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Background Stroke has always been a major threat worldwide but is most severe in China, with 2.5 million new stroke cases each year and 7.5 million stroke survivors, placing a heavy burden on the social and national health care systems. Zhishi Rhubarb Soup (ZRS) is a traditional Chinese medicine (TCM) that has been used clinically for many years in China. To explore the potential mechanism of ZRS in the treatment of stroke, liquid chromatography with mass spectrometry (LC–MS) was performed. Methods In this study, a quantitative proteomic method with LC–MS was used to analyse the proteomic differences between MACO samples treated with ZRS and those without ZRS treatment. Results Liquid chromatography with mass spectrometry (LC–MS) analysis led to the identification of 35,006 peptides, with 5160.0 proteins identified and 4094.0 quantified. Significantly differentially expressed proteins were identified through data analysis, and the difference was found to be more than 1.2 times (P Conclusion In this study, LC–MS/MS was performed to assess the effects of ZRS on differentially expressed proteins in rats with cerebral infarction. These promising results could help to improve the understanding of the effects of drugs on stroke.

BACKGROUND Cervical cancer is a common malignant tumor of the female reproductive system in the world, which is a serious threat to women's life and health. According to the latest report, the incidence of cervical cancer is 11.42 per 100 000, and the mortality rate is 3.77 per 100 000 in Yunnan Province, which is still higher than the national average. Although there have been some relevant studies on the risk factors of cervical cancer in recent years, research on ethnic minorities is lacking in Yunnan Province. OBJECTIVE To analyze and explore the related risk factors of cervical cancer in women of ethnic minorities in Yunnan Province, to provide the scientific basis for the development of cervical cancer prevention and control strategies and measures in this region. METHODS In total 1119 cervical cancer patients diagnosed by histopathology at the Yunnan Cancer Center (Yunnan Cancer Hospital) from January 2010 to December 2019 were selected as the case group. According to the 1:1 matching principle of the case-control study, 1119 patients with nonmalignant tumors of the same nationality, the same hospital, age difference less than 3 years old, were selected as the control group. Univariate and multivariate conditional logistic regression were used for statistical analysis. RESULTS Basic medical insurance for rural residents (OR = 3.659; P = 0.003), human papilloma virus (HPV) infection (OR = 90.030; P

Atopic dermatitis (AD) is a common chronic inflammatory skin condition which impacts psychological wellbeing and social relationships. There have been studies of AD’s impact on quality of life (QoL) in Western countries, but these findings cannot be directly extrapolated to Asian populations with genetic, environmental and cultural differences. Therefore, we aimed to systematically review the literature pertaining to QoL impairment in AD in East and Southeast Asia to characterize the impact of AD on patients and their families, and to identify the factors affecting the degree of QoL impairment. A search of English language papers was conducted on MEDLINE, EMBASE, PSYCInfo, Global Health and Web of Science. Observational studies measuring QoL using single or multi-item instruments in people with self-reported or physician diagnosed atopic dermatitis were included. 27 studies from 29 articles were included and synthesized. There is data documenting QoL impairment in AD sufferers and their families, across a wide range of Asian countries, healthcare settings and ages. Aspects of QoL impacted to a greater extent included symptoms of itch, feelings of embarrassment, and sleep disturbance. Severity of disease affects the degree of impairment of QoL, but there is no apparent link between QoL impairment and patient demographic factors, or other medical factors such as age at diagnosis or duration of illness. Our findings also highlighted the need for clinicians to actively explore the impact of patient’s symptoms, especially in an Asian context where healthcare communications are traditionally doctor-centric.

Remarkable advances in nano delivery systems have provided new hope for tumor prevention, diagnosis and treatment. However, only limited clinical therapeutic effects against solid tumors were achieved. One of the main reasons is the presence of abundant physiological and pathological barriers in vivo that impair tumoral penetration and distribution of the nanodrugs. These barriers are related to the components of tumor microenvironment (TME) including abnormal tumor vasculature, rich composition of the extracellular matrix (ECM), and abundant stroma cells. Herein, we review the advanced strategies of TME remodeling to overcome these biological obstacles against nanodrug delivery. This review aims to offer a perspective guideline for the implementation of promising approaches to facilitate intratumoral permeation of nanodrugs through alleviation of biological barriers. At the same time, we analyze the advantages and disadvantages of the corresponding methods and put forward possible directions for the future researches.

Background Berry syndrome, a rare combination of cardiac anomalies, consists of aortopulmonary window (APW); aortic origin of the right pulmonary artery; interrupted aortic arch (IAA) or hypoplastic aortic arch or coarctation of the aorta; and an intact ventricular septum. There is lack of review articles that elucidate the clinical features, diagnosis, treatment, and outcomes of Berry syndrome. This publication systematically reviews the 89 cases published since 1982 on Berry syndrome. Case presentation A 38-year-old woman presented with a loud murmur and cyanosis. Transthoracic echocardiography demonstrated a severely dilated aorta and main pulmonary artery with a large intervening defect. Distal to the APW, the ascending aorta gave rise to the right pulmonary artery. Additionally, a type A IAA, an intact ventricular septum, and a large patent ductus arteriosus were revealed. Computed tomography angiography with 3-dimensional reconstruction confirmed above findings. This is the first report of a patient of this age with Berry syndrome who did not undergo surgery. Conclusions Berry syndrome is a rare but well-identified and surgically correctable anomaly. Patients with Berry syndrome should be followed up for longer periods to better characterize long-term outcomes.

