Clinical Characteristics and Short-Term Prognosis of Autoimmune Encephalitis: A Single-Center Cohort Study in Changsha, China

Background and Purpose: The incidence and prevalence of autoimmune encephalitis is gradually increasing. This retrospective observational study primarily aimed to analyze the clinical characteristics of autoimmune encephalitis patients in the Second Xiangya Hospital and report patient prognoses after immunotherapy.Methods: The clinical data of 86 patients who were diagnosed with autoimmune encephalitis from October 2014 to September 2018 were collected, and their corresponding clinical characteristics, laboratory examination, treatment, and outcome data analyzed.Results: In our study, 72 patients (83.7%) were positive for anti-NMDAR (N-methyl-D-aspartate receptor) antibody; 5 patients (6%) for anti-GABABR (γ-aminobutyric acid receptor-A); 4 patients (4.7%) for anti-LGI1 (leucine-rich, glioma inactivated 1); 3 patients (3.5%) for anti-Caspr2 (contactin-associated protein-like 2) (1 patient was positive for both anti-LGI1 and anti-Caspr2 antibodies); and 3 patients (3.5%) for onconeural antibodies. Among the 86 patients diagnosed as having autoimmune encephalitis, 50% showed acute disease onset (≤2 weeks). The most common inducing factor was fever or cold (17/86, 19.8%). The main clinical symptoms included, among others, psychiatric disturbances (82.5%), epilepsy (60.5%), autonomic dysfunction (58.1%), sleep disorders (45.3%), consciousness disorders (45.3%), and speech disorders (46.5%). No significant correlation between ICU admission rates and CSF or serum antibody scores was observed. However, CSF antibody scores of (+ + +) and (++) were associated with longer lengths of hospitalization (p < 0.05) and a higher CSF WBC count when compared with CSF antibody scores of (+) in patients with anti-NMDAR encephalitis (p < 0.05). Additionally, there was no significant correlation between mRS score difference on admission and discharge (after immunotherapy) and age, sex, and choice of immune treatment, while immune therapy taken within 15 days from onset was more inclined to be associated with an mRS score difference ≥2 after immunotherapy in patients with anti-NMDAR encephalitis (p = 0.006).Conclusions: Autoimmune encephalitis has an acute or sub-acute onset and presents with psychotic symptoms, epilepsy, and autonomic dysfunction. The sex ratio in anti-NMDAR encephalitis was nearly balanced. Infection was a major factor inducing anti-NMDAR encephalitis, and the CSF antibody scores could be helpful in determining its prognosis since these scores showed associations with hospitalization duration and CSF WBC counts

Caffeine regulates both osteoclast and osteoblast differentiation via the AKT, NF-κB, and MAPK pathways

Background: Although caffeine generally offers benefits to human health, its impact on bone metabolism remains unclear.Aim and Methods: This study aimed to systematically evaluate the long-term effects of caffeine administration on osteoclasts, osteoblasts, and ovariectomy-induced postmenopausal osteoporosis (OP).Results: Our in vitro findings revealed that 3.125 and 12.5 μg/mL caffeine inhibited RANKL-mediated osteoclastogenesis in RAW 264.7 cells through the MAPK and NF-κB pathways, accompanied by the inactivation of nuclear translocation of nuclear factor NFATc1. Similarly, 3.125 and 12.5 μg/mL of caffeine modulated MC3T3-E1 osteogenesis via the AKT, MAPK, and NF-κB pathways. However, 50 μg/mL of caffeine promoted the phosphorylation of IκBα, P65, JNK, P38, and AKT, followed by the activation of NFATc1 and the inactivation of Runx2 and Osterix, ultimately disrupting the balance between osteoblastogenesis and osteoclastogenesis. In vivo studies showed that gavage with 55.44 mg/kg caffeine inhibited osteoclastogenesis, promoted osteogenesis, and ameliorated bone loss in ovariectomized mice.Conclusion: Conversely, long-term intake of high-dose caffeine (110.88 mg/kg) disrupted osteogenesis activity and promoted osteoclastogenesis, thereby disturbing bone homeostasis. Collectively, these findings suggest that a moderate caffeine intake (approximately 400 mg in humans) can regulate bone homeostasis by influencing both osteoclasts and osteoblasts. However, long-term high-dose caffeine consumption (approximately 800 mg in humans) could have detrimental effects on the skeletal system

