stress; IRE1α is also important for regulating other processes related to cellular physiology. Furthermore, IRE1α plays a key role in neurodegenerative diseases that are caused by the phosphorylation of Tau protein, the accumulation of α-synuclein (α-syn) and the toxic effects of mutant Huntingtin (mHtt). Therefore, targeting IRE1α is a valuable approach for treating neurodegenerative diseases and regulating cell functions. This review discusses the role of IRE1α in different cellular processes, and emphasizes the importance of IRE1α in neurodegenerative diseases., Competing Interests: Conflict of interests The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The prevalence and mortality rates of cardiovascular diseases are increasing, and new treatment strategies are urgently needed. From the perspective of basic pathogenesis, the occurrence and development of cardiovascular diseases are related to inflammation, apoptosis, fibrosis and autophagy of cardiomyocytes, endothelial cells and other related cells. The involvement of maternally expressed gene 3 (MEG3) in human disease processes has been increasingly reported. P53 and PI3K/Akt are important pathways by which MEG3 participates in regulating cell apoptosis. MEG3 directly or competitively binds with miRNA to participate in apoptosis, inflammation, oxidative stress, endoplasmic reticulum stress, EMT and other processes. LncRNA MEG3 is mainly involved in malignant tumors, metabolic diseases, immune system diseases, cardiovascular and cerebrovascular diseases, etc., LncRNA MEG3 has a variety of pathological effects in cardiomyocytes, fibroblasts and endothelial cells and has great clinical application potential in the prevention and treatment of AS, MIRI, hypertension and HF. This paper will review the research progress of MEG3 in the aspects of mechanism of action, other systemic diseases and cardiovascular diseases, and point out its great potential in the prevention and treatment of cardiovascular diseases. lncRNAs also play a role in endothelial cells. In addition, lncRNA MEG3 has shown biomarker value, prognostic value and therapeutic response measurement in tumor diseases. We boldly speculate that MEG3 will play a role in the emerging discipline of tumor heart disease., 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, Gao, Sun, Jiao, Ma, Cui, Lou, Xu, Li and Li.)

Mitochondria dysfunction has been defined as one of the hallmarks of aging-related diseases as is characterized by the destroyed integrity, abnormal distribution and size, insufficient ATP supply, increased ROS production, and subsequently damage and oxidize the proteins, lipids and nucleic acid. Mitophagy, an efficient way of removing damaged or defective mitochondria by autophagy, plays a pivotal role in maintaining the mitochondrial quantity and quality control enabling the degradation of unwanted mitochondria, and thus rescues cellular homeostasis in response to stress. Accumulating evidence demonstrates that impaired mitophagy has been associated with many neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) in a variety of patients and disease models with neural death, oxidative stress and disturbed metabolism, either as the cause or consequence. These findings suggest that modulation of mitophagy may be considered as a valid therapeutic strategy in neurodegenerative diseases. In this review, we summarize recent findings on the mechanisms of mitophagy and its role in neurodegenerative diseases, with a particular focus on mitochondrial proteins acting as receptors that mediate mitophagy in these diseases., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Ghrelin contributes to the communication between the brain and gastrointestinal (GI) tract. Both decreased ghrelin levels and functional GI disorders are early events in Parkinson's disease (PD) patients and animal models. However, the reason is not clear. Here it is found that choline acetyltransferase (ChAT)-positive neurons in the dorsal motor nucleus of the vagus nerve (DMV), are lost in PD transgenic mice. In response to the selective damaging of DMV neurons with mu p75-SAP, a rapid reduction both in plasma total and active ghrelin levels is observed. While by contrast, chemogenetic activation of DMV cholinergic neurons can increase the plasma ghrelin levels. Impairment of cholinergic neurons is accompanied by GI disorders, including decreased stool wet weight, stool dry weight, small intestine advancing rate, and gastric emptying rate, while exogenous ghrelin treatment can partially ameliorate GI dysfunction of A53T α-synuclein transgenic mice. Using pseudorabies virus retrograde trace method, the existence of a direct pathway from the stomach fundus to the DMV is shown. Taken together, the findings suggest that the reduction in plasma ghrelin levels in the early stages of PD may be the result of the lesion of cholinergic neurons in the DMV, thus linking neurodegeneration and GI dysfunction in PD., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