Humanin (HN) is a mitochondrial-derived peptide that protects many cells/tissues from damage. We previously demonstrated that HN reduces stress-induced male germ cell apoptosis in rodents. HN action in neuronal cells is mediated through its binding to a trimeric cell membrane receptor composed of glycoprotein 130 (gp130), IL-27 receptor subunit (IL-27R, also known as WSX-1/TCCR), and ciliary neurotrophic factor receptor subunit (CNTFR). The mechanisms of HN action in testis remain unclear. We demonstrated in ex-vivo seminiferous tubules culture that HN prevented heat-induced germ cell apoptosis was blocked by specific anti-IL-27R, anti-gp130, and anti-EBI-3, but not by anti-CNTFR antibodies significantly. The cytoprotective action of HN was studied by using groups of il-27r−/− or ebi-3−/− mice administered the following treatment: (1) vehicle; (2) a single intraperitoneal (IP) injection of HN peptide; (3) testicular hyperthermia; and (4) testicular hyperthermia plus HN. We demonstrated that HN inhibited heat-induced germ cell apoptosis in wildtype but not in il-27r−/− or ebi-3−/− mice. HN restored heat-suppressed STAT3 phosphorylation in wildtype but not il-27r−/− or ebi-3−/− mice. Dot blot analyses showed the direct interaction of HN with IL-27R or EBI-3 peptide. Immunofluorescence staining showed the co-localization of IL-27R with HN and gp130 in Leydig cells and germ cells. We conclude that the anti-apoptotic effects of HN in mouse testes are mediated through interaction with EBI-3, IL-27R, and activation of gp130, whereas the role of CNTFR needs further studies. This suggests a multicomponent tissue-specific receptor for HN in the testis and links HN action with the IL-12/IL-27 family of cytokines.

Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress related psychiatric disorders. Bcl-2 associated athanogene (Bag-1) is a target for the actions of mood stabilizers. Bag-1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag-1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag-1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 minutes and 24 hours. By contrast, after stimulation with CORT for 3 days, localization of the Bag-1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag-1 overexpression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia-like and depression-like behaviors in the sucrose-consumption test and forced swimming test, and these behaviors were rescued by Bag-1 overexpression. These results suggest that Bag-1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag-1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.

Background With guidance from the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th edition, we explored the characteristics of central lymph node metastasis (CLNM) of papillary thyroid micro-carcinoma (PTMC) in elderly patients ≥55 years of age. Our goal was to provide references for establishing a lymph node dissection scheme in such patients. Methods We retrospectively analyzed the clinical data of thyroid cancer patients admitted to the Head and Neck Surgery Center of Sichuan Cancer Hospital, Chengdu, China, from January 2015 to September 2018. Then, we screened and analyzed eligible PTMC cases in strict accordance with our inclusion and exclusion criteria. Results The study included 107 patients, including 24 men and 83 women. Median age was 59.99 ± 4.58 years. The maximum diameter range of the cancer foci was 4-10 mm, and the median was 7.59 ± 1.78 mm. Unilateral lobectomy had been performed in 32 cases, total thyroidectomy in 75 cases and lateral cervical lymph node dissection in 21 cases. There were 60 cases of CLNM (56.07%) and 13 cases of lateral cervical lymph node metastasis (12.10%). The sensitivity of preoperative ultrasound in predicting CLNM was 100%, but its accuracy was only 50.47%. Multivariate logistic regression analysis showed that multiple cancer foci (area under the curve [AUC] = 0.632), extra-thyroidal expansion of cancer focus (AUC = 0.721), and irregular nodules (AUC = 0.603) were independent risk factors for CLNM of PTMC in elderly patients (P < 0.05). Overall predictability for PTMC-CLNM was 80.30%. Conclusion 1) Preoperative color Doppler ultrasound is not recommended as the basis for cervical lymph node dissection in PTMC patients. 2) For multiple cancer foci, irregular nodules, and elderly patients with PTMC extra-thyroidal expansion, we recommend a prophylactic central lymph node dissecting. 3) Nonsurgical observation of PTMC in elderly patients with low risk should be carefully selected.

In this study, in order to evaluate the influences of drying methods on the chemical structures and bioactivities of polysaccharides from okra (OPPs), four drying methods, including microwave drying at 400 W, 600 W, and 800 W, freezing drying, hot air drying, and vacuum drying, were applied to dry okra fruits. Six different OPPs were extracted from okra dried by different drying methods. Results showed that physicochemical characteristics and bioactivities of OPPs varied by different drying methods. Noticeable variations in extraction yields, molecular weights, rheological properties, molar ratios of constituent monosaccharides, contents of uronic acids, degrees of esterification, and contents of total phenolics were observed in OPPs obtained by different drying methods. In addition, results showed that OPPs, especially OPP-H and OPP-V obtained by hot air drying and vacuum drying, respectively, exhibited remarkable antioxidant activities (ABTS, DPPH, and nitric oxide radical scavenging activities, and ferric reducing antioxidant powers), strong in vitro binding capacities (fat, cholesterol, and bile acids binding capacities), and obvious inhibitory activities on α-amylase and α-glucosidase. Results suggested that the hot air and vacuum drying techniques could be appropriate drying methods before extraction of OPPs with high bioactivities for applications in the functional food and medicine industries.

