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Background Systemic sclerosis (SSc) is a multisystem rheumatic disease. Orofacial manifestations are commonly in SSc but maybe usually ignored and overshadowed by other systemic complications. Multiple comparative studies have been conducted to investigate the possible links between SSc and oral manifestations. The present study aimed to investigate the oral health status in patients with SSc. Methods Pubmed, Embase, Web of Science, and Scopus were searched up to July 2020. Following outcomes were evaluated: Probing depth (PD), Attachment loss (AL), Bleeding on probing (BOP), Number or percentage of Sites with PD ≥ 4 mm, Prevalence of periodontitis, Number of teeth, Decayed Teeth, Missing teeth, Filled teeth, DMFT index, and the interincisal distance. Newcastle-Ottawa Scale (NOS) were applied for quality assessment. The statistical analysis was processed using the software STATA. Results 11 eligible studies were included. The maximum interincisor distance was significantly restricted in SSc patients (SMD − 1.061; 95 %CI [− 1.546, − 0.576]; Z = 4.29, P = 0.000).The prevalence of Periodontitis (OR 7.007; 95 %CI [3.529, 13.915]; Z = 5.56, P = 0.000), PD (SMD 3.101; 95 %CI [1.374, 4.829]; Z = 3.52, P = 0.000), AL(SMD 2.584; 95 %CI [0.321, 4.846]; Z = 2.24, P = 0.025), sites with PD ≥ 4mm (SMD 2.071 ; 95 %CI [0.267, 3.875]; Z = 2.25, P = 0.024) and the number of decayed teeth (SMD, 0.186; 95 %CI [0.007, 0.365]; Z = 2.04, P = 0.041) were increased significantly in SSc population in comparison with the controls. Conclusions SSc patients have limited mouth opening, higher periodontitis prevalence, and worse periodontal status, as well as an increased number of decayed teeth. Routinely oral hygiene instruction and initial periodontal treatment is recommended for SSc patients.

Background and Objectives: Kangaroo mother care (KMC) benefits preterm infants' health through increasing breastfeeding, but the longitudinal effects of KMC remain unknown. This study investigates ...

The HAIYPRH (T7) peptide has been widely used as a ligand for constructing tumor-targeted nanodrug delivery systems since it can target the transferrin receptor (TfR) and then enter cells easily with the help of transferrin (Tf). However, the dynamic mechanism by which transferrin promotes the entry of T7-conjugated nanostructures into cells remains unclear. Herein, a force tracing technique based on atomic force microscopy (AFM) was used to track the ultrafast dynamic process of a T7-conjugated gold nanoparticle (AuNP-T7) entering a cell at the single-particle level in real time. Tf helped decrease the endocytosis force and increase the endocytosis speed of AuNP-T7 in A549 cells. However, Tf only increased the endocytosis speed of AuNP-T7 in HeLa cells. In contrast, in Vero cells without TfR overexpression, Tf decreased the endocytosis speed. This report provides important insights for redesigning and developing T7-conjugated nanodrug carriers in targeted nanodrug delivery systems.

Because of structural complexity, a “biosimilar” will not be exactly the same as its reference biologic treatment, but is required to be equivalent in all relevant attributes, including efficacy. T...

Purpose This study aimed to explore the potential role and mechanism of garlic-derived S-allylmercaptocysteine (SAMC), the major water-soluble fraction of garlic, in osteoarthritis (OA) both in vivo and in vitro. Methods The effect of SAMC in a surgical-induced OA model was examined by X-ray, staining, ELISA, and immunoblotting. Then the key role of Nrf2 by SAMC treatment in IL-1β stimulated chondrocytes in vitro was determined by gene-knockdown technique. Results SAMC could stabilize the extracellular matrix (ECM) by decreasing metalloproteinase (MMPs) expression to suppress type II collagen degradation in OA rats. The inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, were elevated in OA, which could be down-regulated by SAMC treatment. This effect was parallel with NF-κB signaling inhibition by SAMC. As oxidative stress has been shown to participate in the inflammatory pathways in OA conditions, the key regulator Nrf2 in redox-homeostasis was evaluated in SAMC-treated OA rats. Nrf2 and its down-stream gene NQO-1 were activated in the SAMC-treated group, accompanied by NAD(P)H oxidases 4 (NOX4) expression down-regulated. As a result, the toxic lipid peroxidation byproduct 4-hydroxynonenal (4HNE) was reduced in articular cartilage. In IL-1β-stimulated primary rat chondrocytes, which could mimic OA in vitro, SAMC could ameliorate collagen destruction, inhibit inflammation, and maintain redox-homeostasis. Interestingly, after Nrf2 gene knockdown by adenovirus, the protective effect of SAMC in IL-1β-stimulated chondrocytes disappeared. Conclusion Overall, our study demonstrated that SAMC targeted Nrf2 to protect OA both in vivo and in vitro, which would be a new pharmaceutical way for OA therapy.

Many clinical trials of treatments for patients hospitalised for COVID-19 use an ordinal scale recommended by the World Heath Organisation. The scale represents intensity of medical intervention, with higher scores for interventions more burdensome for the patient, and highest score for death. There is uncertainty about use of this ordinal scale in testing hypotheses. With the objective of assessing the power and Type I error of potential endpoints and analyses based on the ordinal scale, trajectories of the score over 28 days were simulated for scenarios based closely on results of two trials recently published. The simulation used transition probabilities for the ordinal scale over time. No one endpoint was optimal across scenarios, but a ranked measure of trajectory fared moderately well in all scenarios. Type I error was controlled at close to the nominal level for all endpoints. Because not tied to a particular population with regard to baseline severity, the use of transition probabilities allows plausible assessment of endpoints in populations with configurations of baseline score for which data is not yet published, provided some data on the relevant transition probabilities are available. The results could support experts in the choice of endpoint based on the ordinal scale.

ObjectivePsoriasis is a chronic inflammatory disease with autoimmune aetiology. A possible link between psoriasis and autoimmune thyroid disease (AITD) has been suggested in some studies with inconsistent findings. This meta-analysis aims to determine the association between psoriasis and AITD.DesignA meta-analysis of observational studies.Data sourcesPubMed, EMBASE, Scopus and the Cochrane Library were searched up to 1 November 2021.Eligibility criteria for selecting studiesWe included non-randomised studies, each with over 50 cases in every group, focusing on the rate of comorbidity between psoriasis and AITD.Data extraction and synthesisTwo independent reviewers screened the articles and extracted data. The restricted maximum-likelihood was applied to perform the meta-analysis. OR and 95% CIs were pooled to compare the prevalence of AITD in psoriasis and control groups. Heterogeneity was assessed with I2 statistic. The Newcastle-Ottawa Scale and Agency for Healthcare Research and Quality were applied for quality assessment. The risk of bias was assessed with Risk Of Bias In Non-randomised Studies-of Interventions (ROBINS-I).ResultsEleven available studies with data on 253 313 patients with psoriasis and 1 376 533 controls were included. Meta-analysis showed that patients with psoriasis had a higher prevalence of AITD (OR 1.76, 95% CI 1.35 to 2.28, Z=4.25, pConclusionsOur study indicates that the rate of co-occurring AITD was significantly increased in patients with psoriasis. It suggests that the increased risk of AITD should be concerned in patients with psoriasis.PROSPERO registration numberCRD42020206005.

