The causal relationship between gut microbiota and immune skin diseases: A bidirectional Mendelian randomization.

BACKGROUND: Increasing evidence suggests that alterations in gut microbiota are associated with a variety of skin diseases. However, whether this association reflects a causal relationship remains unknown. We aimed to reveal the causal relationship between gut microbiota and skin diseases, including psoriasis, atopic dermatitis, acne, and lichen planus. METHODS: We obtained full genetic association summary data for gut microbiota, psoriasis, atopic dermatitis, acne, and lichen planus from public databases and used three methods, mainly inverse variance weighting, to analyze the causal relationships between gut microbiota and these skin diseases using bidirectional Mendelian randomization, as well as sensitivity and stability analysis of the results using multiple methods. RESULTS: The results showed that there were five associated genera in the psoriasis group, seven associated genera were obtained in the atopic dermatitis group, a total of ten associated genera in the acne group, and four associated genera in the lichen planus group. The results corrected for false discovery rate showed that Eubacteriumfissicatenagroup (P = 2.20E-04, OR = 1.24, 95%CI:1.11-1.40) and psoriasis still showed a causal relationship. In contrast, in the reverse Mendelian randomization results, there was no evidence of an association between these skin diseases and gut microbiota. CONCLUSION: We demonstrated a causal relationship between gut microbiota and immune skin diseases and provide a new therapeutic perspective for the study of immune diseases: targeted modulation of dysregulation of specific bacterial taxa to prevent and treat psoriasis, atopic dermatitis, acne, and lichen planus.

MSR405: Inhibiting Neuroinflammation after Spinal Cord Injury in Rats.

The treatment of spinal cord injury (SCI) is often ineffective. Additionally, SCI-induced inflammation leads to secondary injury. Current anti-inflammatory hydrophilic drugs fail to reach the nerve injury site due to the blood-brain barrier. Here, we synthesized MSR405, a new lipophilic unsaturated fatty acid derivative of Radix Isatidis and investigated its therapeutic effect in SCI model rats. Furthermore, we systematically investigated its structure, toxicity, anti-inflammatory effect, and the underlying mechanism. MSR405 was injected into the abdominal cavity of the Sprague Dawley SCI model rats, and the effect on their behavioral scores and pathology was estimated to assess the status of neurological inflammation. Our data show that MSR405 treatment significantly improved the motor function of SCI rats, and markedly suppressed the associated neuroinflammation. Moreover, MSR405 could attenuate LPS-induced inflammatory response in BV2 cells (Mouse microglia cells) in vitro. Mechanistically, MSR405 inhibits proinflammatory cytokines, supporting the anti-inflammatory response. Additionally, MSR405 can significantly block the TLR4/NF-κB signaling pathway and nitric oxide production. In summary, MSR405 reduces inflammation in SCI rats through the TLR4/NF-κB signal cascade and can inhibit neuroinflammation after spinal cord injury.

Rosmarinic acid mitigates acrylamide induced neurotoxicity via suppressing endoplasmic reticulum stress and inflammation in mouse hippocampus.

BACKGROUND: Acrylamide (ACR) is a widely used compound that is known to be neurotoxic to both experimental animals and humans, causing nerve damage. The widespread presence of ACR in the environment and food means that the toxic risk to human health can no longer be ignored. Rosmarinic acid (RA), a natural polyphenolic compound extracted from the perilla plant, exhibits anti-inflammatory, antioxidant, and other properties. It has also been demon strated to possess promising potential in neuroprotection. However, its role and potential mechanism in treating ACR induced neurotoxicity are still elusive. PURPOSE: This study explores whether RA can improve ACR induced neurotoxicity and its possible mechanism. METHODS: The behavioral method was used to study RA effect on ACR exposed mice's neurological function. We studied its potential mechanism through metabolomics, Nissl staining, HE staining, immunohistochemical analysis, and Western blot. RESULTS: RA pretreatment reversed the increase in mouse landing foot splay and decrease in spontaneous activity caused by 3 weeks of exposure to 50 mg/kg/d ACR. Further experiments demonstrated that RA could prevent ACR induced neuronal apoptosis, significantly downregulate nuclear factor-κB and tumor necrosis factor-α expression, and inhibit NOD-like receptor protein 3 inflammasome activation, thereby reducing inflammation as confirmed by metabolomics results. Additionally, RA treatment prevented endoplasmic reticulum stress (ERS) caused by ACR exposure, as evidenced by the reversal of significant P-IRE1α,TRAF2,CHOP expression increase. CONCLUSION: RA alleviates ACR induced neurotoxicity by inhibiting ERS and inflammation. These results provide a deeper understanding of the mechanism of ACR induced neurotoxicity and propose a potential new treatment method.