Coal pillar burst mechanism and prevention based on local mine stiffness (LMS) criterion

The frequent occurrence of coal burst seriously threatens the safe and efficient recovery of coal resources. The research on the mechanism of coal burst is the basis of prediction and disaster prevention. Aiming at the coal burst event under the condition that the stress environment is stable and not affected by dynamic load, the concept of local mine stiffness (LMS) is introduced. Taking the mining area with complex mining layout of the mine as the engineering background, the mechanical response of coal pillar in the process of large-scale mining is analyzed by comprehensively using numerical analysis and field measurement, The evolution of LMS in this process is investigated. It is pointed out that the mining leads to the reduction of LMS, the rapid accumulation of energy in the coal seam and its roof and floor system, and the rapid release of energy when the coal pillar is unstable, resulting in impact damage. The engineering verification is carried out by comparing the evolution of LMS with the mining and the field measured ground sound and microseismic data. The research shows that:①the deformation, load and elastic energy accumulation of coal pillar increase with the overall mining operation, but the LMS decreases. The mining space size and the distance between the mining space and the research area are the main influencing factors. The response degree of the two to the mining of the working face is significantly greater than that of the roadway excavation. The significant influence range of the mining of the working face on the LMS reduction is 3.67 times that of the roadway excavation, and the LMS reduction under the unit advancing distance is 6.41 times that of the roadway excavation.②The good correspondence between the evolution of local mine stiffness with the advancement of the working face and the on-site ground sound and microseismic data indicates that the reduction of local mine stiffness caused by coal mining directly affects the failure mode of coal pillars. The energy in the coal seams and their roof and floor systems accumulates rapidly with the reduction of local mine stiffness and is released rapidly when the bearing capacity of coal pillars decreases, resulting in impact damage. ③After using large-diameter drilling to weaken the coal body, the microseismic energy and frequency are significantly reduced, indicating that large-diameter drilling destroys the coal body in this area, reduces its post peak stiffness, and effectively realizes the impact prevention effect

Metabolic health phenotype better predicts subclinical atherosclerosis than body mass index-based obesity phenotype in the non-alcoholic fatty liver disease population

BackgroundNon-alcoholic fatty liver disease (NAFLD), especially lean NAFLD is associated with an increased risk of atherosclerotic cardiovascular disease (CVD). It is not currently known which clinical phenotypes of NAFLD contribute most to individual subclinical atherosclerosis risk. We examined the relationship between body mass index (BMI), the metabolically healthy status, and subclinical atherosclerosis in the NAFLD population.MethodsData from asymptomatic NAFLD subjects who participated in a routine health check-up examination were collected. Participants were stratified by BMI (cutoff values: 24.0–27.9 kg/m2 for overweight and ≥28.0 kg/m2 for obesity) and metabolic status, which was defined by Adult Treatment Panel III criteria. Subclinical atherosclerosis was evaluated by brachial-ankle pulse wave velocity (baPWV) in 27,738 participants and by carotid plaque in 14,323 participants.ResultsWithin each BMI strata, metabolically unhealthy subjects had a significantly higher prevalence of subclinical atherosclerosis than metabolically healthy subjects, whereas fewer differences were observed across subjects within the same metabolic category. When BMI and metabolic status were assessed together, a metabolically unhealthy status was the main contributor to the association of clinical phenotypes with the subclinical atherosclerosis burden (all p < 0.001). When BMI and metabolic abnormalities were assessed separately, the incidence of subclinical disease did not increase across BMI categories; however, it increased with an increase in the number of metabolic abnormalities (0, 1, 2 and ≥3).ConclusionA metabolically healthy status in NAFLD patients was closely correlated with subclinical atherosclerosis, beyond that of the BMI-based obesity phenotype. The application of metabolic phenotyping strategies could enable more precise classification in evaluating cardiovascular risk in NAFLD