Cerebral ischemia/reperfusion injury (IRI) is one of major causes of ischemic organ damage. It is well established that inflammatory cytokines serve as regulatory factors in cerebral oxygen glucose deprivation/reoxygenation (OGD/R). However, the involving mechanism is not clear enough. OGD/R PC12 cells were used as a hypoxia/reoxygenation model. IL-32 expression and cell viability were detected by qRT-PCR and CCK-8 assay, respectively. Cell apoptosis were determined by flow cytometry and western blotting. Protein levels of inflammatory factors, and the activity of MPO, MDA and SOD were analyzed. Furthermore, western blot assay was carried out to assess protein levels of Nrf2, keap1, NQO-1, p-p65, p-IκBα, p65 and IκBα. The results revealed that IL-32 expression was significantly upregulated in PC12 cells induced by OGD/R. Nrf2, keap1 and NQO-1 level was reduced while phosphorylation level of p65 and IκBα was up-regulated in OGD/R-induced PC12 cells. Mechanism investigations found that IL-32 silence elevated the level of Nrf2, Keap1 and NQO-1, reduced p-p65 and p-IκBα level, and regulated the contents of TNF-a, IL-1β, IL-6 and MCP-1 in OGD/R PC12 cells. In addition, knockdown of IL-32 suppressed production of intracellular ROS, elevated SOD activity, reduced MPO and MDA content, and enhanced cell viability. Furthermore, cell apoptosis was induced in OGD/R PC12 cells with IL-32 silence. However, Nrf2 inhibitor reversed the effects of IL-32 knockdown on OGD/R PC12 cells. This research suggests that IL-32 silence may alleviate OGD/R and Nrf2 plays an important role in the protection by IL-32 silence on PC12 cells induced by OGD/R.

In recent years, methylation modification has been determined to be vital for the biological regulation of normal cells, tumor cells, and tumor microenvironment immune cells. Enhancer of zeste homology 2 (EZH2), a component of the Polycomb Repressive Complex 2 (PRC2), catalyzes the trimethylation of the downstream gene in the tri-methylates histone three lysine 27 (H3K27me3) position, which causes chromatin pyknosis, and thus, silences the expression of related genes. In this paper, we reviewed the role of EZH2 in regulating bone marrow mesenchymal stem cell differentiation and the immune cell function in tumor microenvironment, summarized all types of existing EZH2 inhibitors and the main clinical trials, and proposed relevant ideas for potential clinical applications.

Severe neutropenia is defined as an absolute neutrophil count (ANC) of less than 0.5 × 109/L. Severe congenital neutropenia (SCN) is an inborn disorder with maturation arrest of granulocytes due to various genetic abnormalities, which may lead to immunodeficiency. Among several associated genetic mutations, the variants or heterozygous mutations of the ELANE gene coding neutrophil elastase comprise approximately 50% of the genetic causes of SCN. We present a newborn (male) with severe neutropenia due to a novel ELANE gene mutation. The newborn was born at 386/7 weeks gestation to a 25-year-old mother with hypertension and morbid obesity. Pregnancy and delivery were uncomplicated but the baby obtained a complete blood count (CBC) on day of life 2 for a work up of hyperbilirubinemia. He was noted to initially have an ANC of 0.2 × 109/L and 0 on subsequent blood counts. A bone marrow biopsy showed a left shift and consistent with myeloid maturation arrest. In direct DNA sequencing analysis, we found an ELANE gene mutation (Val119Glu, V119E), which may be a new gene mutation to cause SCN. The diagnosis of SCN in newborns is usually based on neutropenia identified on a routine CBC. Sufficient awareness and high suspicion of this rare disease can prevent missed or delayed diagnosis of SCN. Our analysis also suggests a new pathological mutation in the ELANE gene and supports the important role of molecular testing in SCN.

The netB-positive Clostridium perfringens has been considered as the requisite to consistently induce necrotic enteritis (NE). However, use of a netB-positive strain did not guarantee consistent NE reproduction unless high protein diets or Eimeria, conceived as 2 major predisposing factors, was incorporated. To establish a refined model, the roles of dietary fishmeal inclusion, Eimeria inoculation, and netB-positive C. perfringens challenge in NE induction and the confounding effects of Eimeria infection on NE were examined. The results showed that the use of netB-positive C. perfringens without a predisposing factor failed to induce NE. Fishmeal incorporation promoted the occurrence of NE but did not significantly affect the incidence of the disease in conjunction with challenge of netB-positive C. perfringens. However, the additional participation of Eimeria infection in the same induction procedure produced significantly higher numbers of NE cases and promoted more severe lesions in chickens (P < 0.05). Inoculation of Eimeria resulted in a significant higher incidence of NE compared to the non-Eimeria treated group (P < 0.05). The results demonstrated that both netB-positive C. perfringens and predisposing factors were required for the reproduction of disease. Mild-to-moderate coccidial infection (coccidial lesion score ≤ 2) was noted in NE cases in this model but severe coccidial infection did not correlate with the occurrence of NE, indicating mild coccidial infection may be beneficial for the development of NE. If multiple species infection of Eimeria precedes the challenge of C. perfringens, days 19 to 21 (1 to 3 D after the last clostridial challenge) was the time period favorable for observations of NE lesions. The time after this period may be subject to bias of severity, incidence, or mortality of NE owing to the profound coccidial lesions in the intestinal region. This study demonstrated that the co-infection with netB-positive C. perfringens and Eimeria species under fishmeal incorporation produced a desirable NE model, being of value in studying the effectiveness of novel feed additives and alternative mitigation strategies to prevent NE.