ATP-sensitive potassium channels (K ATP channels), a group of vital channels that link the electrical activity of the cell membrane with cell metabolism, were discovered on the ventricular myocytes of guinea pigs by Noma using the patch-clamp technique in 1983. Subsequently, K ATP channels have been found to be expressed in pancreatic β cells, cardiomyocytes, skeletal muscle cells, and nerve cells in the substantia nigra (SN), hippocampus, cortex, and basal ganglia. K ATP channel openers (KCOs) diazoxide, nicorandil, minoxidil, and the K ATP channel inhibitor glibenclamide have been shown to have anti-hypertensive, anti-myocardial ischemia, and insulin-releasing regulatory effects. Increasing evidence has suggested that K ATP channels also play roles in Alzheimer's disease (AD), Parkinson's disease (PD), vascular dementia (VD), Huntington's disease (HD) and other neurodegenerative diseases. KCOs and K ATP channel inhibitors protect neurons from injury by regulating neuronal excitability and neurotransmitter release, inhibiting abnormal protein aggregation and Ca 2+ overload, reducing reactive oxygen species (ROS) production and microglia activation. However, K ATP channels have dual effects in some cases. In this review, we focus on the roles of K ATP channels and their related openers and inhibitors in neurodegenerative diseases. This will enable us to precisely take advantage of the K ATP channels and provide new ideas for the treatment of neurodegenerative diseases., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: To validate that dexlansoprazole, an anti-acid drug, can prevent pulmonary artery hypertension (PAH) in preclinical animal models and find the possible mechanism of action of dexlansoprazole for this new indication., Methods: The efficacy of dexlansoprazole to attenuate PAH in vivo was evaluated in PAH animal models. Plasma guanosine 3', 5'-cyclic phosphate (cGMP) in PAH rats was measured by enzyme linked immunosorbent assay (ELISA). To investigate the anti-PAH effect of dexlansoprazole in vitro, proliferation and migration assays of primary cultured pulmonary artery smooth muscle cells (PASMCs) were performed. Furthermore, dexlansoprazole's function on fibroblast transition of vascular smooth muscle cells (VSMC) was explored by single cell ribonucleic acid (RNA) sequencing and RNAscope., Results: Dexlansoprazole could attenuate the pathologic process in monocrotaline (MCT)-, hypoxia-induced PAH rats and SU5416/hypoxia (SuHy)-induced PAH mice. The intervention with dexlansoprazole significantly inhibited elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular wall thickness. Furthermore, plasma cGMP in MCT-induced PAH rats was restored after receiving dexlansoprazole. In vitro, dexlansoprazole could inhibit PASMCs' proliferation and migration stimulated by platelet derived growth factor-BB (PDGF-BB). Moreover, dexlansoprazole significantly ameliorated pulmonary vascular remodeling by inhibiting VSMC phenotypic transition to fibroblast-like cells in a VSMC-specific multispectral lineage-tracing mouse., Conclusions: Dexlansoprazole can prevent PAH through promoting cGMP generation and inhibiting pulmonary vascular remodeling through restraining PASMCs' proliferation, migration, and phenotypic transition to fibroblast-like cells. Consequently, PAH might be a new indication for dexlansoprazole., Competing Interests: None., (AJTR Copyright © 2022.)

Ferroptosis is defined as an iron-dependent, non-apoptotic cell death pathway, with specific morphological phenotypes and biochemical changes. There is a growing realization that ferroptosis has significant implications for several neurodegenerative diseases. Even though ferroptosis is different from other forms of programmed death such as apoptosis and autophagic death, they involve a number of common protein molecules. This review focuses on current research on ferroptosis and summarizes the cross-talk among ferroptosis, apoptosis, and autophagy that are implicated in neurodegenerative diseases. We hope that this information provides new ideas for understanding the mechanisms and searching for potential therapeutic approaches and prevention of neurodegenerative diseases., (© 2022. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Background: Stratum corneum is located in the outermost layer of the skin and is the most important part of the skin barrier. Stratum corneum mainly contains keratinocytes, lipids, and desmosomes. Their normal metabolic process is closely related to the function of skin barrier., Aims: This paper reviews the structure and function of stratum corneum, influencing factors, skin diseases, and common solutions., Methods: An extensive literature search was conducted on the structure and function of stratum corneum, influencing factors, skin diseases, and common solutions., Results: This paper reviews the structure and function of stratum corneum and the influence of various factors on stratum corneum metabolism. At the same time, the existing skin problems, skin diseases, and common solutions are summarized., Conclusions: This information will help to understand the function, molecular mechanism, and influencing factors of stratum corneum metabolism, and provide new ideas for stratum corneum health management and cosmetic research and development., (© 2022 Wiley Periodicals LLC.)