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model

Background: Microdeletion of the human chromosomal region 16p11.2 (16p11.2+/−) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and efective treatments for 16p11.2+/− syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabo‑ lites in the context of 16p11.2+/− are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural defcits associated with 16p11.2+/−, as well as the underlying molecular mechanisms. // Results: Mice with the 16p11.2+/− showed dysbiosis of the gut microbiota and a signifcant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited signifcant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA efectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive defcits of the mice. Remarkably, IPA treatment signifcantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, with‑ out afecting the transcription and translation of the Mapk3 gene. // Conclusions: Our study reveals that 16p11.2+/− leads to a decline in gut metabolite IPA levels; however, IPA supple‑ mentation notably reverses the behavioral and neural phenotypes of 16p11.2+/− mice. These fndings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory defcit disorders, such as 16p11.2 microdeletion syndrome

Non-targeted Metabolomic Study on Anti-aging Effect of Ripe Pu-erh Tea on D-Galactose-Induced Aging Mice

Delaying aging has become a hot spot of social concern and research. Our previous studies have shown that ripe Pu-erh tea can delay aging in mice by regulating the intestinal flora, but the metabolites in response to endogenous substances in mice are not clear. In this paper, the Morris water maze test was used to detect learning and memory capacity in control, D-galactose-induced aging, and ripe Pu-erh tea-treated mice. Non-targeted metabolomics was used to detect metabolites in the brain tissue and serum of mice from each group for the purpose of exploring the anti-aging effect of ripe Pu-erh tea on D-galactose-induced aging mice, screening differential metabolites among the three groups and analyzing the related metabolic pathways. The results showed that ripe Pu-erh tea improved learning capacity, and regulated 26 differential metabolites in the brain tissue of aging mice, mainly involved in the glycerophospholipid metabolism, vitamin B6 metabolism, histidine metabolism and purine metabolism pathways, among which the glycerophospholipid metabolism and histidine metabolism pathway were the most significant. A total of 11 differential metabolites were identified in serum, mainly involved in the metabolism of vitamin B6 and arachidonic acid, among which vitamin B6 metab olism pathway was the most significant. After the intervention with ripe Pu-erh tea, the contents of glycerophospholipid metabolites including phosphatidylcholine [PC (20:5/20:4)], phosphatidyl ethanlamine [PE (22:2/14:0)], phosphatidylserine [PS (20:5/18:1)] and lysophosphatidylcholine [LysoPC (18:2)], the histidine metabolite carnosine, and the vitamin B6 metabolite pyridoxal 5’-phosphate were significantly increased in aging mice. These results suggest that ripe Pu-erh tea can delay aging by regulating lipid and amino acid metabolism

Efficacy and safety of Lianhua Qingwen granule in the treatment of non-influenza viral pneumonia: a randomized, double-blind, placebo-controlled, multicenter clinical study