Electrocheluminescence (ECL) immunoassay amplified by coreaction accelerators has experienced major breakthroughs in ultrasensitive detection of biomarkers. Herein, CeO2/SnS2 heterostructures were synthesized and applied as a novel coreaction accelerator to enhance the ECL efficiency of the luminol-dissolved O2 system for the first time. Benefiting from the well-matched lattice spacing, ultrafine CeO2 nanoparticles (NPs) were grown in situ on layered SnS2 nanosheets (NSs) with improved dispersion. CeO2/SnS2 as an electroactive substrate can remarkably accelerate the generation of abundant superoxide anion radicals (O2•-) to react with luminol anion radical (L•-), achieving about 2-fold stronger ECL intensity than that of pure CeO2 NPs. To avoid harsh chemical synthesis of conventional ECL labels and simplify the antibody conjugation process, ferritin (Ft) was served as a natural nanocarrier to immobilize luminol molecules (Lum@Ft) via a one-step linkage, whose protein nanocage can easily connect with the detection antibody. Moreover, a robust site-oriented immobilization strategy using HWRGWVC heptapeptide as specific capturer was further adopted to maintain the bioactivity of the capture antibody on the amine-functionalized CeO2/SnS2 surface, which promoted the incubation efficiency markedly. On account of this advanced sensing strategy, a brand new biosensor was constructed for the accurate detection of heart failure biomarkers, which performed with favorable linearity in the range of 0.0001-50 ng/mL and achieved the detection limit of 36 fg/mL.

Human milk oligosaccharides are complex carbohydrates with multibiofunctional health benefits to newborns. Human milk free oligosaccharides (HMOs) are well characterized. However, changes in the N/O-glycome during lactation are poorly reported. Herein, we qualitatively and quantitatively investigated N/O-glycome profiles and their alteration in human milk at different lactation stages. N-Glycans were mainly fucosylated and nonsialylated, nonfucosylated throughout lactation. O-Glycans mainly consisted of sialylated and nonsialylated, nonfucosylated in colostrum and transitional milk, and fucosylated and nonfucosylated, nonsialylated in mature milk. Fucosylated and sialylated N-glycans gradually decreased and increased, respectively, as lactation progressed; O-glycans showed the reverse. Interestingly, changes in HMO abundance decreased during lactation, complementing HMG N/O-glycome changes. In conclusion, temporal HMG glycosylation changes provide the groundwork for developing infant formula that is closer to breast milk at different lactation stages.

As the fifth most common cancer and the second leading cause of cancer related deaths worldwide, hepatocellular carcinoma (HCC) is an aggressive tumor type with poor prognosis causing 250,000 to one million deaths annually. Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) are the two major growing risk factors and both may develop liver fibrosis or even HCC. However, compared with the rate of patients with ASH progressing to HCC annually, it is much lower in NASH patients. The present study is to clarify the protein expression of epigenetic regulators and Inflammasome components in the oncogenesis pathway between ASH and NASH. By using the immunofluorescence method and morphometrically quantitating the fluorescence intensity in liver biopsied specimens from NASH and ASH patients, we studied the protein expression within hepatocytes cytoplasm of candidate epigenetic regulators G9A and LHPP and inflammasome component ASC. Compared with the control group patients, the expression levels of all three proteins were upregulated in the ASH and NASH group of patients (p?0.001 in all molecules). While compared with the ASH group of patients, only the expression levels of G9a were statistically lower in the NASH group of patients (p?

The expansion of electrochemiluminescence (ECL) technology to immunoassay at the core of care emphasizes all immune molecules will not be inactivated in the analysis process. That poses a major challenge to ECL-based biosensors due to the deoxynucleotide sequences of an antigen or antibody could be oxidized through a route of excessive cyclic potential. Herein, an ultrasensitive ECL biosensor was developed based on a novel bioactivity-protected sensing strategy utilizing Au nanoclusters (Au NCs) as low-potential luminophor for detection of procalcitonin (PCT). Bovine serum albumin (BSA)-templated Au NCs exhibited a low-potential anodic ECL signal in triethylamine (TEA) solution at 0.87 V, where it is suitable for the survival of immune molecules. Taking advantage of good conductivity and high surface area, a Cu2S snowflake not only functions as a satisfying substrate for connecting immune molecules but also acts as co-reaction accelerator to produce more cationic radicals TEA•+, which could improve the ECL intensity needed to meet the requirements of trace analysis. Otherwise, HWRGWVC (HC-7) heptapeptide as specific antibody immobilizer for site-oriented fixation was introduced to further maintain the bioactivity of an antibody. In view of the preceding discussion, the obtained biosensor exhibited ultrahigh immune recognition to targets so that the detection limit was as low as an unprecedented value of 2.36 fg/mL, which will be of great significance to the application and development of a biosensor in the future.