Objective: The present study aims to explore the effects of different numbers of fiberoptic bronchoscopic examinations on the nosocomial infection/colonization of carbapenem-resistant Enterobacteriaceae (CRE)., Methods: The data of 129 patients admitted to the intensive care unit of a grade 3A hospital were retrospectively analyzed, and CRE nosocomial infection/colonization situations in patients with fiberoptic bronchoscope application times of 1, 2, 3, and ≥4 were statistically analyzed., Results: The incidence of nosocomial infection/colonization of CRE increased significantly when the number of fiberoptic bronchoscopic examinations was ≥3., Conclusion: Nosocomial infection/colonization of CRE is highly correlated with an increased number of fiberoptic bronchoscopic examinations., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Wang et al.)

Accumulating evidence suggests that ATP-sensitive potassium (K ATP ) channels play an important role in the selective degeneration of dopaminergic neurons in the substantia nigra (SN). Furthermore, the expression of the K ATP channel subunit sulfonylurea receptor 1 (SUR1) is upregulated in the remaining nigral dopaminergic neurons in Parkinson's disease (PD). However, the mechanism underlying this selective upregulation of the SUR1 subunit and its subsequent roles in PD progression are largely unknown. In 3-, 6-, and 9-month-old A53T α-synuclein transgenic (α-SynA53T +/+ ) mice, only the SUR1 subunit and not SUR2B or Kir6.2 was upregulated, accompanied by neuronal damage. Moreover, the occurrence of burst firing in dopaminergic neurons was increased with the upregulation of the SUR1 subunit, whereas no changes in the firing rate were observed except in 9-month-old α-SynA53T +/+ mice. After interference with SUR1 expression by injection of lentivirus into the SN, the progression of dopaminergic neuron degeneration was delayed. Further studies showed that elevated expression of the transcription factors FOXA1 and FOXA2 could cause the upregulation of the SUR1 subunit in α-SynA53T +/+ mice. Our findings revealed the regulatory mechanism of the SUR1 subunit and the role of K ATP channels in the progression of dopaminergic neuron degeneration, providing a new target for PD drug therapy., (© 2022 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Iron deposits are neuropathological hallmark of Parkinson's disease (PD). Iron regulatory protein 2 (IRP2) is a key factor in regulating brain iron homeostasis. Although two ubiquitin ligases that promote IRP2 degradation have been identified, the deubiquitylase for stabilization of IRP2 in PD remains undefined. Here, we report OTUD3 (OTU domain-containing protein 3) functions as a deubiquitylase for IRP2, interacts with IRP2 in the cytoplasm, de-polyubiquitylates, and stabilizes IRP2 protein in an iron-independent manner. Depletion of OTUD3 results in a disorder of iron metabolism. OTUD3 knockout mice display nigral iron accumulation, motor deficits, and nigrostriatal dopaminergic neurodegeneration, which resembles the pathology of PD. Consistently, decreased levels of OTUD3 are detected in transgenic PD mice expressing A53T mutant of human α-synuclein. Five single nucleotide polymorphism mutations of OTUD3 are present in cases of sporadic PD or controls, although no significant associations of OTUD3 SNPs with sporadic PD are detected. Taken together, these findings demonstrate that OTUD3 is a bona fide deubiquitylase for IRP2 and plays a critical role in the nigral iron deposits in PD., (© 2022. The Author(s).)