Objective Urinary incontinence is highly prevalent among women, with a substantial effect on health-related quality of life. This article aimed to investigate the independent factors for urinary incontinence (UI) and the relative importance of each factor. Methods This study was a cross-sectional survey of Chinese women in Guangzhou. Female 20 years and older were invited to participate. The International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form was used to determine whether respondents are experiencing UI. Univariate and multivariate unconditional logistic regression analyses were performed to determine the significant risk factors associated with UI. Results A total of 2626 women were invited to participate in the survey. The response rate was 80.5% (2114/2626). The prevalence of UI among the study population was 31.2%. Old age, increased body mass index, childbirth, family history of any female pelvic floor disorders, symptoms of chronic cough or rhinitis, wearing a corset, and often drinking were independent risk factors for UI. Conclusions Urinary incontinence is common among Chinese women in Guangzhou. Among the factors that we are concerned with, old age and vaginal delivery are the two with greatest impact. Moreover, wearing a corset and drinking are the 2 lifestyle factors associated with UI.

As potential ligands, targeted peptides have become an important part in the construction of intelligent drug delivery systems (DDSs). The targeting interaction of peptides with receptors is a key point affecting the efficacy of targeted nano-drugs. Herein, three common peptides (HAIYPRH (T7), YHWYGYTPQNVI (GE11), and RGD) that have been widely used in cancer targeted therapy and tumor diagnostics, targeting the corresponding receptors (transferrin receptor (TfR), epidermal growth factor receptor (EGFR), and ανβ3 integrin receptor), were selected as examples to study the targeting interacton on living cell surface at the single-molecule level by using single-molecule force spectroscopy (SMFS) based on atomic force microscopy (AFM). The dissociation activation energy in the absence of an external force (ΔGβ,0) of T7-TfR, GE11-EGFR, and RGD-ανβ3 integrin is evaluated at single-molecule level. Among these three peptide-receptor pairs, the T7-TfR bond is the most stable with a smaller dissociation kinetic rate constant at zero force (Koff), larger kinetic on-rate constant (Kon), and shorter interaction time (τ). Furthermore, T7 can target TfR even more effectively on A549 cell membrane after treatment with drugs. Our methodology can also be applicable to the study of other ligand targeted DDSs.

Numerous neuroimaging studies have investigated the neural mechanisms of two mutually independent yet closely related cognitive processes aiding humans to navigate complex societies: social hierarchy-related learning (SH-RL) and social hierarchy-related interaction (SH-RI). To integrate these heterogeneous results into a more fine-grained and reliable characterization of the neural basis of social hierarchy, we combined coordinate-based meta-analyses with connectivity and functional decoding analyses to understand the underlying neuropsychological mechanism of SH-RL and SH-RI. We identified the anterior insula and temporoparietal junction (dominance detection), medial prefrontal cortex (information updating and computation), and intraparietal sulcus region, amygdala, and hippocampus (social hierarchy representation) as consistent activated brain regions for SH-RL, but the striatum, amygdala, and hippocampus associated with reward processing for SH-RI. Our results provide an overview of the neural architecture of the neuropsychological processes underlying how we understand, and interact within, social hierarchy.

This study aimed to investigate the influence of serum folate, vitamin B12 (VitB12) levels, and inflammation-based scores on the motor performance status in Parkinson's disease (PD). We retrospectively collected data from 148 consecutive patients with idiopathic PD first admitted to our hospital. We measured whole blood count, albumin, lactate dehydrogenase, C-reactive protein, folate, and VitB12 levels and calculated the inflammation-based scores. The following scales were applied to assess the motor performance status: activity of daily living scale (ADL, the Barthel Index), the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III), and Hoehn–Yahr (H–Y) classification. The geometric mean of folate and VitB12 levels were 11.87 (ng/ml) and 330.52 (pmol/L), respectively. Folate deficiency (serum level < 4.0 ng/ml) and VitB12 deficiency (serum level < 133 pg/ml) were present in 0.7 and 5.4% of the patients, respectively. The mean prognostic nutritional index (PNI) and systemic immune-inflammation index (SII) were 47.78 ± 4.42 and 470.81 ± 254.05, respectively. The multivariate analyses showed that serum VitB12 level (P = 0.002) and SII (P = 0.005) were significant factors for ADL score; serum folate (P = 0.027) and VitB12 (P = 0.037) levels for UPDRS-III score; and serum folate (P = 0.066) and VitB12 (P = 0.017) levels for H–Y classification. The elevated folate level did correlate with greater decline in UPDRS-III score (P = 0.023) and H–Y classification (P = 0.003), whereas there was an obvious increase in ADL score (P = 0.048). SII was negatively associated (P < 0.001) with the ADL score. The three-dimensional drawing, combined with the effect of folate and VitB12 levels, showed that the lowest level of folate was associated with the lowest ADL score and the highest UPDRS-III score and H–Y classification. This study indicates that serum folate, VitB12 levels, and SII are significant factors influencing the motor performance status in patients with PD. SII is negatively associated with ADL. Elevated serum folate level correlates with mild motor impairment in patients with PD.

The influence of neuroinflammation in the development and progression of Parkinson's disease (PD) remains unknown. Macrophage migration inhibitory factor (MIF) is a multipotent and key cytokine involved in the pathogenesis of acute and chronic inflammatory and immune disorders. The aim of this study was to investigate the neuroprotective effects mediated by MIF in PD. Cellular apoptosis was measured by RT-qPCR analysis, fluorescence-activated cell sorting (FACS) analysis and western blotting. JC-1 staining was used to analyze the mitochondrial membrane potential (MMP). The formation of autophagosomes was detected by western blot analysis. Autophagic flux was assessed by tandem mRFP-GFP-LC3 fluorescence microscopy. Expression of MIF, cleaved-PARP and LC3B-II was increased significantly in both acute and chronic PD animal models. MIF was positively associated with IL-10 (P 0.001), but inversely with TNF-α (P 0.05). The PD cells (1 mM MPP+ treated group) showed an increase in early-apoptotic cells by FACS. Upregulating MIF expression resulted in a lower concentration of cleaved-PARP than the control group (P 0.001). The MMP was higher in the MIF upregulated group than in the MIF knockdown group (P 0.001). Upregulating MIF expression resulted in a higher concentration of LC3B-II than the control group (P 0.001). Finally, LC3 puncta were markedly increased in the MIF upregulated group and in the MIF + MPP+ group. This study indicates that MIF mediates a neuroprotective effect via suppressing inflammatory responses, inhibiting apoptosis and inducing autophagy in PD.

