Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain.

BACKGROUND: Depression is a recurrent and devastating mental disease that is highly prevalent worldwide. Prolonged exposure to stressful events or a stressful environment is detrimental to mental health. In recent years, an inflammatory hypothesis has been implicated in the pathogenesis of stress-induced depression. However, less attention has been given to the initial phases, when a series of stress reactions and immune responses are initiated. Peripheral CD4+ T cells have been reported as the major contributors to the occurrence of mental disorders. Chronic stress exposure-evoked release of cytokines can promote the differentiation of peripheral CD4+ cells into various phenotypes. Among them, Th17 cells have attracted much attention due to their high pathogenic potential in central nervous system (CNS) diseases. Thus, we intended to determine the crucial role of CD4+ Th17 cells in the development of specific subtypes of depression and unravel the underpinnings of their pathogenetic effect. METHODS: In the present research, a daily 6-h restraint stress paradigm was employed in rats for 28 successive days to mimic the repeated mild and predictable, but inevitable environmental stress in our daily lives. Then, depressive-like symptoms, brain-blood barrier (BBB) permeability, neuroinflammation, and the differentiation and functional changes of CD4+ cells were investigated. RESULTS: We noticed that restrained rats showed significant depressive-like symptoms, concomitant BBB disruption and neuroinflammation in the dorsal striatum (DS). We further observed a time-dependent increase in thymus- and spleen-derived naïve CD4+ T cells, as well as the aggregation of inflammatory Th17 cells in the DS during the period of chronic restraint stress (CRS) exposure. Moreover, increased Th17-derived cytokines in the brain can further impair the BBB integrity, thus allowing more immune cells and cytokines to gain easy access to the CNS. Our findings suggested that, through a complex cascade of events, peripheral immune responses were propagated to the CNS, and gradually exacerbated depressive-like symptoms. Furthermore, inhibiting the differentiation and function of CD4+ T cells with SR1001 in the early stages of CRS exposure ameliorated CRS-induced depressive-like behaviour and the inflammatory response. CONCLUSIONS: Our data demonstrated that inflammatory Th17 cells were pivotal in accelerating the onset and exacerbation of depressive symptoms in CRS-exposed rats. This subtype of CD4+ T cells may be a promising therapeutic target for the early treatment of stress-induced depression.

PCSK9 mediates dyslipidemia induced by olanzapine treatment in schizophrenia patients.

RATIONALE: It is controversial whether dyslipidemia induced by antipsychotics in schizophrenia patients is due to weight gain or direct effects of drug treatment. However, recent evidence showed that olanzapine can cause acute dyslipidemia independent of weight change, and the underlying mechanism remains unclear. OBJECTIVE: To study the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in olanzapine-induced dyslipidemia, we analyzed in schizophrenic patients and in experimental models involving mice and cells to understand the mechanism. METHODS: Disturbances in lipid homeostasis caused by 8-week olanzapine treatment were prospectively evaluated in first-episode schizophrenic patients. Additionally, mice were administered olanzapine for 5 or 8 weeks to delineate liver actions for PCSK9 contributing to olanzapine-induced dyslipidemia. RESULTS: Olanzapine directly affected lipid metabolism, suggesting dyslipidemia is independent of weight gain in schizophrenia patients. Olanzapine administration significantly increased plasma PCSK9, which was positively correlated with the increment in low-density lipoprotein cholesterol (LDL-C) (r=0.77, p<0.001). Increased expression of PCSK9 in liver tissue of olanzapine-treated mice occurred prior to olanzapine-induced LDL-C abnormality. Hepatic sterol regulatory element binding protein-2 (SREBP-2) protein levels increased in mice treated with olanzapine but largely declined in olanzapine (10µM) treated HepG2 cells, which suggested high concentration of olanzapine-induced PCSK9 increase was not SREBP-2-dependent. However, expressions of sterol regulatory element binding protein-1c (SREBP-1c) significantly increased in the higher dose treated groups, which was consistent with PCSK9 increases. Activation of SREBP-1c after high-dose olanzapine treatment promotes PSCK9 expression, and consequently the degradation of low-density lipoprotein receptors results in LDL-C increase. CONCLUSIONS: Lipid disturbances caused by olanzapine are independent of weight gain. The study explored the relationship between SREBP-1c and PCSK9 in regulating lipoprotein metabolism after olanzapine treatment in vitro and in vivo. Further exploration of olanzapine-induced PCSK9 regulatory mechanisms may help identify control points for inhibition of olanzapine-mediated dyslipidemia.