As the fifth most common cancer and the second leading cause of cancer related deaths worldwide, hepatocellular carcinoma (HCC) causes up to one million deaths annually. Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) are becoming the two major risk factors because both may develop liver fibrosis and hepatocellular carcinoma (HCC) if left untreated. However, compared with 3-10% of patients with ASH may progress to HCC annually, about only 0.5% NASH patients may progress to HCC annually. The present study is to clarify the protein expression differences of tumor suppressor genes (TSGs) between ASH and NASH. In liver biopsied specimens from NASH and ASH patients, using an immunofluorescence method and morphometrically quantitating the fluorescence intensity, we studied the protein expression within hepatocytes cytoplasm of candidate TSGs including RUNX3, GSTP1, and RASSF1A. Compared with the control group of patients, the expression levels of all three proteins were upregulated in the ASH group of patients (p .001 in all molecules). While RUNX3 was upregulated, GSTP1 and RASSF1 did not change in the NASH group of patients. The most important finding is that compared with the ASH group of patients, the expression levels of all three TSG proteins, RUNX3, GSTP1, and RASSF1, were significantly lower in the NASH group of patients (p .001 in all three molecules). These results confirmed our previous finding that there are significant differences of many molecules including TSGs that changed in NASH compared to ASH. Thus, we conclude that there are significantly different TSGs and pathways involved during the pathogenesis of HCC development in NASH compared to ASH that may help to develop different strategies for prevention and treatment of NASH and ASH patients.

In corneal epithelium, tight junctions play a vital role in its barrier function. Human cornea is highly susceptible to damage by dust. Continued daily exposure to dust has been associated with increased risks of corneal injury. Studies demonstrated that water extract of dust induced cytotoxicity in human corneal epithelial cells (HCECs); however, its effects on corneal epithelial barrier function are unknown. In this study, we determined the concentrations of heavy metals in water extracts of dust, with office dust having higher concentrations of heavy metals than housedust, and Cu and Zn being highest among metals for both dust. Changes in barrier function and its associated mechanism after exposing HCECs to water extracts of dust at 48 μg/100 μ L for 7 d were evaluated. Water extracts of both dust caused decrease of TEER value (39–73%), down-regulation of gene expression related to tight junction and mucin (0.2–0.8 fold), and loss of ZO-1 immunoreactivity from cellular borders, with office dust having greater potential than housedust to disrupt corneal epithelial barrier function. Our data implied the importance to reduce heavy metals in dust to reduce their adverse impacts on human eyes.

Peripheral nerve injuries (PNIs) often result in persistent neuropathic pain, seriously affecting quality of life. Existing therapeutic interventions for PNI-induced neuropathic pain are far from satisfactory. Extracellular signal-regulated kinases (ERKs) and p38 have been found to participate in triggering and maintaining PNI-induced neuropathic pain. However, ERK and p38 also contribute to axonal regeneration and motor function recovery after PNI, making it difficult to inhibit ERK and p38 for therapeutic purposes. In this study, we simultaneously characterized neuropathic pain and motor function recovery in a mouse sciatic nerve crush injury model to identify the time window for therapeutic interventions. We further demonstrated that delayed delivery of a combination of ERK and p38 inhibitors at three weeks after PNI could significantly alleviate PNI-induced neuropathic pain without affecting motor function recovery. Additionally, the combined use of these two inhibitors could suppress pain markedly better than either inhibitor alone, possibly reducing the required dose of each inhibitor and alleviating the side effects and risks of the inhibitors when used individually.

Major depressive disorder (MDD) is a common, chronic, recurrent disease. The existing drugs are ineffective for approximately half of patients, so the development of antidepressant drugs with novel mechanisms is urgent. Cumulative evidence has shown neuro-inflammation plays a key role in the etiology of major depressive disorder. Clinical studies implicated that bile acids, an important component of gut-brain axis, inhibit neuro-inflammation and mediate the pathophysiology of the MDD. Here, we found that ganoderic acid A (GAA) modulated bile acid receptor FXR (farnesoid X receptor), inhibited brain inflammatory activity, and showed antidepressant effects in the chronic social defeat stress depression model, tail suspension, forced swimming, and sucrose preference tests. GAA directly inhibited the activity of the NLRP3 inflammasome, and activated the phosphorylation and expression of the AMPA receptor by modulating FXR in the prefrontal cortex of mice. If we knocked out FXR or injected the FXR-specific inhibitor z-gugglesterone (GS), the antidepressant effects induced by GAA were completely abolished. These results suggest that GAA modulates the bile acid receptor FXR and subsequently regulates neuroimmune and antidepressant behaviors. GAA and its receptor FXR have potential as targets for the treatment of MDD.