Background Radix Salviae Miltiorrhizae (RSM), a well-known traditional Chinese medicine, has been shown to inhibit tumorigenesis in various human cancers. However, the anticancer effects of RSM on human hepatocellular carcinoma (HCC) and the underlying mechanisms of action remain to be fully elucidated. Methods In this study, we aimed to elucidate the underlying molecular mechanisms of RSM in the treatment of HCC using a network pharmacology approach. In vivo and in vitro experiments were also performed to validate the therapeutic effects of RSM on HCC. Results In total, 62 active compounds from RSM and 72 HCC-related targets were identified through network pharmacological analysis. RSM was found to play a critical role in HCC via multiple targets and pathways, especially the EGFR and PI3K/AKT signaling pathways. In addition, RSM was found to suppress HCC cell proliferation, and impair cancer cell migration and invasion in vitro. Flow cytometry analysis revealed that RSM induced cell cycle G2/M arrest and apoptosis, and western blot analysis showed that RSM up-regulated the expression of BAX and down-regulated the expression of Bcl-2 in MHCC97-H and HepG2 cells. Furthermore, RSM administration down-regulated the expression of EGFR, PI3K, and p-AKT proteins, whereas the total AKT level was not altered. Finally, the results of our in vivo experiments confirmed the therapeutic effects of RSM on HCC in nude mice. Conclusions We provide an integrative network pharmacology approach, in combination with in vitro and in vivo experiments, to illustrate the underlying therapeutic mechanisms of RSM action on HCC.

Cigarette smoke (CS) is the major cause of chronic obstructive pulmonary disease (COPD). CS heightens inflammation, oxidative stress and apoptosis. Ergosterol is the main bioactive ingredient in Cordyceps sinensis (C. sinensis), a traditional medicinal herb for various diseases. The objective of this work was to investigate the effects of ergosterol on anti-inflammatory and antioxidative stress as well as anti-apoptosis in a cigarette smoke extract (CSE)-induced COPD model both in vitro and in vivo. Our results demonstrate that CSE induced inflammatory and oxidative stress and apoptosis with the involvement of the Bcl-2 family proteins via the nuclear factor kappa B (NF-κB)/p65 pathway in both 16HBE cells and Balb/c mice. CSE induced epithelial cell death and increased the expression of nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), malondialdehyde (MAD) and the apoptosis-related proteins cleaved caspase 3/7/9 and cleaved-poly-(ADP)-ribose polymerase (PARP) both in vitro and in vivo, whereas decreased the levels of superoxide dismutase (SOD) and catalase (CAT). Treatment of 16HBE cells and Balb/c mice with ergosterol inhibited CSE-induced inflammatory and oxidative stress and apoptosis by inhibiting the activation of NF-κB/p65. Ergosterol suppressed apoptosis by inhibiting the expression of the apoptosis-related proteins both in vitro and in vivo. Moreover, the usage of QNZ (an inhibitor of NF-κB) also partly demonstrated that NF-κB/p65 pathway was involved in the ergosterol protective progress. These results show that ergosterol suppressed COPD inflammatory and oxidative stress and apoptosis through the NF-κB/p65 pathway, suggesting that ergosterol may be partially responsible for the therapeutic effects of cultured C. sinensis on COPD patients.

Guanine (G) oxidation products, such as 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-oxo-guanine (8-OXOG), have been widely studied as promising biomarkers for DNA oxidative damage. In this work, we develop a new method to detect G oxidative products released from live cells after chromium (VI) ion or hydrogen peroxide treatments by using a glass nanopipette-based flexible gold nanoelectrode (fGNE). Specific response to G oxidative products with high sensitivity can be detected from the fGNE tip through integrated electrochemical measurements and surface-enhanced Raman spectroscopy. The fGNE apex can be positioned very close to the cell membrane noninvasively because of its high flexibility and nanoscale tip size. With the assistance of the electrophoretic force, the fGNEs can effectively collect and detect the G-derived DNA damage products released from individual cells in the cell culture medium with high sensitivity.

During COVID-19 outbreak hospitals were congested and infliximab was interrupted. Thus, we performed this observational study to understand the consequent burden of complications in these special cluster of psoriatic patients. We followed up 56 psoriatic patients who were receiving Infliximab treatment by telephone. The majority of patients had lesions exacerbation, accompanied by anxiety emotion. It is suggested that reserving common drugs for psoriasis at home is necessary. Besides, telemedicine should be advocated as a main medical visit mode during the outbreak of COVID-19.

Background: The IL-23/17 axis plays central role in the pathogenesis of several immune-mediated inflammatory diseases (IMIDs). IL-23/17 antagonists showed significant improvement in the treatment for psoriasis and other IMIDs, including psoriasis(PSO), psoriatic arthritis(PsA), rheumatoid arthritis(RA) and ankylosing spondylitis(AS).Objective: To assess the safety of IL-23/17 antagonists therapy on patients with psoriasis and other IMIDs.Methods: Pooled analysis from thirty-nine placebo-controlled randomized clinical trials (RCTs) of IL-23/17 axis antagonists for IMIDs. Incidences of adverse events (AEs), serious adverse events (SAEs) and AEs of interest were applied to evaluate the safety profile.Result: A Total of 15967 patients were exposed to IL-23/17 axis antagonists. The proportions of patients suffered at least one AE in antagonists group and placebo-control group are 67.5% and 51.1% respectively. Incidence of SAE was increased in patients treated with IL-23/17 axis antagonists compared to patients given placebo (relative risk 2.03; 95% CI, 1.62, 2.56). Incidence of AEs of interest were all increased in patients treated with IL-23/17 axis antagonists compared to patients given placebo.Conclusion: In this analysis, we found increased risk of AEs, SAEs, nervous system disorder, cardiovascular disorder and hypertension among patients with IMIDs treated with IL-23/17 axis antagonists.