Human neural stem cells promote mitochondrial genesis to alleviate neuronal damage in MPTP-induced cynomolgus monkey models.

Currently, there is no effective treatment for Parkinson's disease (PD), and the regenerative treatment of neural stem cells (NSCs) is considered the most promising method. This study aimed to investigate the protective effect and mechanism of NSCs on neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced cynomolgus monkey (Macaca fascicularis) model of PD. We first found that injecting NSCs into the subarachnoid space relieved motor dysfunction in PD cynomolgus monkeys, as well as reduced dopaminergic neuron loss and neuronal damage in the substantia nigra (SN) and striatum. Besides, NSCs decreased 17-estradiol (E2) level, an estrogen, in the cerebrospinal fluid (CSF) of PD cynomolgus monkeys, which shows NSCs may provide neuro-protection by controlling estrogen levels in the CSF. Furthermore, NSCs elevated proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a), mitofusin 2 (MFN2), and optic atrophy 1 (OPA1) expression, three genes mediating mitochondrial biogenesis, in the SN and striatum of PD monkeys. In addition, NSCs suppress reactive oxygen species (ROS) production caused by MPTP, as well as mitochondrial autophagy, therefore preserving dopaminergic neurons. In summary, our findings show that NSCs may preserve dopaminergic and neuronal cells in an MPTP-induced PD cynomolgus monkey model. These protective benefits might be attributed to NSCs' ability of modulating estrogen balance, increasing mitochondrial biogenesis, and limiting oxidative stress and mitochondrial autophagy. These findings add to our understanding of the mechanism of NSC treatment and shed light on further clinical treatment options.

[Effect of moxibustion on plaque psoriasis complicated with obesity].

OBJECTIVE: To observe the clinical efficacy of moxibustion combined with coptis chinensis ointment sealing on plaque psoriasis complicated with obesity. METHODS: A total of 52 patients of plaque psoriasis complicated with obesity were randomized into an observation group (26 cases) and a control group (26 cases, 2 cases dropped off). Coptis chinensis ointment sealing was adopted in the control group. On the basis of the treatment in the control group, moxibustion was applied at ashi point (area of local target lesions), Zhongwan (CV 12) and bilateral Zusanli (ST 36), Fenglong (ST 40), Quchi (LI 11), Tianshu (ST 25), Shangjuxu (ST 37) in the observation group. The treatment was given 30 min each time, once a day for 4 weeks in both groups. The psoriasis area and severity index (PASI) score, obesity related indexes (body mass, waist circumference, body mass index [BMI]), triglyceride, cholesterol, uric acid and plasma glucose were compared before and after treatment, and the clinical efficacy was evaluated in the two groups. RESULTS: After treatment, the PASI scores were decreased compared with those before treatment in the two groups (P<0.01), and the PASI score in the observation group was lower than that in the control group (P<0.05); the body mass, waist circumference, BMI, triglyceride, cholesterol, uric acid and plasma glucose were decreased compared with those before treatment in the observation group (P<0.01, P<0.05), the triglyceride and cholesterol in the observation group were lower than those in the control group (P<0.05). The total effective rate was 53.8% (14/26) in the observation group, which was superior to 20.8% (5/24) in the control group (P<0.05). CONCLUSION: Moxibustion combined with coptis chinensis ointment sealing can effectively improve the clinical symptoms in patients of plaque psoriasis complicated with obesity.

Hybrid Density Functional Tight Binding (DFTB)─Molecular Mechanics Approach for a Low-Cost Expansion of DFTB Applicability.