Targeting neuroinflammation: The therapeutic potential of ω-3 PUFAs in substance abuse.

Substance abuse is a chronic relapsing disorder that results in serious health and socioeconomic issues worldwide. Addictive drugs induce long-lasting morphologic and functional changes in brain circuits and account for the formation of compulsive drug-seeking and drug-taking behaviors. Yet, there remains a lack of reliable therapy. In recent years, accumulating evidence indicated that neuroinflammation was implicated in the development of drug addiction. Findings from both our and other laboratories suggest that ω-3 polyunsaturated fatty acids (PUFAs) are effective in treating neuroinflammation-related mental diseases, and indicate that they could exert positive effects in treating drug addiction. Thus, in the present review, we summarized and evaluated recently published articles reporting the neuroinflammation mechanism in drug addiction and the immune regulatory ability of ω-3 PUFAs. We also sought to identify some of the challenges ahead in the translation of ω-3 PUFAs into addiction treatment.

Human torpor: translating insights from nature into manned deep space expedition.

During a long-duration manned spaceflight mission, such as flying to Mars and beyond, all crew members will spend a long period in an independent spacecraft with closed-loop bioregenerative life-support systems. Saving resources and reducing medical risks, particularly in mental heath, are key technology gaps hampering human expedition into deep space. In the 1960s, several scientists proposed that an induced state of suppressed metabolism in humans, which mimics 'hibernation', could be an ideal solution to cope with many issues during spaceflight. In recent years, with the introduction of specific methods, it is becoming more feasible to induce an artificial hibernation-like state (synthetic torpor) in non-hibernating species. Natural torpor is a fascinating, yet enigmatic, physiological process in which metabolic rate (MR), body core temperature (Tb ) and behavioural activity are reduced to save energy during harsh seasonal conditions. It employs a complex central neural network to orchestrate a homeostatic state of hypometabolism, hypothermia and hypoactivity in response to environmental challenges. The anatomical and functional connections within the central nervous system (CNS) lie at the heart of controlling synthetic torpor. Although progress has been made, the precise mechanisms underlying the active regulation of the torpor-arousal transition, and their profound influence on neural function and behaviour, which are critical concerns for safe and reversible human torpor, remain poorly understood. In this review, we place particular emphasis on elaborating the central nervous mechanism orchestrating the torpor-arousal transition in both non-flying hibernating mammals and non-hibernating species, and aim to provide translational insights into long-duration manned spaceflight. In addition, identifying difficulties and challenges ahead will underscore important concerns in engineering synthetic torpor in humans. We believe that synthetic torpor may not be the only option for manned long-duration spaceflight, but it is the most achievable solution in the foreseeable future. Translating the available knowledge from natural torpor research will not only benefit manned spaceflight, but also many clinical settings attempting to manipulate energy metabolism and neurobehavioural functions.

Ginsenoside Rg1 alleviates repeated alcohol exposure-induced psychomotor and cognitive deficits.

BACKGROUND: Chronic alcohol consumption disrupts psychomotor and cognitive functions, most of which are subserved by the dysfunction of hippocampus. Dysregulated excitatory glutamatergic transmission is implicated in repeated alcohol induced psychomotor and cognitive impairment. Ginsenoside Rg1, one of the main active ingredient of the traditional tonic medicine Panax ginseng C.A. Meyer (Araliaceae), has been used to treat cognitive deficits. Particularly, Rg1 has been demonstrated to improve hippocampus-dependent learning in mice and attenuate glutamate-induced excitotoxicity in vitro. Thus, in the present research, we sought to investigate the therapeutic effects of Ginsenoside Rg1 on repeated alcohol induced psychomotor and cognitive deficits in hippocampal-dependent behavioral tasks and unravel the underpinnings of its neuroprotection. METHODS: Male ICR (CD-1) mice were consecutively intragastrically treated with 20% (w/v) alcohol for 21 days. Then, behavior tests were conducted to evaluate repeated alcohol induced psychomotor and cognitive deficits. Histopathological changes, and biochemical and molecular alterations were assessed to determine the potential neuroprotective mechanism of Rg1. RESULTS: The results suggested that Rg1, at the optimal dose of 6 mg/kg, has the potential to ameliorate repeated alcohol induced cognitive deficits by regulating activities of NR2B containing NMDARs and excitotoxic signaling. CONCLUSION: Our findings further provided a new strategy to treat chronic alcohol exposure induced adverse consequences.