RATIONALE Tenofovir (TFV) is a first-line antiviral agent against hepatitis B virus (HBV) and is recommended for the prevention of mother-to-infant transmission of HBV. To study the distribution of TFV in umbilical cord plasma and amniotic fluid of HBV-infected pregnant women, a rapid and sensitive method for TFV determination was developed and validated. METHODS The quantification method was developed using liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). The analytes were separated on an Acquity UPLC HSS T3 column under gradient elution with methanol and 0.01% ammonia solution in 10 mM ammonium acetate/water. This is the first reported method for the determination of TFV using alkaline rather than acidic mobile phases. Linearity, accuracy, precision, limit of quantification, specificity and stability were assessed. RESULTS Detection of TFV was achieved within 4 min. The calibration curves for TFV quantification showed excellent linearity in the range of 1-500 ng/mL. The intra- and interbatch precision and accuracy ranged from -4.35% to 6.92%. This method was successfully applied to determination of samples from 50 HBV mono-infected women undergoing tenofovir disoproxil fumarate therapy. The mean concentrations of TFV in the umbilical cord and amniotic fluid samples were 29.2 (4.6-86) and 470.9 (156-902) ng/mL, respectively, which showed a moderate positive correlation (r = 0.5299, P

The garlic-derived organosulfur compound S-allylmercaptocysteine (SAMC) has been reported to exhibit anti-inflammatory and anti-oxidative activities, whereas its potential therapeutic effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is unknown. In this study, we focused on exploring the therapeutic effects of SAMC on LPS-induced ALI mice and the involvement of underlying molecular mechanisms. BalB/c mice were treated with SAMC (10, 30 and 60 mg/kg) or positive control N-acetylcysteine (NAC, 500 mg/kg) by gavage after intratracheal instillation of LPS for 30 min and were sacrificed 24 h after LPS administration. Our results indicate that the treatment with SAMC not only ameliorated the histological changes but also decreased LPS-triggered lung edema. Moreover, SAMC displayed an anti-inflammatory effect through reducing inflammatory cells infiltration, myeloperoxidase (MPO) formation and inhibiting pro-inflammatory cytokines/mediator production including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) via suppressing the activation of nuclear factor-kappaB (NF-κB) signaling pathway. Furthermore, SAMC attenuated oxidative stress evoked by LPS via diminishing malondialdehyde (MDA) formation and reversing glutathione (GSH) and superoxide dismutase (SOD) depletion. Meanwhile, SAMC up-regulated expressions of endogenous antioxidant/detoxifying proteins including heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1(NQO1) through reversing the suppression of Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-2 related factor 2 (Nrf2) signaling pathway. Our results demonstrate that SAMC effectively attenuated LPS-induced ALI which was largely dependent upon inhibition of inflammation and oxidative stress via NF-κB and Keap1/Nrf2 signaling pathways.

Posaconazole is a broad-spectrum antibacterial drug for the treatment of invasive fungal infections. However, its clinical usage is limited by a lot of adverse reactions such as diarrhea. S-allylmercaptocysteine (SAMC), a garlic organosulfur compound, has a strong antioxidative and anti-inflammatory activity. This study aimed to examine the protective effects of SAMC on posaconazole-induced adverse effects. Mice were treated with the blank control, enteric coated posaconazole microparticles (POS group) and its combination with SAMC (Combination group). Oxidative stress markers, antioxidative activities and histological changes in the study mice were investigated. We found that the percentage of mice diarrhea was reduced by 20% in the combination group after administration for 1 week. The results reveal that the levels of TNF-α (p < 0.05), IL-1β (p < 0.01) and IL-6 (p < 0.01) in the serum of the POS group were significantly higher compared to the control group while the combination group decreased the POS-induced cytokine elevations (p < 0.05). The MDA content in colon tissues of the POS group increased distinctly (p < 0.01) compared with the control group. The combination groups dosed with the low and high strengths of SAMC decreased the MDA level about 20% and 30%, respectively, compared to the POS group. The histopathological results display that the colonic tissues of the combination groups had significant improvement in mucosal adhesions and inflammatory infiltration versus the POS group. Briefly, SAMC could alleviate the POS-induced adverse reactions by the mechanisms of antioxidation and anti-inflammation.

Background The neuroprotective effects of kallidinogenase against acute cerebral infarction have been demonstrated, and the use of microbubbles has been suggested as a therapeutic mechanism for drug delivery. This study was designed to investigate the optimal parameters for preparing kallidinogenase-loaded microbubbles (KLMs) and to evaluate the effects of KLM-targeted therapy on neurogenesis and angiogenesis following experimental acute cerebral infarction in rats. Materials and Methods KLMs were prepared by mechanical shaking. Male Wistar rats were randomly divided into an ultrasound-mediated KLM-treated group and 4 control groups. Treatments were administered via daily tail vein injection on 6 consecutive days, starting at 24 hours after middle cerebral artery occlusion (MCAO). The ultrasound-treated groups were subjected to a 2-MHz pulse of ultrasonic irradiation on the lateral skull of the ischemic side for 10 minutes during injection. Cell proliferation was examined using a 5-bromo-2-deoxyuridine assay. Infarct volume and neurological function were evaluated on days 3 and 7 after MCAO. Results The ultrasound-mediated KLM and kallidinogenase treatments significantly increased the numbers of doublecortin-immunoreactive cells in the subventricular zone (SVZ) and laminin+ cells in the peri-infarction region on day 7 after MCAO, compared with the other 3 groups (all P Conclusions Treatment with the ultrasound-mediated KLMs promoted the proliferation of SVZ neuroblasts and vascular regeneration, which contributed to functional improvement after stroke. These findings provide a novel therapy for ischemic stroke.

Graphical abstract, With the outbreak and rapid spread of COVID-19, the world health situation is unprecedentedly severe. Systemic lupus erythematosus (SLE) is a common autoimmune disease, which can cause multiple organ damage. Numerous studies have shown that immune factors have important roles in the pathogenesis of both COVID-19 and SLE. In the early stages of COVID-19 and SLE pathogenesis, IFN-α expression is frequently increased, which aggravates the virus infection and promotes SLE development. In addition, increased IL-6 levels, caused by different mechanisms, are observed in the peripheral blood of patients with severe COVID-19 and SLE, stimulating a series of immune cascades that lead to a cytokine storm, as well as causing B cell hyperfunction and production of numerous of antibodies, aggravating both COVID-19 and SLE. In this review, we explore the background immunopathological mechanisms in COVID-19 and SLE and analyze the advantages and disadvantages of commonly used SLE drugs for patients with COVID-19, to optimize treatment plans for patients with SLE who develop COVID-19.