The density functional-based tight binding (DFTB) method has seen a rise in adoption for materials modeling, as it offers significant improvement in scalability with accuracy comparable to the density functional theory (DFT) when good parameterizations exist. The cost reduction in DFTB compared to DFT is achieved by the pre-parameterization of the elements of the Hamiltonian matrix as well as the repulsion potential between all pairs of atoms. Parameterization for new systems with accuracies competitive with DFT in specific applications requires specialized manpower and computational resources. This prevents the application of the DFTB method to systems for which it was not parameterized. In this work, we explore an approach to address the problem of missing parameters of DFTB by modeling the interactions with missing Slater-Koster parameters with an interatomic interaction potential. When the distance between two atoms modeled at the force-field level is sufficiently large, the approach results in accurate structural and electronic properties. The resulting calculation is therefore a hybrid between DFTB and molecular mechanics, a pure DFTB for atoms with a complete set of interatomic parameterizations, and a mix between DFTB and molecular mechanics for atoms with a missing interatomic parameterization. The approach is expected to be particularly useful for hybrid materials and interfaces. The method is tested on the examples of 2D materials, mixed oxides, and a large-scale calculation of an oxide-oxide interface.

Precipitation and local adaptation drive spatiotemporal variations of aboveground biomass and species richness in Tibetan alpine grasslands.

The Tibetan Plateau contains the highest and largest alpine pasture in the world, which is adapted to the cold and arid climate. It is challenging to understand how the vast alpine grasslands respond to climate change. We aim to test the hypothesis that there is local adaptation in elevational populations of major plant species in Tibetan alpine grasslands, and that the spatiotemporal variations of aboveground biomass (AGB) and species richness (S) can be mainly explained by climate change only when the effect of local adaptation is removed. A 7-year reciprocal transplant experiment was conducted among the distribution center (4950 m), upper (5200 m) and lower (4650 m) limits of alpine Kobresia meadow in central Tibetan Plateau. We observed interannual variations in S and AGB of 5 functional groups and 4 major species, and meteorological factors in each of the three elevations during 2012-2018. Relationships between interannual changes of AGB and climatic factors varied greatly with elevational populations within a species. Elevation of population origin generally had a greater or an equal contribution to interannual variation in AGB of the 4 major species, compared to temperature and precipitation effects. While the effect of local adaptation was removed by calculating differences in AGB and S between elevations of migration and origin, relative changes in AGB and S were mainly explained by precipitation change rather than by temperature change. Our data support the hypothesis, and further provide evidence that the monsoon-adapted alpine grasslands are more sensitive to precipitation change than to warming.

Design, synthesis, antiviral activities of ferulic acid derivatives.

A series of novel ferulic acid derivatives were designed and synthesized, and the twenty-one compounds were evaluated for their antiviral activities against Respiratory syncytial virus (RSV), herpes simplex virus type 1 (HSV-1), and enterovirus type 71 (EV71). These derivatives with the core structure of diphenyl acrylic acids had cis-trans isomers, which were confirmed by 1H NMR, HPLC, and UV-vis spectra for the first time. The A5 had a selective effect against RSV but no work on herpes simplex virus type 1 and enterovirus type 71, which showed a therapeutic index (TI) of 32 and was significantly better than ferulic acid. The A5 had no scavenging effect on free radicals, but the A2 as the degradation of A5 showed an obvious scavenging effect on DPPH· and ABTS+·. In addition, the A5 had no toxicity to endothelial cells and even showed a proliferative effect. Therefore, the A5 is worth further optimizing its structure as a lead compound and investigating the mechanism of inhibiting Respiratory syncytial virus.

Integrative analysis of lncRNA-miRNA-mRNA-associated competing endogenous RNA regulatory network involved in EV71 infection.

The competing endogenous RNA (ceRNA) axis has been shown to play a critical role in the pathogenesis of various viral infections. Generally, the ceRNA network involves long non-coding RNAs (lncRNAs) that act as sponges for miRNA to regulate mRNA expression. However, no information is available regarding the involvement of ceRNA networks in Enterovirus type 71 (EV71) infections. In the present study, data obtained from Gene Expression Omnibus (GEO) database was analyzed using various bioinformatics tools. EV71 infection in rhabdomyosarcoma (RD) cells was associated with differential expression of six lncRNAs, 28 miRNAs, and 349 mRNAs. Gene function enrichment analysis suggested induction of cytoplasmic vesicle process upon EV71 infection. The ceRNA networks were constructed, in which 20 hub genes were predicted by protein-protein interaction. To confirm the MALAT1/miR-194-5p/DUSP1 ceRNA regulatory axis in EV71 infection, real-time quantitative polymerase chain reaction (qRT-PCR) and luciferase reporter assay were performed. The results of the study also revealed the involvement of the MALAT1/miR-194-5p axis in apoptosis induced by EV71 infection, while no association with autophagy was observed. Thus, the present study provided novel insights into the pathogenic mechanism of EV71 infection.