ObjectiveTo observe the effectiveness and safety of Lianhua Qingwen granule in the treatment of non-influenza viral pneumonia.MethodsThis study was a multicenter, randomized, double-blind, placebo-controlled trial. Subjects who met the inclusion and exclusion criteria and were clinically diagnosed with viral pneumonia (negative for influenza virus) were randomly divided into the Lianhua Qingwen granule trial group and placebo control group. Patients in the trial group was given Lianhua Qingwen granule, 2 bags at a time, 3 times a day, and the controls were given placebo, with a treatment course of 7 days. Patients’ clinical symptoms and signs, and treatment-associated adverse events were observed. Subjects should be included in the full analysis set (FAS) as long as they were all given the medication and had an effectiveness test performed after randomization. Subjects should be included in the Per Protocol Set (PPS),a subset of the total analysis set, which should contain those with strong compliance, no protocol violations, and complete baseline values for the primary indicators.ResultsA total of 169 subjects were enrolled in 12 subcenters, including 151 (76 in the trial group and 75 in the control group) in the FAS and 140 (68 in the trial group and 72 in the control group) in the PPS. After 7 days of treatment, the clinical symptom relief rates were 82.98% (FAS) and 87.12% (PPS) in the trial group, and 75.11% (FAS) and 76.02% (PPS) in the control group, respectively. The clinical symptom relief rates in the trial group were significantly higher than those in the control group (p < 0.001). Significant improvements in single symptoms of cough and expectoration in the trial group were observed compared with the control group (p < 0.05). There were no statistical differences in fever, sputum color change, chest pain, muscle pain, dyspnea, chills, and thirst between the two groups (p > 0.05).SafetyThere were no significant differences in body weight, vital signs, blood routine, urine routine, stool routine, and blood biochemical indicators (CK, AST, ALT, Cr, and Bun) between the two groups before and after treatment (p > 0.05). During treatment, there were no significant differences in the incidence of adverse events and serious adverse events between the two groups (p > 0.05).ConclusionLianhua Qingwen granules improved the clinical symptoms of patients with non-influenza virus pneumonia, especially ameliorating cough and expectoration. Lianhua Qingwen granules were associated with good safety

Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression

T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. In this study, we examine the role and mechanism of Th17 cells in the pathogenesis of autoimmune hepatitis (AIH). The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. The hepatic expressions of IL-17, IL-23, ROR-γt, IL-6 and IL-1β in patients with AIH were also significantly increased and were associated with increased inflammation and fibrosis. IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis

Design, synthesis and bioactivity screening of small molecules based on natural product scaffolds