Tea is a high-value cash crop, and it is a popular beverage globally owing to its unique flavor and health benefits. Selenium can increase tea yield, and the increasing demand for selenium-enriched tea has made it a research hotspot. However, the effect of selenium on the quality and cold resistance of tea has rarely been studied. The purpose of this study was to examine the effects of exogenous selenium application on the physiological and biochemical properties, antioxidant enzyme activity, and quality of tea under low-temperature stress (4℃). The results showed that selenium treatment increased the net photosynthetic rate of leaves under low-temperature stress. Furthermore, it reduced the contents of malondialdehyde and hydrogen peroxide to stabilize plant photosynthesis and the membrane system and to improve the cold tolerance of tea.Moreover, selenium treatment regulates the content of proline and increases the activities of superoxide dismutase, ascorbate peroxidase, peroxidase and catalase to prevent oxidative damage caused by cold stress. In addition, treatment with selenium regulated changes in the secondary metabolites of tea under low-temperature stress, including reducing the oxidation products of polyphenols, increasing the polyphenol content, increasing sugar accumulation, and promoting the synthesis of various tea amino acids to improve tea quality.

Gastric cancer remains as a common lethal malignancy worldwide. Developing novel anti-gastric cancer drugs with minimal side effects is necessary to address this public health issue. S-allylmercaptocysteine (SAMC), one of the water-soluble organosulfur garlic derivatives, has been demonstrated as a suppressive agent against tumors. In this study, we examined the effect of SAMC on human gastric carcinoma growth in vivo and explored the underlying mechanism. Human gastric cancer SGC-7901 cells were inoculated subcutaneously in BALB/c nude mice. When xenograft tumors reached about 100 mm3, mice were treated with SAMC for 30 days. We observed that SAMC administration in mice effectively delayed the growth of SGC-7901 xenografts without signs of toxicity. TUNEL staining confirmed that the tumors from SAMC-treated mice exhibited a markedly higher apoptotic index. Mechanistic studies suggested that this activity may arise from its effects on the caspase activation and modulation of MAPK and PI3K/Akt signaling pathways. Taken together, these data support development of SAMC as a potential agent for gastric cancer therapy.

Diallyl trisulfide (DATS), a natural agent derived from garlic, has been tested for its antigastric cancer activities in various preliminary studies. However, more systematic pharmacodymatic (PD) and mechanistic evaluations are clearly needed. The aim of this study was to investigate the antitumor effects of DATS in the treatment of human gastric cancer cell SGC-7901 both in vitro and in vivo using widely recommended study procedures. DATS suppressed cancer cells proliferation and induced cell cycle arrest accompanied by an increase in the expressions of cyclin A2 and cyclin B1 in SGC-7901 cancer cells. DATS also caused an increase in apoptotic cell death, which involved in accumulations of bax, p53, and cytochrome C and reduction of Bcl-2 expressions. Besides, activation of JNK, ERK and p38 phosphorylation in DATS-treated cells suggested that mitogen-activated protein kinase (MAPKs) pathways were involved in DATS-induced apoptosis. Meanwhile, DATS significantly inhibited tumor growth and promoted tumor apoptosis in a xenograft model of gastric cancer cell SGC-7901. DATS inhibited tumor migration and invasion by modulating MMP9 and E-cadherin protein expressions. In addition, DATS treatment evidently increased the cytokine secretions of IL-12, TNF-α and IFN-γ (p

Diallyl trisulfide (DATS), a garlic organosulfide, has shown excellent chemopreventive potential. Cisplatin (DDP) is widely used to treat solid malignant tumors, but causing serious side effects. In the current study, we attempted to elucidate the chemopreventive mechanisms of DATS in human gastric cancer BGC-823 cells in vitro, and to investigate whether DATS could enhance the anti-tumor efficacy of DDP and improve quality of life in BGC-823 xenograft mice in vivo. Treatment with DATS (25–400 μmol/L) dose-dependently inhibited the viability of BGC-823 cells in vitro with an IC50 of 115.2±4.3 μmol/L after 24 h drug exposure. DATS (50–200 μmol/L) induced cell cycle arrest at G2/M phase in BGC-823 cells, which correlated with significant accumulation of cyclin A2 and B1. DATS also induced BGC-823 cell apoptosis, which was accompanied by the modulation of Bcl-2 family members and caspase cascade activation. In BGC-823 xenograft mice, administration of DATS (20–40 mg·kg−1·d−1, ip) dose-dependently inhibited tumor growth and markedly reduced the number of Ki-67 positive cells in tumors. Interestingly, combined administration of DATS (30 mg·kg−1·d−1, ip) with DDP (5 mg/kg, every 5 d, ip) exhibited enhanced anti-tumor activity with fewer side effects. We showed that treatment of BGC-823 cells with DATS in vitro and in vivo significantly activated kinases such as p38 and JNK/MAPK and attenuated the Nrf2/Akt pathway. This study provides evidence that DATS exerts anticancer effects and enhances the antitumor efficacy of DDP, making it a novel candidate for adjuvant therapy for gastric cancer.

A 43-year-old woman presented with a 4-day history of right limb weakness. While biking 4 days earlier, she felt a weakness in her right hand and leg. She had a history of hypertension for more than 2 years, and was taking extended-release nifedipine tablets (40 mg) and perindopril (4 mg) daily, but her blood pressure was difficult to control (fluctuations of 150–180/90–115 mm Hg). The patient did not smoke or drink alcohol, and had no family history of similar diseases. The authors thank Dr. Haiyan Lou and Dr. Xiaodong Teng for their contributions.

Diallyl trisulfide (DATS), an organosulfuric component of garlic oil, exhibits potential anticancer and chemopreventive effects. Cisplatin (DDP), a common chemotherapeutic agent, has provided great therapeutic contributions to treating solid tumors, but with serious side effects. Here, we verified the anti-tumor properties of DATS on lung cancer in vitro and in vivo, and evaluated synergistic effects of DATS combined with DDP on the NCI-H460 xenograft model. Significantly decreased cell viabilities, cell cycle G1 arrest, and apoptosis induction were observed in DATS treated NCI-H460 cells (p

Ethnopharmacological relevance Traditional Chinese medicine Yifei Tongluo Granules has been employed clinically with the combination of chemotherapy agents to treat patients with multidrug-resistant tuberculosis. However, the mechanisms underlying the therapeutic potential have not been well elucidated. The present study was employed to verify immunomodulatory effect and to investigate the underlying mechanisms which have not been explored. Materials and methods The study samples of total extracts (FB-E) and polysaccharides (FB-P) were prepared by the extraction of the Yifei Tongluo Granules using appropriate techniques. A simple immunodeficient mice model was established by challenging Balb/c mice with cyclophosphamide in order to avoid the handling of tuberculosis viruses. The in vivo study was thus designed to systematically elucidate the immuno-enhancement effects of Yifei Tongluo Granules extracts in immunosuppressed mice induced by cyclophosphamide. Balb/c mice were orally ingested once daily with the low and high doses of two different extracts for ten consecutive days, respectively, accompanied by intraperitoneal injection of cyclophosphamide (60 mg/kg) on days 1–3 and 10. Results Compared with the model group, the treatment of immunodeficient mice with the low and high doses of the extracts FB-E or FB-P enhanced spleen and thymus indices, T- and B-cell proliferation as well as increased the activities of splenic natural killer, lymphokine activated killer, cytotoxic T lymphocyte cells and peritoneal macrophage phagocytosis. In addition, the FB-E or FB-P treatment balanced the ratio of Th1/Th2 and up-regulated the CD4+/CD8+ ratio in the serum. Conclusions These results demonstrate, for the first time, that the treatment of the cyclophosphamide-challenged mice with the Yifei Tongluo Granules extracts resulted in accelerated recovery of immunosuppression, sugguesting that the immunomodulation might be the mechanism for the observed clinical benefits of Yifei Tongluo Granules. Our findings provide preliminary mechanistic study evidences for clinical application of Yifei Tongluo Granules in patients with immunodeficient diseases such as tuberculosis.