BACKGROUND Kisspeptin and its receptor KISS1R have been found to be essential regulators of reproductive function. Previous data have revealed the presence of Kiss1 and Kiss1r mRNAs in the hypothalamus and the testis of humans and rodents. However, the precise location and possible physiological role of the kisspeptin/KISS1R system in the testis remain ambiguous. METHODS We first produced an anti-KISS1R immunoglobulin Y antibody for KISS1R identification. To detect the exact sites of KISS1R and kisspeptin expression in the testis, we conducted immunohistochemistry assays on sections of testes. We used real-time polymerase chain reactions to identify Kiss1r in mice and to determine the expression levels of testicular genes. Finally, to verify the upstream regulation on the Kisspeptin/KISS1 receptor system, we treated primary mouse Leydig cells and MA-10 cells with luteinizing hormone (LH) and Br-cAMP, respectively, and examined Kiss1 and Kiss1r mRNA expression. RESULTS Immunohistochemistry assays revealed that kisspeptin was expressed in Leydig cells and KISS1R was localized in the seminiferous tubules. With real-time polymerase chain reactions, we found Kiss1r mRNA was constitutively expressed in the mouse testis from birth until the postnatal fourth week. Furthermore, mRNA expression of Kiss1 was synchronized with that of Insl3 and Cyp19a. However, the expression of the LH receptor-encoding gene increased 1 week earlier than did Kiss1 expression. This indicated that the kisspeptin/KISS1R system in the testis may be controlled by LH and cAMP signaling pathways. Finally, we confirmed that Kiss1 mRNA expression was increased in both LH-treated primary Leydig cells and Br-cAMP-treated MA-10 cells (p

At present, the novel Covid-19 pneumonia is prevalent, affecting millions of people. Here, we summarized the pharmacological basis of adenosine, adenosine receptors, adenosine agonist cordycepin (3'-deoxyadenosine), and Cordyceps product in the brain protection and amelioration of pneumonia to provide useful information to cope with the global pandemic of novel coronavirus (COVID-19). Adenosine, a mediator of innate immunity, is abundantly secreted by the injured lung tissues during inflammation. Through the activation of adenosine receptors A1, A2A, A2B and A3, adenosine plays an important role in protecting against acute lung injury and brain injury. Cordycepin (3-deoxyadenosine) is an activator of adenosine receptors. It can enhance human immunity, promote anti-inflammatory processes, inhibit RNA virus reproduction, protect against brain, lung, liver, heart, and kidney damage, and ameliorate lung-fibrosis in clinical and animal models. Cordyceps and cordycepin products could be used as a potential medicinal adenosine receptor agonist that can play a beneficial role in the amelioration of Covid-19 pneumonia and protection of brain.

Multiple sclerosis (MS), as an inflammatory demyelinating disorder of central nervous system, is the leading cause of non-traumatic neurologic disability in young adults. The pathogenesis of MS remains unknown, however, a dysregulation of glia-neuroimmune signaling plays a key role during progressive disease stage. Most of the existing drugs are aimed at the immune system, but there is no approved drug by promoting remyelination after demyelination so far. There is a great interest in identifying novel agents for treating MS bytargeting to switch the immune imbalance from pro-inflammation and apoptosis to anti-inflammation and regeneration during remyelination phase. Here, we reported that ganoderic acid A (GAA) significantly enhanced the remyelination and rescued motor deficiency in two animal models of MS, including cuprizone-induced demyelination and myelin oligodendrocyte glycoprotein (MOG) 35-55-induced experimental autoimmune encephalomyelitis model. In these two independent MS animal models, GAA modulated neuroimmune to enhance the anti-inflammatory and regeneration markers IL-4 and BDNF, inhibited inflammatory markers IL-1β and IL-6, followed by down-regulation of microglia activation and astrocyte proliferation. Pharmacological and genetic ablation of farnesoid-X-receptor (FXR) abolished GAA-induced remyelination and restoration of motor deficiency in MS mice. Thus, GAA is a novel and potential therapeutic agent that can rescue MS neuroimmune imbalance and remyelination through an FXR receptor-dependent mechanism. Clinical investigation on the therapeutic effect of GAA in improving remyelination of the MS patients to rescue the motor function is warranted.

Three-dimensional (3D) image reconstruction of tumors based on serial histological sectioning is one of the most powerful methods for accurate high-resolution visualization of tumor structures. However, 3D histological reconstruction of whole tumor has not yet been achieved. We established a high-resolution 3D model of molecular marked whole laryngeal cancer by optimizing the currently available techniques. A series of 5,388 HE stained or immunohistochemically stained whole light microscopic images (200 ×) were acquired (15.61 TB).The data set of block-face images (96.2 GB) was also captured. Direct volume rendering of serial 6.25 × light microscopy images did not demonstrate the major characteristics of the laryngeal cancer as expected. Based on fusion of two datasets, the accurate boundary of laryngeal tumor bulk was visualized in an anatomically realistic context. In the regions of interest, micro tumor structure, budding, cell proliferation and tumor lymph vessels were well represented in 3D after segmentation, which highlighted the advantages of 3D reconstruction of light microscopy images. In conclusion, generating 3D digital histopathological images of a whole solid tumor based on current technology is feasible. However, data mining strategy should be developed for complete utilization of the large amount of data generated.