Objective: To analyze and summarize the clinical efficacy and safety of lymphocyte apheresis combined with plasma exchange in the treatment of patients with hepatitis B virus-related liver failure at the ascending stage., Methods: A observational study was conducted. A total of 69 hepatitis B virus-related liver failure at the ascending stage patients who were hospitalized at Affiliated Guangzhou Eighth People's Hospital of Guangzhou Medical University from January 2016 to December 2020 were enrolled in this study. The patients were grouped according to their condition and wishes, including 38 patients treated with conservative medical treatment (control group) and 31 patients treated with lymphocyte apheresis combined with plasma exchange based on comprehensive medical treatment (study group). Clinical data were compared between the two groups 1-4 weeks after treatment, including dynamic changes of total bilirubin (TBil), international normalized ratio (INR), alanine aminotransferase (ALT), model for end-stage liver disease (MELD) score, and the rate of clinical improvement at 4 weeks after treatment. In addition, the adverse effects and dynamic changes of white blood cell count (WBC), lymphocyte count (LYM), platelet count (PLT), and hemoglobin (Hb) within 4 weeks after treatment were compared between the two groups., Results: Both groups showed significant improvement in clinical parameters after 1-4 weeks of initiation of therapy. The improvement of TBil, INR and MELD score at 1-4 weeks after treatment were significantly better in the treatment group than those in the control group [TBil (μmol/L): 248 (117, 335) vs. 398 (328, 464) at 1 week, 173 (116, 278) vs. 326 (184, 476) at 2 weeks, 107 (84, 235) vs. 355 (129, 467) at 3 weeks, 70 (61, 172) vs. 290 (82, 534) at 4 weeks; INR: 1.72±0.70 vs. 2.13±0.69 at 1 week, 1.67±0.61 vs. 2.28±1.35 at 2 weeks, 1.65±0.75 vs. 2.15±0.92 at 3 weeks, 1.61±0.93 vs. 2.19±1.17 at 4 weeks; MELD score: 18.35±5.32 vs. 23.38±4.56 at 1 week, 16.47±5.16 vs. 23.71±7.94 at 2 weeks, 16.30±5.75 vs. 22.64±6.99 at 3 weeks, 14.63±6.76 vs. 20.97±8.19 at 4 weeks], with significant differences (all P < 0.05). In addition, ALT levels at 1 week and 2 weeks after treatment in the study group were significantly lower than those in the control group [U/L: 128 (93, 206) vs. 240 (167, 436) at 1 week, 64 (42, 110) vs. 85 (69, 143) at 2 weeks, both P < 0.05]. The rate of clinical improvement at 4 weeks after treatment in the study group was 54.84% (17/31), which was significantly higher than that in the control group [28.95% (11/38)], with statistically significant difference (P < 0.05). There was no significant difference in the rate of new infection between the study group and the control group [22.58% (7/31) vs. 34.21% (13/38), P > 0.05]. Additionally, expect that the PLT level at 1 week after treatment in the study group was significantly lower than that in the control group (×10 9 /L: 101±42 vs. 128±59, P < 0.01), there was no significant difference in WBC, LYM or Hb at different time points after treatment between the two groups., Conclusions: Clinical efficacy of lymphocyte apheresis combined with plasma exchange based on comprehensive medical treatment in the treatment of patients with hepatitis B virus-related liver failure at the ascending stage is superior to conservative medical treatment alone, which can improve clinical improvement rate and recovery rate of liver function with high safety.

Ghrelin was first identified as an endogenous ligand of the growth hormone secretagogue receptor (GHSR) in 1999, with the function of stimulating the release of growth hormone (GH), while nesfatin-1 was identified in 2006. Both peptides are secreted by the same kind of endocrine cells, X/A-like cells in the stomach. Compared with ghrelin, nesfatin-1 exerts opposite effects on energy metabolism, glucose metabolism, gastrointestinal functions and regulation of blood pressure, but exerts similar effects on anti-inflammation and neuroprotection. Up to now, nesfatin-1 remains as an orphan ligand because its receptor has not been identified. Several studies have shown the effects of nesfatin-1 are dependent on the receptor of ghrelin. We herein compare the effects of nesfatin-1 and ghrelin in several aspects and explore the possibility of their interactions., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Iron regulatory proteins (IRPs) and iron regulatory element (IRE) systems are well known in the progression of neurodegenerative disorders by regulating iron related proteins. IRPs are also regulated by iron homeostasis. However, an increasing number of studies have suggested a close relationship between the IRPs/IRE system and non-iron-related neurodegenerative disorders. In this paper, we reviewed that the IRPs/IRE system is not only controlled by iron ions, but also regulated by such factors as post-translational modification, oxygen, nitric oxide (NO), heme, interleukin-1 (IL-1), and metal ions. In addition, by regulating the transcription of non-iron related proteins, the IRPs/IRE system functioned in oxidative metabolism, cell cycle regulation, abnormal proteins aggregation, and neuroinflammation. Finally, by emphasizing the multiple regulations of IRPs/IRE system and its potential relationship with non-iron metabolic neurodegenerative disorders, we provided new strategies for disease treatment targeting IRPs/IRE system., (Copyright © 2021. Published by Elsevier B.V.)