(1) Background: Diabetic nephropathy, a microvascular complication of diabetes, is one of the principal causes of end-stage renal disease worldwide. The aim of this study was to explore the therapeutic effects of ergosterol on diabetic nephropathy. (2) Methods: Streptozotocin (STZ)-induced C57BL/6 diabetic mice were treated with ergosterol (10, 20, 40 mg/kg/day) for 8 weeks by oral gavage. The in vitro study employed rat mesangial cells exposed to 30 mM glucose for 48 h in the presence of 10 or 20 &mu, M ergosterol. (3) Results: Ergosterol treatment improved body weights, ameliorated the majority of biochemical and renal functional parameters and histopathological changes, and reduced extracellular matrix (ECM) deposition in diabetic mice. In vitro, ergosterol suppressed proliferation, reduced the levels of ECM proteins, and increased the expression of matrix metalloproteinase-2 and -9 in high glucose-induced mesangial cells, Furthermore, ergosterol markedly improved transforming growth factor-&beta, 1 (TGF-&beta, 1) expression, enhanced phosphorylation levels of drosophila mothers against decapentaplegic 2 (Smad2), and regulated the downstream factors in vivo and in vitro. (4) Conclusions: Ergosterol alleviated mesangial cell proliferation and the subsequent ECM deposition by regulating the TGF-&beta, 1/Smad2 signaling pathway.

Surgery and chemotherapy are the gold-standard treatments for ovarian cancer. The major cause of treatment failure in patients with ovarian cancer is tumoral heterogeneity and drug resistance. Paclitaxel (PTX) is one of the most commonly used first-line drugs for ovarian cancer chemotherapy. Unfortunately, the mechanisms of PTX chemoresistance remain unclear. Here, we examined the effects of post-translational neddylation on the sensitivity of ovarian cancer cells (OCCs) to PTX-induced apoptosis. Disruption of protein neddylation with the first-in-class inhibitor MLN4924 dramatically neutralized PTX-mediated antiproliferative, antimigration, and apoptotic effects in human OCCs. Moreover, MLN4924 treatment interrupted PTX-induced microtubule polymerization. Importantly, two neddylation conjugating E2 enzymes, UBE2M and UBE2F, were found to play essential roles in PTX-induced cytotoxicity and tubulin polymerization in OCCs. In summary, our findings demonstrated that disruption of protein neddylation by MLN4924 conferred resistance to PTX and provided insights into the potential mechanisms of PTX chemoresistance in ovarian cancer.

In this study, the aim was to investigate the effect of bergenin on immune function and antioxidation in cyclophosphamide (Cy)-induced immunosuppressed mice. Firstly, we estimated its effect on immune organs. Histological analysis and indexes of immune organs showed that cyclophosphamide exhibited spleen and thymus injury compared with the normal control, which was alleviated by bergenin. Secondly, bergenin also enhanced the humoral immune function through increasing the level of IgM and IgG in serum. Thirdly, bergenin also enhanced the cellular immune function. The results indicate that bergenin increased peritoneal macrophage functions, the proliferation of T and B lymphocytes, NK and CTL cell activities, and T (CD4+ and CD8+) lymphocyte subsets. Besides, bergenin also had the ability to modulate the Th1/Th2 balance. Moreover, bergenin prevented the Cy-induced decrease in numbers of peripheral RBC, WBC and platelets, providing supportive evidence for their anti-leukopenia activities. Finally, bergenin also reversed the Cy-induced decrease in the total antioxidant capacity including activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). In conclusion, bergenin protected against Cy-induced adverse reactions by enhancing humoral and cellular immune functions and augmenting antioxidative activity and could be considered as a potential immunomodulatory agent.

In this study, two different species of lactic acid bacteria (LAB) (Lactobacillus plantarum and Pedocococcus pentosaceus) with high exopolysaccharide (EPS) yield were selected from a pickled water. Further, edible films based on cassava starch (CS) were developed containing LAB, and sodium carboxymethylcellulose (CMC). After addition of probiotics, the antioxidant activity of the composite film was significantly enhanced. Further, as the probiotic content increased, the antioxidant activity continuously increased. Moreover, L. plantarum showed uniform distribution in the CS/CMC matrix, forming a denser structure, which effectively blocked the penetration of water molecules and exhibited ultraviolet protection. Finally, due to the intermolecular interaction between probiotics and the CS/CMC matrix, the water vapor and light transmission rates were reduced, effectively blocking water and light to prevent lipid oxidation deterioration in food packaging. Banana shelf life has qualitatively improved with 2% LAB added composite film and its application in food packaging has been affirmed.