Major depressive disorder (MDD) is a prevalent, chronic, and recurrent disease. At least one-third of patients have treatment-resistant depression; therefore, there is an urgent need for novel drug development. Cumulative studies have suggested an inflammatory mechanism for the pathophysiology of MDD. Ganoderma lucidum polysaccharides (GLP) is an anti-inflammatory and immunomodulatory agent. Here, we found that an injection of GLP led to a rapid and robust antidepressant effect after 60 min in the tail suspension test. This antidepressant effect remained after 5 days of treatment with GLP in the forced swim test. Unlike psychostimulants, GLP did not show a hyperactive effect in the open field test. After 60 min or 5 days of treatment, GLP exhibited an antidepressant effect in a chronic social defeat stress (CSDS) depression animal model. Moreover, after 5 days of treatment, GLP attenuated the expression of the proinflammatory cytokines IL-1β and TNF-α, enhanced the expression of the anti-inflammatory cytokine IL-10 and the neurotrophic factor BDNF, and inhibited the activation of microglia and proliferation of astrocytes in the hippocampus of CSDS mice. In addition, after 5 days of treatment, GLP significantly enhanced GluA1 S845 phosphorylation as well as GluA1 and GluA2 expression levels in the hippocampus of CSDS mice. To determine whether the antidepressant effect was mediated by Dectin-1, we found that GLP treatment enhanced Dectin-1 expression in the hippocampus in CSDS mice, and the Dectin-1-specific inhibitor laminarin almost completely blocked the antidepressant effect of GLP. This study identified GLP, an agonist of Dectin-1, as a novel and rapid antidepressant with clinical potential and multiple beneficial mechanisms, particularly in regulating the neuroimmune system and, subsequently, AMPA receptor function.

Summary Background This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study. Methods This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389. Findings 603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2–749·2) and 571·0 (467·6–697·3), with seroconversion rates at 96% (95% CI 93–98) and 97% (92–99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8–22·7) and 18·3 (14·4–23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85–93) of 253 and 113 (88%, 81–92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented. Interpretation The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation. Funding National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.

FAT10 expression is highly up-regulated by pro-inflammatory cytokines IFNγ and TNFα in all cell types and tissues. Increased FAT10 expression may induce increasing mitotic non-disjunction and chromosome instability, leading to tumorigenesis. In this review, we summarized others’ and our work on FAT10 expression in liver biopsy samples from patients with alcoholic hepatitis (AH). FAT10 is essential to maintain the function of liver cell protein quality control and Mallory–Denk body (MDB) formation. FAT10 overexpression in AH leads to balloon degeneration and MDB aggregation formation, all of which is prevented in fat10-/- mice. FAT10 causes the proteins’ accumulation, overexpression, and forming MDBs through modulating 26s proteasome’s proteases. The pathway that increases FAT10 expression includes TNFα/IFNγ and the interferon sequence response element (ISRE), followed by NFκB and STAT3, which were all up-regulated in AH. FAT10 was only reported in human and mouse specimens but plays critical role for the development of alcoholic hepatitis. Flavanone derivatives of milk thistle inhibit TNFα/IFNγ, NFκB, and STAT3, then inhibit the expression of FAT10. NFκB is the key nodal hub of the IFNα/TNFα-response genes. Studies on Silibinin and other milk thistle derivatives to treat AH confirms that overexpressed FAT10 is the major key molecule in these networks.

Haemophilus parasuis is the main agent of Glasser's disease, which causes substantial losses in pig production. However, the pathogenic mechanism and virulence factors of H. parasuis have not been fully determined. In this study, berberine is shown to have a good therapeutic effect in vivo against H. parasuis; the minimal inhibitory concentration (MIC) in vitro was 2 μg/mL. Berberine inhibited H. parasuis adhesion to and invasion of PK-15 pig kidney cells. Proteomics studies of H. parasuis after berberine treatment identified a total of 97 differentially-expressed proteins; 35 upregulated and 62 downregulated. Bioinformatics analysis showed that berberine may inhibit the growth of H. parasuis by affecting outer membrane proteins, transferrins, and energy metabolism. This study provides a basis for the development of new antibacterial agents.

Background:Glioblastoma(GBM) is a common malignant tumor of the brain. It has been verified that melatonin(MEL) can inhibit glioma proliferation. But its mechanism has not been fully elucidated. We intend to examine the mechanism of MEL on glioma cells from the perspective of pyroptosis and Nrf2. Methods:Expression of MEL receptor in glioma was detected by western blot. GBM cell viability treated with temozolomide(TMZ) plus MEL was detected by CCK-8. Pyroptosis rate was determinate by flow cytometric analysis. Western blot was used to detect the Nrf2 and pyroptosis related protein level after MEL treatment. Orthotopic tumor growth inhibition study was performed to further investigate the tumor inhibition effect of TMZ plus MEL.Results:We first confirmed MEL receptor was abundant in glioma tissue and cell lines. After combined treatment of TMZ and MEL, cell viability decreased significantly as compared to those of TMZ treatment alone. Also, the ratio of pyroptosis and ROS level increased, followed by elevated expression of pyroptosis related protein. Furthermore, MEL can induce a diminution of Nrf2 expression in glioma in dose- and time-dependent manner. TMZ can increase Nrf2-ARE pathway expression, which also can be deprived by MEL. Its inhibition of Nrf2 depends on dephosphorylation of IGF-1/AKT/mTOR pathway. More importantly, after overexpression of Nrf2 in glioma cells, the level of pyroptosis-related protein elevated by MEL decreased, suggesting that the effect of MEL on promoting pyroptosis is dependent on its inhibition of Nrf2. In vivo results further confirmed that MEL plus TMZ induced significantly decreased tumor size and increased pyroptosis rate, but had no significant effect on mouse body weight, ALT, AST.Conclusion:MEL can inhibit the phosphorylation of IGF-1/AKT/mTOR pathway at millimol level, which further reduces the expression of Nrf2 and promotes pyroptosis of glioma cells. Considering the modest efficacy of TMZ chemotherapy, MEL can be considered as a potential chemotherapy sensitizer to improve the chemotherapy effect of glioma.