Primary pulmonary NUT carcinoma: a clinicopathological analysis of seven cases / 中华病理学杂志

Objective: To investigate the clinicopathological characteristics of primary pulmonary NUT carcinoma. Methods: A total of 7 cases of primary pulmonary NUT carcinoma were collected from Fujian Provincial Hospital (n=5), Fuzhou Taijiang Hospital (n=1) and Binzhou City People's Hospital of Shandong Province (n=1) from January 2021 to April 2023. The clinical, histopathological, and immunohistochemical features were analyzed, and NUT rearrangement were detected by fluorescence in situ hybridization (FISH) with break-apart probes. Results: Seven cases were all male with age ranging from 32 to 73 years. The main clinical manifestations were cough, expectoration and chest tightness. Microscopically, NUT carcinoma was composed of monotonous proliferation of primitive-appearing small-to-medium round cells, with few eosinophilic cytoplasm, arranged in solid sheets, nests or clusters. Abrupt keratinization was typically observed in 4 cases (4/7), with high mitotic activities and necrosis. Immunohistochemistry (IHC) showed that the tumors were positive for NUT (7/7), CK7 (4/4), CK5/6 (5/6), p40 (6/7). Ki-67 index were 30%-80%. NUT gene segregation (7/7) was detected by FISH break probes. Conclusions: Primary pulmonary NUT carcinoma is rare and highly malignant. Diagnosis depends on histopathology and IHC, with molecular detection as an adjunct for diagnosis. Pathologists should be aware of the clinicopathological characteristics to avoid misdiagnosis.

The therapeutic mechanism of Shenyuan Gan in lipopolysaccharide-induced neuroinflammation in BV2 microglial cells / 数字中医药（英文）

@#Objective To study the therapeutic effects of Shenyuan Gan (参远苷, SYG) on the inflammatory response in BV2 microglial cells induced by lipopolysaccharide (LPS). Methods The cytotoxicity of SYG to BV2 microglial cells was evaluated using a Cell Counting Kit-8 (CCK-8) assay, and the effect of SYG concentrations on LPS-induced BV2 microglial cells was studied. The morphological changes were observed using an optical microscope. The nitric oxide (NO) concentration in cell culture supernatant was determined using Griess reagent. The expression of cytokines and inflammatory mediators were also measured by an enzyme-linked immunosorbent assay (ELISA). Western blot analysis was used to determine the levels of inducible NO synthase (iNOS), nuclear factor-kappa B (NF-κB) p65, alpha inhibitor of NF-κB (IκB-α), phosphorylation-IκB-α (p-IκB-α), NOD-like receptor 3 (NLRP3), and caspase-1 expression. Moreover, the expression of iNOS, NLRP3, and ionized calcium binding adapter molecule 1 (Iba1) was also observed using immunofluorescent staining. Results SYG had a low cytotoxic effect on BV2 microglial cells and could significantly decr-ease LPS-induced morphological changes of BV2 microglial cells (P < 0.05). ELISA results showed that SYG significantly inhibited the LPS-induced increase in interleukin (IL)-1β and IL-6 in BV2 microglia cells (P < 0.05), and Western blot analysis showed that the phosphorylation levels of iNOS, NF-κB p65, and IκB-α as well as NLRP3 and caspase-1 expression were also significantly decreased, and IκB-α expression was increased after SYG treatment (P < 0.05, compared with the LPS-treated group). The immunofluorescence results were consistent with the Western blot results, and Iba1 staining indicated that the cell morphology tended to be resting. These results indicate that SYG has a certain inhibitory effect on LPS-induced inflammation in BV2 microglial cells. Conclusion SYG can inhibit LPS-induced release of inflammatory factors in BV2 microglial cells by affecting the phosphorylation levels of NF-κB p65 and IκB-α. SYG is a valuable candidate for treating neuroinflammation-related diseases.