The World Alzheimer Report 2018 [1] estimated that there were currently 50 million people in the world with dementia, which was equivalent to the population of South Korea or Spain. Alzheimer's disease (AD), as the most common dementia, accounts for about two-thirds of the number of people with dementia. AD is a neurodegenerative disease characterized by an insidious onset, after which cognitive function is gradually reduced, ultimately leading to the loss of body function [2]. Current research indicates that the occurrence of AD is mainly related to the abnormal aggregation of two proteins in the brain [3]. One protein is beta-amyloid (Aβ). When people have Alzheimer's disease, their content of this protein will reach abnormal levels, with plaques being formed between neurons, destroying the function of cells. The other abnormal phenomenon involves the tau protein level, which causes neurofibrillary tangles to be formed in neuronal cells, thereby blocking the neuron's transport system. These two injuries induce the gradual loss of neurons and synapses, ultimately leading to the loss of cognitive ability.Currently, the method most frequently used to diagnose AD internationally is the standard proposed by the International Association for Neurological Diseases and Communication [4] and is mainly based on the identification of Aβ peptide accumulation and tau protein entanglements in the brain. However, these standards have significant shortcomings, the diagnosis of AD is diagnosed accurately in late-stage AD patients. At this point, there is widespread brain damage, and there may be no time for drug intervention. In fact, more and more people realize that cell degeneration in AD patients may occur many years before the onset of clinical symptoms [5], and as the disease occurs, multiple pathways work synergistically to activate the vicious cycle, disrupting the formation of neurons in synapses and eventually leading to the decline of cognitive function.Interestingly, the metabolic decline detected by positron emission tomography (FDG-PET) was one of the earliest recognized symptoms in patients with mild cognitive impairment in the early stages of AD [6], suggesting that metabolism may play a role in early AD mechanisms. We need to recognize that AD is a disease caused by a variety of factors and that there are many changes involved in the process, including changes in some of the iconic small-molecule metabolites in the body caused by metabolic disorders. Metabolites are usually biological endpoints, and their levels usually represent complete information on cellular function and the phenotypic characteristics of cellular or organismal responses to genetic and environmental changes [7]. There are many studies on small molecules that may be associated with AD, such as amino acids, fatty acids, neurotransmitters, etc [8-10]. Among these small molecular metabolites, VOCs are the products or intermediates of the body's metabolism, which are closely related to the pathophysiological mechanism of the organism. Their expression levels can also reflect the health status of organisms [11, 12]. The study of VOCs may provide a good starting point for explaining the mechanism of AD.Research on VOCs requires analytical techniques with high practicability, sensitivity and selectivity. At present, chromatographic methods for detecting VOCs in diseases mainly include methods such as GC-MS [13] and GC-TOF-MS [14]. In addition, there is a relatively novel method for detecting VOCs, namely, gas chromatography-ion mobility spectrometry (GC-IMS) [15]. GC-IMS is a technology that combines the two separate technologies of gas chromatography and ion mobility spectrometry. It covers the advantages of both technologies, including the advantages of the high sensitivity of IMS and the high selectivity of GC. Undoubtedly, it has a high application prospects. GC-IMS achieves material separation in two dimensions, mainly based on two parameters. The first parameter is the residence time of the material associated with the gas chromatographic retention time in the column, as different materials have different retention times. The other parameter is derived from the drift time in ion mobility drift tube after the ionization of a specific chemical. In the field of gas chromatography, HS-GC-IMS has become a very widely used coupling technique for the separation of volatile and semi-volatile materials. At present, GC-IMS has very wide applications in the detection of drugs and chemical reagents [16], breath analysis [17, 18], bacterial growth monitoring [19, 20], food quality and safety control [21], etc. However, GC-IMS analysis of VOCs in faeces and urine has rarely been reported, especially for AD.Mice have become a common model for studying AD because they share 99% of human genes, have a relatively short life span (approximately 2-3 years), are easy to handle and raise, and have a simple form of reproduction. Several features exhibited by senescence-accelerated mice (SAM) [22] have made them a model for studying human ageing, including the early onset of age-related amyloidosis, degenerative joint disease, cataracts, osteoporosis, and osteoarthritis. Among SAM strains, senescence-accelerated mouse prone 8 (SAMP8) [23] is a type of animal model used for studying rapid ageing. The main features of SAMP8 mice are age-accumulated accelerated degenerative changes of learning and memory function and pathological changes in the central nervous system and hippocampus, including the cortex and other parts. It is an ideal model for studying learning and memory disorders during the pathogenesis of AD. Because senescence-accelerated mouse resistant1 (SAMR1) exhibit a normal ageing processes and because defects and changes observed in SAMP8 mice are not observed in SAMR1 mice, they are often used as a control group.In this experiment, SAM strains were used as the experimental subjects. Two different chromatographic methods, HS-SPME-GC-MS and HSGC-IMS, were used to fingerprint the VOCs in faeces and urine of AD model mice.

Background Wogonin has been reported to exhibit various biological activities such as anti-inflammation, anti-microbial, and anti-tumor. Previous studies have demonstrated that wogonin could down-regulate Cyclin D1 activity on multiple cancers. However, the related mechanisms have not been fully elucidated so far. Purpose The aim of the current study was to explore whether wogonin can suppress hepatocellular carcinoma (HCC) progression and the mechanism of wogonin in inhibiting Cyclin D1 expression. Methods Herein, we assessed the anti-tumor activity of wogonin against hepatocellular carcinoma (HCC) by MTT assay, clonogenic assay, cell cycle analysis and orthotopic xenograft mouse models. Western blot, immunofluoscence assay, co-immunoprecipitation assay, docking program, surface plasmon resonance, site-directed mutagenesis assay and immunohistochemical assay were performed for exploring the underlying mechanisms of wogonin-induced growth inhibition in HCC. Results Our results showed that non-toxic dosage of wogonin (10, 20 µM) could inhibit cells proliferation and suppress cells cycle progression in MHCC97L and HepG2 cell. Moreover, the findings from the western blot and immunofluoscence assay confirmed the inhibition action of wogonin (10, 20 µM) on Cyclin D1 expression in MHCC97L cells, and wogonin (10, 20 µM) pre-treatment was capable of promoting Cyclin D1 ubiquitination and degradation in MHCC97L cell. In addition, wogonin promoted phosphorylation of Cyclin D1 on threonine-286 site, the mutation of threonine-286 to alanine-286A blocked Cyclin D1 proteolysis induced by wogonin. Wogonin-promoted Cyclin D1 phosphorylation and subsequent proteolysis may associate with the activation of GSK3beta in cancer cells. The phosphorylated form of GSK3beta (active form) expression was significantly increased after wogonin (20 µM) exposure. Molecular docking study and Biacore SPR analysis of GSK3beta mutant further validated the high-affinity wogonin binding site on GSK3beta. Moreover, in vivo studies further confirmed that phospho-GSK3beta Tyr216 was over-expressed in HCC specimens after wogonin treatment while the amount of Cyclin D1 was significantly decreased. Conclusion In summary, our data reveal a novel molecular mechanism by which wogonin induces HCC cells cycle arrest and suppresses tumor proliferation.

Nocardia usually manifests as opportunistic infections in immunocompromised hosts. Here, we report a rare case of an immunocompetent patient with lymphocutaneous nocardiosis. The patient was a 34-y...