Precipitation Alters the Effects of Temperature on the Ecosystem Multifunctionality in Alpine Meadows.

Precipitation and temperature are major controls on multiple ecosystem functions in alpine grasslands. There is scant evidence for the interactive effects of temperature and precipitation changes on the ecosystem multifunctionality (EMF) in alpine meadows. To explore the interactive effects of temperature and precipitation changes on the EMF in alpine meadows, we transplanted meadow blocks reciprocally among three altitudes (4,650, 4,950, and 5,200 m) on the central Tibetan Plateau. Compared with the home sites (control), the EMF has a trend to increase when meadow blocks were downward transplanted (experimental warming) to the high-precipitation sites but decrease as meadow blocks were downward transplanted to the low-precipitation sites. However, the experimental cooling (upward transplantation) consistently reduced the EMF regardless of the precipitation change. The increase of EMF under the experimental warming was closely related to the variation of both plant and soil functions, whereas the reduction of EMF under the cooling was highly correlated with the decrease of plant function. Our results highlight that climate warming effects on the EMF are greatly associated with precipitation changes in the semi-arid alpine ecosystems.

Clinical effect of T-SPOT.TB test for the diagnosis of tuberculosis.

BACKGROUND: The goal of this study was to further investigate the clinical effectiveness of the T-SPOT.TB test in diagnosing tuberculosis (TB), including the effects of T-SPOT.TB test on evaluating diverse TB types and locations. METHODS: We collected 20,332 specimens from patients suspected to have TB. Afterwards, we performed an integrative analysis of T-SPOT.TB results and clinical diagnoses, and evaluated the composition ratio and positive detection rate of the T-SPOT.TB test in various age groups, sample types, and hospital departments. In addition, we compared the spot number and composition rate between latent TB infection (LTBI), active TB infection, and old TB infection groups. The active TB group was then further divided into pulmonary TB (PTB), pulmonary and extrapulmonary TB (PETB), and extrapulmonary TB (EPTB) subgroups, and we evaluated whether there were statistical differences in spot number and composition rate between subgroups. RESULTS: Positive results from the T-SPOT.TB test were found across different age groups, specimen types, and hospital departments. Elderly patient groups, pleural effusion samples, and thoracic surgery departments showed the highest rates of positivity. There were no statistically significant differences in spot number of CFP-10 and ESAT-6 wells between disease groups or active TB subgroups. The composition rate, however, was significantly different when ESAT-6 and CFP-10 wells were double-positive. The spot number and composition rate were statistically different between the three disease groups, but showed no significant differences between the three subgroups of active TB. CONCLUSIONS: The results of T-SPOT. TB test showed differences in LTBI, active TB and old TB. Additionally, a higher spot number level was observed in the active TB group.

Effects of a Ganoderma atrum polysaccharide against pancreatic damage in streptozotocin-induced diabetic mice.

This study aimed at exploring the role of a Ganoderma atrum polysaccharide (PSG-1) in pancreatic damage in streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice. The results suggested that blood glucose was significantly increased in the STZ group in comparison with the control group. After 4 weeks of treatment with PSG-1 or metformin (MET), blood glucose levels in the PSG-1 and MET groups were apparently lower than in the STZ group, indicating that PSG-1 triggered hypoglycemic effects in vivo. Moreover, experiments demonstrated that PSG-1 markedly decreased apoptosis of islet cells by inhibiting the mitochondrial apoptotic pathway and activating the PI3K/Akt survival pathway. PSG-1 also exerted anti-inflammatory effects, as evidenced by the dramatically decreased levels of IL-1ß, TNF-α and INF-γ and restraint of the TLR4-dependent NF-κB signal pathway. Meanwhile, PSG-1 maintained homeostasis of redox systems by increasing the activities of anti-oxidant enzymes and decreasing the amount of malondialdehyde in the pancreas. Together, these data provide evidence that PSG-1 can be employed as an alternative dietary supplement to ameliorate T1DM.

[Detection of carcinoembryonic antigen levels in pleural effusion and serum and their ratio for differential diagnosis of pleural effusion resulting from tuberculosis and lung cancer].