Safety and efficacy of citrate anticoagulation for septic patients with liver patients / 中国实用护理杂志

Objective@#To evaluate the efficacy and safety of citrate anticoagulation for continuous renal placement therapy (CRRT) in septic patients with liver dysfunction.@*Methods@#The data of septic patients who needed to CRRT and were admitted into the department of critical care medicine from January 2016 to December 2017 were enrolled in this study. Liver dysfunction was defined as Child-Turotte-Pugh (CTP) score >4. A total of fifty-six patients met the criteria. According to the patient′s actual condition, they were divided into citrate groups (29 cases) and low molecular weight heparin (LMWH) group (29 cases). Patients in LMWH group were given slow molecular weight heparin. The efficacy and safety were compared between the two groups. The filter lifetime, after treatment the activated partial thromboplastin time (APTT),hemoglobin (Hb) were compared between the two groups.@*Results@#The average filter lifetime in citrate group was (25.0±12.2) h which was longer than (13.7±4.5) h in LMWH group (t=13.17, P<0.01). The average service life of each filter was (4.2±1.9) h which was lower than (8.7±3.6) in LMWH group (t=8.395, P<0.05).@*Conclusions@#Regional Citrate anticoagulation is a safe and effective option for CRRT in septic patients with liver dysfunction, without causing electrolyte disturbance and internal environment.

Effect of Kudiezi Injection on inflammation and TLR-4/NF-κB signal in cerebral ischemia reperfusion rats / 药物评价研究

Objective To investigate the protective effects of Kudiezi (KDZ) Injection on cerebral ischemia reperfusion injury in rats and to explore its protective mechanism.Methods The rat model of middle cerebral artery occlusion (MCAO) was established by modified suture method,and cerebral blood flow was monitored using laser Doppler flowmetry (LDF).Male SD rats were randomly divided into control group,model group,Kudiezi Injection high and low dose groups.After ischemia-reperfusion for 24 h,the neurological scores were evaluated.After anesthesia,the blood samples and brain tissues were collected,and the expression of inflammatory was detected by Elisa.Western blotting was used to detect the expression of TLR-4 and NF-κB protein.Results Behavioral scores showed that neural function defect was serious in model group compared with control group (P ＜ 0.01).In model group,cerebral index and cerebral infarction area were significantly higher than those of the control group;After KDZ intervention,the symptoms of neurological deficit was alleviated (P ＜ 0.01),the cerebral index and cerebral infarction area of mode were decreased,and the neuronal necrosis was reduced.Kudiezi Injection could significantly reduce the cerebral homogenate and serum levels of TNF-α (P ＜ 0.05) and increase IL-10 level (P ＜ 0.05).Westem blotting showed that Kudiezi Injection could reduce the expression of TLR-4 and NF-κB protein (P＜0.05).Conclusion Kudiezi Injection has protective effect on cerebral ischemia reperfusion rats.After ischemia-reperfusion,Kudiezi Injection could reduce the levels of TNF-α and raise IL-10.Its mechanism may be associated to the down-regulation of TLR-4/NF-κB signaling pathway.

Effect of Kudiezi Injection on inflammation and TLR-4/NF-κB signal in cerebral ischemia reperfusion rats / 药物评价研究

Objective To investigate the protective effects of Kudiezi (KDZ) Injection on cerebral ischemia reperfusion injury in rats and to explore its protective mechanism.Methods The rat model of middle cerebral artery occlusion (MCAO) was established by modified suture method,and cerebral blood flow was monitored using laser Doppler flowmetry (LDF).Male SD rats were randomly divided into control group,model group,Kudiezi Injection high and low dose groups.After ischemia-reperfusion for 24 h,the neurological scores were evaluated.After anesthesia,the blood samples and brain tissues were collected,and the expression of inflammatory was detected by Elisa.Western blotting was used to detect the expression of TLR-4 and NF-κB protein.Results Behavioral scores showed that neural function defect was serious in model group compared with control group (P ＜ 0.01).In model group,cerebral index and cerebral infarction area were significantly higher than those of the control group;After KDZ intervention,the symptoms of neurological deficit was alleviated (P ＜ 0.01),the cerebral index and cerebral infarction area of mode were decreased,and the neuronal necrosis was reduced.Kudiezi Injection could significantly reduce the cerebral homogenate and serum levels of TNF-α (P ＜ 0.05) and increase IL-10 level (P ＜ 0.05).Westem blotting showed that Kudiezi Injection could reduce the expression of TLR-4 and NF-κB protein (P＜0.05).Conclusion Kudiezi Injection has protective effect on cerebral ischemia reperfusion rats.After ischemia-reperfusion,Kudiezi Injection could reduce the levels of TNF-α and raise IL-10.Its mechanism may be associated to the down-regulation of TLR-4/NF-κB signaling pathway.