Iron overload can induce oxidative stress, thereby inducing cell peroxidation. Arachidonic acid (ARA) is widely expressed in mammalian cells and esterified to membrane phospholipids. To explore the effect of iron overload on the metabolism of membrane phospholipids MES23.5 cells were treated with various concentrations of ferric ammonium citrate (FAC) to induce oxidative stress. Using UHPLC (I-Class LC, Waters) coupled to a QTRAP (AB Sciex 5500) technology, the contents of 13 substances of ARA and its metabolites were detected. When the cells were given two different concentrations of FAC, we found that both high and low concentrations decrease the expression of ARA (p=0.002, p=0.02) compared with the control group. ARA has three metabolic pathways: the COX pathway, LOX pathway and CYP450 pathway. Compared with the control group, the LTB4 content in the LOX pathway was decreased (p=0.10) after treatment with lowconcentration FAC, while the LTB4 content was increased in the high-concentration treatment group (p=0.06). However, the content of 12S-HETE (p=0.23, p=0.05) in the LOX metabolic pathway decreased with increase of FAC concentration. Similarly, the content of 15S-HETE also decreased with increase of FAC concentration (p=0.17, p=0.02). The other downstream metabolites of ARA, 9S-HODE (p=0.54, p=0.18) and 13S-HODE (p=0.81, p=0.13) were not significantly changed. The contents of thromboxane B2 (TXB2), leukotriene D4 (LTD4), prostaglandin E2 (PGE2), 8-iso-prostaglandin F2α (8-iso-PGF2α), prostaglandin F2α (PGF2α), 6-keto-PGF1α, and prostaglandin D2 (PGD2) were too low to be detected in MES23.5 cells. The above results indicate that oxidative stress caused by iron overload reduces the LOX metabolic pathway of ARA.

Parkinson's disease (PD) is characterized by the accumulation of alpha-synuclein (α-Syn) in the substantia nigra (SN) and the degeneration of nigrostriatal dopaminergic (DAergic) neurons. Some studies have reported that the pathology of PD originates from the gastrointestinal (GI) tract, which also serves as an energy portal, and develops upward along the neural pathway to the central nervous system (CNS), including the dorsal motor nucleus of vagus (DMV), SN, and hypothalamus, which are also involved in energy metabolism control. Therefore, we discuss the alterations of nuclei that regulate energy metabolism in the development of PD. In addition, due to their anti-inflammatory, antiapoptotic and antioxidative roles, metabolism-related peptides are involved in the progression of PD. Furthermore, abnormal glucose and lipid metabolism are common in PD patients and exacerbate the pathological changes in PD. Therefore, in this review, we attempt to explain the correlation between PD and energy metabolism, which may provide possible strategies for PD treatment., Competing Interests: Conflicts of interest The authors disclose no potential conflicts of interest., (Copyright: © 2021 Liu et al.)

Long non-coding RNAs (lncRNAs) is a class of eukaryotic transcripts with length of more than 200 bp. They contribute to the regulation of gene expressions involved in multiple processes including the skin cell proliferation, differentiation, and reconstruction of the secondary hair follicles (SHFs). In this study, firstly, we identified 16 putative lncRNAs from SHFs of cashmere goat based on the EST sequences from NCBI database. Secondly, we investigated their transcriptional pattern in SHFs of cashmere goat, and constructed their ceRNA regulatory networks. The RT-qPCR results showed four lncRNAs (lncRNA-475074, -052149, -052140, and -051789) were significantly up-regulated, and nine lncRNAs (lncRNA-711032, -475083, -475070, -052139, -052127, -052037, -051903, -051847, and -051804) were significantly down-regulatd in anagen SHFs of cashmere goat. CeRNA networks analysis revealed complex interactional relationship among lncRNAs, miRNAs and mRNAs. Further, the KEGG pathway enrichment was performed for the potential target genes of the identified lncRNAs based on bioinformatics technique, and the results indicated that differentially expressed lncRNAs directly or indirectly might regulate potential target genes. Our results from this study will provide a significant information for further exploring the functions and possible mechanisms of the identified lncRNAs in SHFs of cashmere goat.