SIRT3 is a NAD+-dependent mitochondrial protein deacetylase implicated in the regulation of central metabolism and mitochondrial proteostasis. SIRT3 is downregulated in clear cell renal cell carcinoma (ccRCC), which is the most common form of renal cancer. Although ccRCC is characterized by a typical Warburg-like phenotype, mitochondrial dysfunction and elevated fat deposition, it is unknown whether SIRT3 plays a role in tumorigenesis and the development of this disease. In the present study, we found that SIRT3 overexpression and knockdown had opposing effects on the growth of ccRCC cells, decreasing and increasing the rate of cell proliferation, respectively. SIRT3 overexpression also increased mitochondrial mass in ccRCC cells. Unexpectedly, SIRT3 overexpression increased ROS levels, and sensitized cells to oxidative stress. Metabolomics and quantitative proteomics showed that SIRT3 overexpression alterd cellular metabolism and reversed the Warburg effect in ccRCC cells. Further studies demonstrated that SIRT3 promoted mitochondrial biogenesis by increasing both the expression and deacetylation of TFAM (transcription factor A, mitochondrial). Mutagenesis experiments revealed that acetylation of TFAM at K154 impaired TFAM interaction with mitochondrial DNA, thereby decreasing the activity of the protein and, consequently, mitochondrial biogenesis. Overall, our results suggest that SIRT3 regulates mitochondrial biogenesis and that its downregulation promotes a Warburg phenotype in ccRCC.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging high-fatality infectious disease caused by a novel phlebovirus belonging to the Bunyaviridae family. Thus, the independent predictors of death in this disease must be identified to improve the survival of affected patients. A total of 25 hospitalized patients with SFTS virus infection were enrolled in our study, and their medical records and laboratory data were reviewed. The risk factors for death were examined by binary logistic regression. The patient age was significantly higher in the deceased cases than in those who recovered (P = .020). Moreover, the occurrence of shock, respiratory failure, hemorrhagic manifestations, kidney dysfunction, and arrhythmia was significantly more common in the deceased cases than in the recovered cases (P = .016, P = .004, P = .005, P = .002, P = .038). Univariate binary logistic regression showed that shock, arrhythmia, and hemorrhage, as well as PCT, serum creatinine (Scr), and blood urea nitrogen (BUN) elevations, were the risk factors for death (odds ratio, OR 28.5, P = .015; OR 13.5, P = .027; OR 36, P = .008; OR 28.5, P = .015; OR 36, P = .008; and OR 76.0, P = .004). However, the BUN increase was the only independent risk factor for death indicated by multivariate logistic regression (OR 76.0, P = .004). SFTS presents with a high fatality rate. When patients with SFTS manifest shock, arrhythmia, hemorrhage, PCT increase, and Scr and BUN elevations, especially BUN > 8.2 μmol/L, health care providers should be alerted and must administer early intervention to prevent the progress to death.

Glutaredoxins (GRXs), small redox proteins that use reduced glutathione as an electron donor, are key components of the cellular antioxidant system. In this study, we used Saccharomyces cerevisiae as a model system to investigate the effects of GRX deletion on yeast chronological life span (CLS). Deletion of either Grx1 or Grx2 shortened yeast CLS. Quantitative proteomics revealed that GRX deletion decreased the expression of stress-response proteins, leading to increased cellular reactive oxygen species accumulation and, subsequently, intracellular acidification. This activated the Ras/protein kinase A (PKA) signaling pathway. Genetic and biochemical analyses demonstrated that Ras/PKA activation decreased stress resistance and increased biosynthesis, requiring yeast cells to grow under unfavorable conditions and resulting in a shortened CLS. Our results provided new insights into mechanisms underlying exacerbation of the aging process by oxidative stress.

Ubiquitin proteasome system (UPS) consists of ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), proteasomes, and deubiquitinating enzymes (DUBs). Ubiquitin, E1s, several E2s, E3s, and proteasomes play an important role in the regulation of cardiac homeostasis and dysfunction; however, less is known about the role of DUBs in the heart. Here, we uncovered a crucial role of cyclindromatosis (CYLD), a DUB, in mediating cardiac maladaptive remodeling and dysfunction. CYLD expression was dramatically upregulated in the cardiomyocytes of hypertrophic and failing human and murine hearts. Knockout of CYLD improved survival rate and alleviated cardiac hypertrophy, fibrosis, apoptosis, oxidative stress, and dysfunction in mice that were subjected to sustained pressure overload induced by transverse aortic constriction. Deep sequencing and gene array analyses revealed that the most dramatically changed genes are those involving in the free radical scavenging pathway and cardiovascular disease, including fos, jun, myc, and nuclear factor erythroid-2 related factor 2 (Nrf2) in the heart. Moreover, knockdown of CYLD enhanced mitogen-activated protein kinase (MAPK) ERK- and p38-mediated expression of c-jun, c-fos, and c-myc, which govern Nrf2 expression in cardiomyocytes. The CYLD deficiency-induced suppression of reactive oxygen species (ROS) formation, death and hypertrophy in cardiomyocytes was blocked by additional knockdown of Nrf2. Taken together, our findings demonstrate for the first time that CYLD mediates cardiac maladaptive remodeling and dysfunction, most likely via enhancing myocardial oxidative stress in response to pressure overload. At the molecular level, CYLD interrupts the ERK- and p38-/AP-1 and c-Myc pathways to suppress Nrf2-operated antioxidative capacity, thereby enhancing oxidative stress in the heart.

The lentiviral accessory protein Vpx is critical for viral infection of myeloid cells and acts by hijacking CRL4(DCAF1) E3 ubiquitin ligase to induce the degradation of the host restriction factor SAMHD1. It has been observed that the sequences from HIV-2 and SIVsmm/SIVmac Vpx contain a poly-proline tail which is distinct from other SIV Vpx proteins. However, the role of this region in Vpx function is controversial. Herein, we found proteasome-dependent degradation of a Vpx mutant lacking the poly-proline tail in the nucleus in a CRL4(DCAF1) E3 ligase-independent fashion. Unlike wild-type Vpx, the poly-proline tail mutant Vpx is partly defective in enhancing viral infection in macrophages. Our findings suggest that during Vpx evolution, Vpx of the HIV-2/SIVsm/SIVmac lineage is targeted by a CRL4(DCAF1) E3 ligase-independent ubiquitination pathway, and have gained this interesting region, allowing them to maintain nuclear accumulation as part of their adaptation to host cell regulation.

ObjectiveThe effect of polyomavirus infection in HSCT recipients is poorly understood.MethodsWe evaluated 38 HSCT recipients. Polyomavirus was detected by nested qualitative polymerase chain reaction (PCR) assays of urine. The risk factors for BK virus and JC virus were analysed. The kidney and liver functions of infected and uninfected patients were compared.ResultsBK virus, JC virus, and simian virus 40 were detected in 21%, 42%, and 0% of HSCT recipients respectively. HCMV infection was found to be an independent risk factor for JC virus infection (odds ratio (OR): 8.528), while transplants with mismatched HLA are more susceptible to BK virus infection (OR: 12.000). Liver function of JC virus-infected subjects was worse than that of uninfected subjects.ConclusionWe must be vigilant for opportunistic polyomavirus infections in HSCT recipients, especially those with HCMV co-infection or a mismatched HLA transplant. When unexplained liver function deterioration is observed, JC virus infection should be considered.