Progression of related diseases of desmoglein abnormal and pharmacological intervention / 中国药理学通报

Desmoglein,which is a kind of Ca2+ dependent desmosomal cadherins protein,is a major part of the desmosomes.The desmoglein that distributes in the epithelium,myocardium and other tissues plays a very important role in the cell junction.In recent years,the detection of the abnormal expression and function of the desmoglein was proved in many diseases,such as skin,mucous membrane and tumor related diseases.Drugs may have an important effect in the treatment of diseases by interfering with the expression and function of desmoglein.In this paper,the distribution of several subtypes of the family of desmosomes and their functions in the related diseases are reviewed,which may also provide some new clues for the new drug research on the target of desmogleins.

Chemical constituents from Chloranthus japonicus / 中成药

AIM To study the chemical constituents from Chloranthus japonicus Sieb..METHODS The ethyl acetate fraction of 95％ ethanol extract from C.japonicus was isolated and purified by silica,Sephadex LH-20,ODS and PHPLC column,then the structures of obtained compounds were identified by physicochemical properties and spectral data.RESULTS Ten compounds were isolated and identified as p-hydroxyphenethyl (1),diisooctanephthalate (2),diisobutylphthalat (3),umbelliferone (4),ursolic acid (5),7α-hydroxysitosterol (6),chloranthalactone E (7),chloranthalactone B (8),apigenin (9),3-Sitosterol (10).CONCLUSION Compounds 1-3,6 are isolated from genus Chloranthus for the first time,compounds 4,5,9 are first isolated from this plant.

Detecting hepatitis B virus large surface protein to filtrate the occult HBV infection / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>Detecting hepatitis B virus large surface protein (HBLP) with serological method to filtrate the occult HBV infection and study the clinical detection strategy.</p><p><b>METHODS</b>Two thousands HBsAg negative stochastic serum samples were collected from the copy tubes in daily work to detect hepatitis B Virus markers (HBVM) with national EHSA regent kits and put them -20 degrees C frostily. The 2000 samples were detected with HBLP and filtrated the positive samples. The HBsAg markers were doubly counterchecked with other two adding kinds of national ELISA regent kits (total 3 kinds) at the filtrated samples. The last samples were doubly tested again with American MONOLISA HBsAg ULTRA regents. HBV DNA levels were quantitative analyzed with fluorescence quantitative PCR (FQ-PCR) and taking the mean results.</p><p><b>RESULTS</b>Fifteen HBLP positive samples were detected out from the 2000 serum samples. We educed the conform negative results from the three kinds of national regents but conform positive results from the American MONOLISA HBsAg ULTRA regents in repeating HBsAg detection at the 15 samples. The HBV DNA FQ-PCR quantitative results were all less than 500 copies/mi and divided into two cases hetween 400-500 copies/nil, three cases 300-400 copies/ml, five cases 200-300 copies/ml, four cases 100-200 copies/ml and one case was less than l00copies/ml.</p><p><b>CONCLUSION</b>The false HBsAg negative results for serum samples are more generally through national regents than through importations and HBLP results mayhe are positive in these samples. Detecting HBLP marker is propitious to filtrate the occult HBV infection. This study provided a kind of serological reference for actively searching for the detecting strategy in occult HBV infection field.</p>