OBJECTIVE: To study the clinical value of detecting carcinoembryonic antigen levels in pleural effusion (PCEA) and serum (SCEA) and their ratio (P/S) in the differential diagnosis of pleural effusions resulting from tuberculosis and lung cancer. METHODS: This retrospectively study was conducted among 82 patients with pleural effusion caused by pulmonary tuberculous (TB; control group) and 120 patients with pleural effusion resulting from lung cancer in our hospital between April, 2016 and March, 2018. PCEA, SCEA and P/S were compared between the two groups and among the subgroups of lung cancer patients with squamous cell carcinoma (SqCa), adenocarcinoma (ACA), small cell carcinoma (SCLC). The receiveroperating characteristic curve (ROC) analysis was used to confirm the optimal critical value to evaluate the diagnostic efficiency of different combinations of PCEA, SCEA and P/S. RESULTS: PCEA, SCEA and P/S were significantly higher in the overall cancer patients and in all the 3 subgroups of cancer patients than in the patients with TB (P < 0.05). The areas under the ROC curve of PCEA, SCEA and P/S were 0.925, 0.866 and 0.796, respectively; PCEA had the highest diagnostic value, whose diagnostic sensitivity, specificity, accurate rate, and diagnostic threshold were 83.33%, 96.34, 88.61%, and 3.26 ng/ml, respectively; SCEA had the lowest diagnostic performance; the diagnostic performance of P/S was between that of SCEA and PCEA, but its combination with SCEA greatly improved the diagnostic performance and reduced the rates of misdiagnosis and missed diagnosis. Parallel tests showed that the 3 indexes combined had significantly higher diagnostic sensitivity than each or any two of the single indexes (P < 0.05), but the diagnostic specificity did not differ significantly. The area under the ROC curve of combined detections of the 3 indexes was 0.941 for diagnosis of lung cancer-related pleural effusion, higher than those of any other combinations of the indexes. CONCLUSIONS: The combined detection of PCEA, SCEA and P/S has a high sensitivity for diagnosis of lung cancer-related pleural effusion and provides important information for rapid and accurate diagnosis of suspected cases.

The type 1 transmembrane glycoprotein B7-H3 interacts with the glycolytic enzyme ENO1 to promote malignancy and glycolysis in HeLa cells.

The role of the type 1 transmembrane glycoprotein B7-H3 is controversial in tumorigenesis; thus, a better clarification of its involvement in cancer is crucial. In the present study, 79.3% of cervical cancer samples were found to be B7-H3 positive and the expression of B7-H3 was positively correlated with the clinical features of the samples. Silencing B7-H3 using small interfering RNA or blocking it with intracellular ScFv attenuated the malignancy of HeLa cells. By pull-down assay and liquid chromatography-mass spectrometry in HeLa cells, the glycolytic enzyme ENO1 was found to interact with B7-H3. Subsequently, the involvement of B7-H3 in glycolysis was investigated. We observed decreases in the levels of ATP and lactate, as well as c-Myc and lactate dehydrogenase A, upon B7-H3 downregulation in HeLa cells. The results of the present study provide evidence for B7-H3 mediating tumor glycolysis.

Leaf unfolding of Tibetan alpine meadows captures the arrival of monsoon rainfall.

The alpine meadow on the Tibetan Plateau is the highest and largest pasture in the world, and its formation and distribution are mainly controlled by Indian summer monsoon effects. However, little is known about how monsoon-related cues may trigger spring phenology of the vast alpine vegetation. Based on the 7-year observations with fenced and transplanted experiments across lower to upper limits of Kobresia meadows in the central plateau (4400-5200 m), we found that leaf unfolding dates of dominant sedge and grass species synchronized with monsoon onset, regardless of air temperature. We also found similar patterns in a 22-year data set from the northeast plateau. In the monsoon-related cues for leaf unfolding, the arrival of monsoon rainfall is crucial, while seasonal air temperatures are already continuously above 0 °C. In contrast, the early-emerging cushion species generally leafed out earlier in warmer years regardless of precipitation. Our data provide evidence that leaf unfolding of dominant species in the alpine meadows senses the arrival of monsoon-season rainfall. These findings also provide a basis for interpreting the spatially variable greening responses to warming detected in the world's highest pasture, and suggest a phenological strategy for avoiding damages of pre-monsoon drought and frost to alpine plants.