Natural products are valuable sources of biologically active compounds containing diverse structures, such as benzofuran, pyrazole, and purine. Scientists are now leveraging these structures to develop small molecules with medicinal properties, which have demonstrated breakthroughs in areas such as oncology, antimicrobial research, cardiovascular diseases, ophthalmic diseases, and neurodegenerative diseases. This dissertation comprises four sections dedicated to synthesising, screening and biology evaluating bioactive small molecules based on natural product scaffolds. By introducing structural modifications and functional groups, these small molecules are tailored to address recent, yet unresolved, targets such as Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in anti-tumour research, Sortase A in antimicrobial research, small C-terminal domain phosphatase 1 (Scp1) and Aldehyde Oxidase 1 (AOX1) to reduce oxidative damage and prevent skin cancer. The discovery of small molecule inhibitors targeting KRAS represents a significant breakthrough in cancer therapy. Based on the previous work, we used the structural scaffolds of natural products to design and synthesise a batch of pyrazole derivatives and purine derivatives. Most compounds did not show cytotoxicity on BEAS-2B cells, with some demonstrating moderate activity against KRAS mutation cell lines, exhibiting IC50 values ranging from 2.9 μM to 19.5 μM. Notably, compound XXIX exhibited inhibitory activity against H358, A549, and A427 cell lines, with IC50 values of 4.7 μM, 4.0 μM, and 3.0 μM, respectively, emerged as a promising pan-KRAS inhibitor, potentially serving as a SHP2 inhibitor or impacting the phosphoinositide 3-kinases (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway. Current single mutation-based KRAS inhibitors still face challenges in addressing resistance mechanisms and optimising efficacy across patient populations. These findings underscore the therapeutic potential of pan-KRAS inhibitors in various malignancies. Sortase A (SrtA) is a surface protein virulence factor. It functions as a cysteine transpeptidase found in the majority of gram-positive bacteria, playing a crucial role in anchoring surface proteins to the bacterial cell wall. Deletion of SrtA has been shown to mitigate infections without compromising bacterial viability. In this study, we assessed a series of benzofuranene cyanide derivatives and several compounds demonstrated notable inhibitory effects against SrtA. III-1, III-15, III-34 and V-1 exhibited potent inhibitory effects on biofilm formation, displaying half-maximal inhibitory (IC50) values ranging from 2.1 μM to 54.2 μM. Invasion assays revealed that these four compounds led to a reduction in S. aureus uptake by 293T cells, with decreases ranging from 4% to 24.0%. Moreover, III-15 was found to decrease the level of cell wall-associated protein A by 26.5%. Structure-activity relationship analyses and docking studies indicated that the acrylonitrile moiety of these compounds played a crucial role in enhancing their activity. Protein mass spectrometry showed that acrylonitrile, as a Michael acceptor, effectively inhibited SrtA activity by covalently binding to the thiol group of Cys184. Glioma, a highly aggressive primary brain tumour with limited treatment options, poses a significant challenge. Studies suggest that high levels of the RE-1 silencing transcription factor (REST) protein contribute to brain tumours and neurological diseases. However, REST is not an ideal drug target due to its role as a transcription factor. On the other hand, Scp1 triggers REST activation by dephosphorylating its phosphoserine residues, making it a potential drug target. This study aimed to discover more potent Scp1 inhibitors, for which a series of geniposide and genipin derivatives were investigated. It was found that compound 3-1d can cause a destabilisation of REST and lead to its degradation in a dose-dependent manner. As a result, the expression levels of REST-silenced genes such as DYRK1A, ELAVL1, USP37, CELSR3, CHGB, BDNF, and SCN2 genes were increased. The compound was tested on NODSCID mice with glioma for 14 days without any observed toxicity. It was found that the group treated with compound 3-1d experienced a significant decrease in tumour growth compared to the untreated group. On day 14, the area of luminescence measured in square centimetres was 2.4 times larger in the untreated group than in the treated group. Additionally, the average radiance efficiency (measured in p/s/cm2sr) was 1.9 times greater in the untreated group than in the treated group. Our findings provide the first evidence of the anti-glioma properties of Scp1 inhibitors both in vitro and in vivo. These findings offer hope for the development of more effective treatments for glioma. AOX1 is an attractive target for drug development and therapeutic strategies to combat oxidative damage. Effective AOX1 inhibitors require optimisation through in vitro analyses, which is essential for selecting potential inhibitors for in vivo and clinical investigation. Limited experimental models for drug development pose a challenge to clinical trials. Our study involved the screening of a mini compound library consisting of 287 compounds with different scaffolds. We used the p-DMAC assay to identify 79 compounds that exhibited better inhibition of human AOX1 activity than known AOX1 inhibitor raloxifene. We further narrowed our selection down to 7 active compounds, all of which demonstrated inhibition of both human and mouse liver extracts. Subsequently, we conducted tests to assess their cytotoxicity on human skin cells. After the testing, we selected 2 compounds, along with raloxifene, for further experiments. Through our experiments, we discovered that YX5 and YX128 have remarkable abilities to reduce the increase in 4-HNE levels induced by UVA irradiation and the increase in 8-OHdG levels induced by UVB irradiation. This demonstrated the compounds’ effectiveness in preventing oxidative damage to DNA/RNA and lipids, thereby preventing the occurrence of skin cancer. This dissertation successfully designed, synthesised, and screened small molecules based on natural active compound scaffolds, and conducted their bioactivity studies in the fields of antibacterial, antitumour, and antioxidant therapies. These findings form the basis for advancing research, development, and application of natural product scaffolds in the design and synthesis of small molecules. Through the introduction of different functional groups, they facilitate the development of small-molecule drugs, thereby opening up new avenues for drug discovery and therapeutic strategies.</p