Aberrant α-synuclein (α-Syn) accumulation resulting from proteasome dysfunction is considered as a prominent factor to initiate and aggravate the neurodegeneration in Parkinson's disease (PD). Although the involvement of 26S proteasome in proteostasis imbalance has been widely accepted, our knowledge about the regulation of immunoproteasome function and its potential role in α-Syn pathology remains limited. Immunoproteasome abundance and proteolytic activities depend on the finely tuned assembly process, especially β-ring formation mediated by the only well-known chaperone proteasome maturation protein (POMP). Here, we identified that α-Syn overexpression was associated with a reduction in immunoproteasome function, which in turn limited the degradation of polo-like kinase 2 (PLK2), exacerbated α-Syn Ser129 phosphorylation and aggregation, ultimately leading to the neurodegeneration. These effects could be dramatically attenuated by β5i overexpression. Mechanistically, α-Syn suppressed the transcriptional regulation of POMP by nuclear factor erythroid 2-related factor 2 (NRF2), thereby preventing the assembly of immunoproteasome β subunits. Dopaminergic neurons-specific overexpression of NRF2-POMP axis effectively rescued the aggregation of α-Syn and PD-like phenotypes. These findings characterized abnormal immunoproteasome assembly as a key contributor governing α-Syn accumulation and neurodegeneration, which might open up a new perspective for the implication of immunoproteasome in PD and provide approaches of manipulating immunoproteasome assembly for therapeutic purposes., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: This study is aimed at the determination of the effect of the immune-regulatory factor NLRX1 on the antiviral activity of hepatocytes against an external stimuli favoring hepatitis B virus infection, and to explore its mechanism of action., Methods: A HepG2-NTCP model was established using the LV003 lentivirus. Cells were transfected using an overexpression vector and NLRX1 siRNA to achieve overexpression and interference of NLRX1 expression (OV-NLRX1, si-NLRX1). Levels of HBsAg and HBcAg were determined using Western blotting analysis and immunohistochemical analysis. The levels of hepatitis B virus DNA and hepatitis B virus cccDNA were determined by real-time quantitative polymerase chain reaction. The expression and transcriptional activity of IFN-α, IFN-β, and IL-6 were measured using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and promoter-luciferase reporter plasmids. Co-immunoprecipitation was used to determine the effect of NLRX1 on the interaction between MAVS and RIG-1. Western blotting was used to obtain the phosphorylation of essential proteins in the MAVS-RLRs signaling pathways., Results: NLRX1 promoted HepG2-NTCP cell hepatitis B virus infection. Compared to the control group, the levels of HBsAg, HBcAg, hepatitis B virus cccDNA, and hepatitis B virus DNA increased in the OV-NLRX1 group and decreased in the si-NLRX1. Co-immunoprecipitation results showed that NLRX1 competitively inhibited the interaction between MAVS and RIG-1, and inhibited the phosphorylation of p65, IRF3, and IRF7. Additionally, NLRX1 reduced the transcription activity and expression levels of the final products: IFN-α, IFN-β, and IL-6., Conclusions: NLRX1 can counteract innate immune response induced by an external stimuli favoring hepatitis B virus infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells. Inhibition of the MAVS-RLR-mediated signaling pathways leads to a decline in the expression levels of I-IFN and IL-6.

New neurons are generated throughout life in distinct regions of the mammalian brain due to the proliferation and differentiation of neural stem cells (NSCs). Ubiquitin, a post-translational modification of cellular proteins, is an important factor in regulating neurogenesis. Deubiquitination is a biochemical process that mediates the removal of ubiquitin moieties from ubiquitin-conjugated substrates. Recent studies have provided growing evidence that deubiquitylases (DUBs) which reverse ubiquitylation process play critical roles in NSCs maintenance, differentiation and maturation. This review mainly focused on the relationship of DUBs and NSCs, and further summarized recent advances in our understanding of DUBs on regulating NSCs biological behaviors., (© 2021 Wiley Periodicals LLC.)