Autologous bone marrow stem cell transplantation for treatment terminal liver diseases / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the effect of autologous bone marrow-derived stem cell (BMSCs) transplantation in the treatment of liver failure and decompensated hepatic cirrhosis.</p><p><b>METHODS</b>Bone marrow was harvested (65-95 ml) from 24 patients in the transplantation group. The BMSCs were isolated and infused into liver or spleen of patients via hepatic or splenic artery. At different time points after the transplantation, the patients' liver function and prothrombin time (PT) were evaluated, and the survival rate and symptoms of the patients were recorded.</p><p><b>RESULTS</b>All the serum biochemical indexes remained stable 2 weeks after the transplantation, and at 4 weeks after transplantation, albumin level increased significantly in comparison with the preoperative level (P<0.05). At 12 weeks, the albumin level further increased (P<0.01) along with Pre-ALB (P<0.01), while total bilirubin, tolal bile acid, PT and fibrinogen were all significantly lowered (P<0.05), and globulin, ALT, and AST remained unchanged (P>0.05). One week after the transplantation, improved appetite was observed in 22 cases (91.67%), and 21 cases (87.5%) showed better physical strength; at 2 weeks, hepatic face improved in 15 cases (62.5%), and spider telangiectasia was significantly reduced in one case; at 12 weeks, the survival rate of the patients was 62.5%, and 9 died or gave up treatment due to chronic liver failure complicated by spontaneous bacterial peritonitis, hepatorenal syndrome, or DIC. No complications associated with the transplantation occurred in these patients.</p><p><b>CONCLUSION</b>BMSC transplantation can significantly improve the liver function of patients with terminal liver disease with good safety and effectiveness.</p>

Clinical feature and immunological analysis of a cluster of medical workers with severe acute respiratory syndrome in Guangzhou / 中华传染病杂志

Objective To discuss epidemiological, clinical and laboratory characteristics,chest radiography, serum immunology and conditions in convalescence in patients with severe acute respiratory syndrome(SARS). Methods We retrospectively analyzed clinical data of 22 medical workers with SARS and observed the change of Immunoglobulin M and Immunoglobulin G in their serial sera immunology. Results The patients ranged from 23 to 53 years old (mean age 32.5?7.0). The incubation period ranged from 2 to 7 days(mean period 4.1?1.49 ). Infectious patterns suggested through air droplet or close contact transmission. The most common symptoms included fever(100%), chilly(68.2%), followed by nonproductive cough (72.7%) and dyspnea (63.6%) associated with infiltrates on chest radiography (77.3%). Normal in white blood count or Leukopenia (90.9%) , Lymphopenia (45.5%) and elevated alanine aminotransferase levels (54.5%) were common. By testing the serum IgM and IgG antibody of patients, we found a positive result in 2 weeks after the onset of SARS. Though IgM antibody show negative 3 months later, IgG antibody remained a high level. Conclusions SARS appears to be highly infectious.Fever and subsequent respiratory syndrome is the most common symptom and sign. Our research has disclosed that a positive serum IgM antibody means a infection in the near future, while a positive serum IgG antibody indicates a infection of past and probably with immunity.

Investigation on the function and morphometrics of cultured primary rat ~hepatocytes / 中国病理生理杂志

AIM: To investigate the function and morphological changes of long-term cultured primary rat hepatocytes. METHODS: Rat primary hepatocytes were isolated by two-step in situ collagenase perfusion method, and then were purified by density and grade centrifugal method with Percoll. Cell viability was observed by 0.4% trypan blue. The hepatocytes were seeded into 6 wells plate with HepatoZYME-SFM medium. ALT, AST, albumin and urea levels in the supernatant were measured, CYPⅠA1 was detected with EROD method. RESULTS: (2-3)?108 cells per whole liver were obtained with viability and purity above 90% after purified with Percoll. Hepatocytes cultured in HepatoZYME-SFM grew well with normal hepatocyte morphometrics. ALT, AST levels in the supernatant decreased after 3-day culture, and kept at a stable level after 6-9 days. Albumin secretion and urea synthesis were maintained at high levels in 18 days, while CYPⅠA 1 enzyme activity was only detected in 3-6 days. CONCLUSIONS: Percoll was used to increase the viability and purity of freshly isolated rat hepatocytes. Hepatocyte morphometrics and their biological synthesized function are effectively maintained in HepatoZYME-SFM medium.