Summary Background A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. Methods We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays. This study is registered with ClinicalTrials.gov, NCT04313127. Findings Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 [46%]), fatigue (47 [44%]), headache (42 [39%]), and muscle pain (18 [17%]. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination. Interpretation The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation. Funding National Key R&D Program of China, National Science and Technology Major Project, and CanSino Biologics.

Listeria monocytogenes is the causative agent of human listeriosis which has high hospitalization and mortality rates for individuals with weakened immune systems. The survival and dissemination of L. monocytogenes in adverse environments can be reinforced by the formation of biofilms. Therefore, this study aimed to understand the mechanisms underlying listerial biofilm development. Given that both nutrient availability and quorum sensing (QS) have been known as the factors influencing biofilm development, we hypothesized that the signal from a sentinel metabolite S‐adenosylmethionine (SAM) and Agr‐based QS could be synchronous in L. monocytogenes to modulate nutrient availability, the synthesis of extracellular polymeric substances (EPSs), and biofilm formation. We performed biofilm assays and quantitative real‐time PCR to investigate how biofilm volumes and the expression of genes for the synthesis of EPS were affected by SAM supplementation, agr deletion, or both. We found that exogenously applied SAM induced biofilm formation and that the expression of genes encoding the EPS synthesis machineries was regulated by SAM and/or Agr QS. Moreover, the gene transcription of components acting in the methyl cycle for SAM synthesis and Agr QS was affected by the signals from the other system. In summary, we reveal an interconnection at the transcriptional level between metabolism and QS in L. monocytogenes and highlight the critical role of metabolite‐oriented QS in biofilm development., This study revealed mechanisms underlying EPS synthesis for biofilm development of Listeria monocytogenes. Especially, it elaborated on the cooperation of signal molecules in metabolic pathways and the quorum sensing (QS) network. These findings pave a way for systematically targeting key regulators in L. monocytogenes metabolism and QS to prevent biofilm development.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1.

Background Bloodstream infection (BSI) remains a considerable cause of morbidity and mortality for cancer patients. With a better understanding of it, better methods can be used. The primary objective of this study was to describe the characteristics of BSIs in our institution, and the second was to determine the possible risk factors associated with them. Materials and methods Data of cancer patients from 2009 to 2015 at our institution were included. Medical information and blood cultures were analyzed to determine the BSI rate. The χ and Fisher exact tests were used for categorical data and to determine risk factors associated with BSIs and pathogens. Results A total of 565 (8.6%) events were diagnosed with BSIs. Although gram-negative bacteria (52.6%) were the most commonly isolated pathogens, gram-positive microorganisms (45.0%) were also prevalent. Oral and gastrointestinal organisms were common. Pathogens were more likely to be identified in patients with central venous catheters and in patients with prolonged neutropenia (P Conclusions This study provides updated epidemiology in BSIs and helps with the prevention and management of suspected BSIs in vulnerable patients. Better anti-infection therapy could be provided to these patients based on the isolated pathogens.

Background: We aimed to assess the safety, tolerability and immunogenicity of a recombinant adenovirus type 5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a SARS-Cov-2 strain. This is the first-in-human study of a candidate vaccine against COVID-19. Methods: We conducted a single-center, open-label, dose-escalating clinical trial of Ad5 vectored COVID-19 vaccine. Healthy adults aged between 18-60 years were sequentially enrolled and allocated to receive a single intramuscular injection in one of three dose groups: 5 × 10^10, 1×10^11, and 1·5×10^11 viral particles. Safety was assessed over the next 28 days. Specific antibodies were measured on enzyme-linked immunosorbent assay (ELISA), and the neutralizing antibody responses induced by vaccination were detected by using SARS-CoV-2 virus neutralization and pseudovirus neutralization tests. T-cell responses were accessed by enzyme-linked immunospot (ELISpot) and flow-cytometry assays. Results: A total of 108 participants were recruited and received low dose, middle dose, or high dose vaccine, with 36 in each dose group. 30(83·3%), 30(83·3%), and 27(75·0%) recipients in the low dose, middle dose, and high dose groups reported at least one adverse reaction within the first 7 days after the vaccination. The most common injection-site adverse reaction was pain, the most commonly reported systematic adverse reactions were fever, fatigue, headache, and muscle pain. A majority of the adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. Both ELISA antibodies and neutralizing antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T cell response peaked at day 14 post-vaccination. Conclusions: The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in health adults, and rapid specific T cell responses were noted since day 14. Trial Registration: The study is registered with ClinicalTrials.gov, number NCT04313127. Funding Statement: National Key R&D Program of China (2020YFC10841400), National Science and Technology Major Project (2016ZX10004001, 2018ZX09201005), and CanSino Biotechnology Inc. Declaration of Interests: Mr. Gou report being employees of Tianjin CanSino Biotechnology Inc, No other potential conflict of interest relevant to this article was reported. Ethics Approval Statement: The protocol and informed consent were approved by the Institutional Review Board of the Jiangsu Provincial Center of Disease Control and Prevention. Written informed consents from all participants were obtained before screening. This study was undertaken by Jiangsu Provincial Center of Disease Control and Prevention, Hubei Provincial Center for Disease Control and Prevention and Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology in accordance with the Declaration of Helsinki and Good Clinical Practice.