Ghrelin has been identified as a multifunctional peptide that has a potential application for treating Parkinson's disease (PD). The objective of this study was to assess the effects of subcutaneous administration of low-dose ghrelin via miniosmotic pumps on PD progression. The decreased levels of total and active ghrelin in plasma were rescued by ghrelin administration in PD mice. Interestingly, ghrelin did not affect weight gain in wild-type mice but improved weight loss in PD mice. We observed the attenuation of dopaminergic neuron loss in substantia nigra and a low level of dopamine content in the striatum in PD mice with ghrelin treatment. Ghrelin administration could improve the microenvironment of dopaminergic neurons by inhibiting microglial proliferation and proinflammatory cytokine expression and could enhance cell survival by upregulating Bcl-2/Bax ratio and superoxide dismutase1 protein level in the substantia nigra of PD mice. Subcutaneous administration of low-dose ghrelin could prevent the onset of the progression of PD and also provide a possible method for ghrelin application to cure PD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Proteasome is the principal hydrolytic machinery responsible for the great majority of protein degradation. The past three decades have testified prominent advances about proteasome involved in almost every aspect of biological processes. Nonetheless, inappropriate increase or decrease in proteasome function is regarded as a causative factor in several diseases. Proteasome abundance and proper assembly need to be precisely controlled. Indeed, various neurodegenerative diseases including Parkinson's disease (PD) share a common pathological feature, intracellular protein accumulation such as α-synuclein. Proteasome activation may effectively remove aggregates and prevent the neurodegeneration in PD, which provides a potential application for disease-modifying treatment. In this review, we build on the valuable discoveries related to different types of proteolysis by distinct forms of proteasome, and how its regulatory and catalytic particles promote protein elimination. Additionally, we summarize the emerging ideas on the proteasome homeostasis regulation by targeting transcriptional, translational, and post-translational levels. Given the imbalanced proteostasis in PD, the strategies for intensifying proteasomal degradation are advocated as a promising approach for PD clinical intervention.

Rationale : Previous studies of coronavirus disease 2019 (COVID-19) were mainly focused on cross-sectional analysis. In this study, we sought to evaluate the dynamic changes of immunological and radiographic features, and the association with the outcome of pulmonary lesions in COVID-19 patients. Methods : Peripheral blood samples and radiographic data were collected longitudinally for up to 8 weeks from 158 laboratory-confirmed COVID-19 patients. The chest computed tomography (CT) scans were scored based on a semi-quantification assessment according to the extent of pulmonary abnormalities; the temporal change of the immunological and radiographic features was analyzed. Results: Compared with mild and moderate patients, severe patients had significantly decreased counts of lymphocytes, CD4 + T cells, CD8 + T cells, and CD19 + B cells but dramatically elevated counts of neutrophils and levels of interleukin (IL)-6. Sequential monitoring showed a sustained increase in lymphocytes counts and significantly decreased levels of IL-6 in severe patients during the disease course. Notably, patients with persistent pulmonary lesions (CT score ≥ 5 in week 8) showed high levels of IL-6 during the follow-up period, compared with those with recovery lesions (CT score < 5 in week 8). More importantly, the peak expression of IL-6 prior to the aggravated lung injury was mainly found in patients with persistent lesions, and multivariate analysis showed that IL-6 level upon admission was an independent factor associated with the persistent pulmonary injury. Conclusion: Prolonged elevation of IL-6 is associated with persistent pulmonary lesions in COVID-19 patients. Sequential monitoring and timely intervention of IL-6 may favor the clinical management of COVID-19., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Growth hormone secretagogue receptor 1a (GHSR1a), a member of the G protein-coupled receptor (GPCR) family, is a functional receptor of ghrelin. The expression levels and activities of GHSR1a are affected by various factors. In past years, it has been found that the ghrelin-GHSR1a system can perform biological functions such as anti-inflammation, anti-apoptosis, and anti-oxidative stress. In addition to mediating the effect of ghrelin, GHSR1a also has abnormally high constitutive activity; that is, it can still transmit intracellular signals without activation of the ghrelin ligand. This constitutive activity affects brain functions, growth and development of the body; therefore, it has profound impacts on neurodegenerative diseases and some other age-related diseases. In addition, GHSR1a can also form homodimers or heterodimers with other GPCRs, affecting the release of neurotransmitters, appetite regulation, cell proliferation and insulin release. Therefore, further understanding of the constitutive activities and dimerization of GHSR1a will enable us to better clarify the characteristics of GHSR1a and provide more therapeutic targets for drug development. Here, we focus on the roles of GHSR1a in various biological functions and provide a comprehensive summary of the current research on GHSR1a to provide broader therapeutic prospects for age-related disease treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Nonmotor symptoms are of pivotal importance in Parkinson's disease (PD), among which depressive disorder occurs in more than 45% of PD cases. Decreased levels of noradrenaline (NA) and serotonin (5-HT) in the central nervous system are relevant to it; however, the underlying mechanism is largely unknown. To this end, we conducted behavioral assays to analyze the depressive phenotype in transgenic mice with overexpressed A53T human α-synuclein (A53T mice) and examined alterations of NAergic and 5-HTergic systems in the neuron degeneration, neurotransmitter production, and degradation aspects of the mouse. As compared to controls, A53T mice displayed elevated depressive-like behavior at 6 months, which presents earlier than motor deficits do at 12 months. We detected reduced levels of NA and 5-HT in the hippocampus and NA in the locus coeruleus of 6-month A53T mice. There was no loss of NAergic and 5-HTergic neurons or decreased neurotransmitter synthesis in the brain. However, the expression of MAO-A, an enzyme responsible for NA and 5-HT degradation, was upregulated in A53T mice. Mechanistically, Sirt1 was downregulated which lead to an increase in FoxO1 acetylation, which subsequently increased the transcription of MAO-A . Activation of Sirt1 by resveratrol or inhibition of MAO-A by moclobemide administration could restore brain NA and 5-HT levels and attenuate the depressive-like behavior of A53T mice. Taken together, our results provided a novel correlation between Sirt1 and MAO-A, and compounds targeting on these molecules are beneficial for improving depression in the A53T mouse model of PD.

Ghrelin plays a neuroprotective role in the process of dopaminergic (DAergic) neurons degeneration in Parkinson's disease (PD). However, it still largely unknown whether ghrelin could affect the midbrain neural stem cells (mbNSCs) from which DAergic neurons are originated. In the present study, we observed that ghrelin enhanced mbNSCs proliferation, and promoted neuronal differentiation especially DAergic neuron differentiation both in vitro and ex vivo. The messenger RNA levels of Wnt1, Wnt3a, and glial cell line-derived neurotrophic factor were increased in response to the ghrelin treatment. Results showed that Wnt/β-catenin pathway was relevant to this DAergic neuron differentiation induced by ghrelin. Our finding gave a new evidence that ghrelin may enable clinical therapies for PD by its neurogenesis role., (© 2020 Wiley Periodicals, Inc.)

Circular RNAs (CircRNAs) are a type of non-coding RNAs, which contain a covalently closed loop structure without 5' to 3' free ends. CircRNAs play essential roles in the regeneration of secondary hair follicle (SHF) and cashmere growth in goats. CircRNA-1926 was previously identified in SHF of cashmere goats, but its potential roles are unclear. In this study, we confirmed the expression of circRNA-1926 in SHF bulge of nine cashmere goats with a significantly higher level at anagen than that of telogen. Through the use of both overexpression and siRNA interference, we showed that circRNA-1926 promoted the differentiation of SHF stem cell into hair follicle lineage in cashmere goats which was evaluated via indictor genes Keratin 7 and Keratin 17. Using RNA pull-down, we found that circRNA-1926 bound with miR-148a/b-3p. Additionally, our data indicated that circRNA-1926 promoted the expression of the CDK19 gene. Using dual-luciferase reporter assays, it was revealed that circRNA-1926 positively regulated the CDK19 expression through miR-148a/b-3p. The results from this study demonstrated that circRNA-1926 contributes the differentiation of SHF stem cells into hair follicle lineages in cashmere goats via sponging miR-148a/b-3p to enhance CDK19 expression.