Excessive mechanical loading promotes osteoarthritis development by upregulating Rcn2.

Exposure of articular cartilage to excessive mechanical loading is closely related to the pathogenesis of osteoarthritis (OA). However, the exact molecular mechanism by which excessive mechanical loading drives OA remains unclear. In vitro, primary chondrocytes were exposed to cyclic tensile strain at 0.5 Hz and 10 % elongation for 30 min to simulate excessive mechanical loading in OA. In vivo experiments involved mice undergoing anterior cruciate ligament transection (ACLT) to model OA, followed by interventions on Rcn2 expression through adeno-associated virus (AAV) injection and tamoxifen-induced gene deletion. 10 µL AAV2/5 containing AAV-Rcn2 or AAV-shRcn2 was administered to the mice by articular injection at 1 week post ACLT surgery, and Col2a1-creERT: Rcn2flox/flox mice were injected with tamoxifen intraperitoneally to obtain Rcn2-conditional knockout mice. Finally, we explored the mechanism of Rcn2 affecting OA. Here, we identified reticulocalbin-2 (Rcn2) as a mechanosensitive factor in chondrocytes, which was significantly elevated in chondrocytes under mechanical overloading. PIEZO type mechanosensitive ion channel component 1 (Piezo1) is a critical mechanosensitive ion channel, which mediates the effect of mechanical loading on chondrocytes, and we found that increased Rcn2 could be suppressed through knocking down Piezo1 under excessive mechanical loading. Furthermore, chondrocyte-specific deletion of Rcn2 in adult mice alleviated OA progression in the mice receiving the surgery of ACLT. On the contrary, articular injection of Rcn2-expressing adeno-associated virus (AAV) accelerated the progression of ACLT-induced OA in mice. Mechanistically, Rcn2 accelerated the progression of OA through promoting the phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (Stat3).

Thermoelectrically Driven Dual-Mechanism Regulation on SERS and Application Potential for Rapid Detection of SARS-CoV-2 Viruses and Microplastics.

Electric-induced surface-enhanced Raman scattering (E-SERS) has been widely studied for its flexible regulation of SERS after the substrate is prepared. However, the enhancement effect is not sufficiently high in the E-SERS technology reported thus far, and no suitable field of application exists. In this study, a highly sensitive thermoelectrically induced SERS substrate, Ag/graphene/ZnO (AGZ), was fabricated using ZnO nanoarrays (NRs), graphene, and Ag nanoparticles (NPs). Applying a temperature gradient to the ZnO NRs enhanced the SERS signals of the probe molecules by a factor of approximately 20. Theoretical and experimental results showed that the thermoelectric potential enables the simultaneous modulation of the Fermi energy level of graphene and the plasma resonance peak of Ag NPs, resulting in a double enhancement in terms of physical and chemical mechanisms. The AGZ substrate was then combined with a mask to create a wearable thermoelectrically enhanced SERS mask for collecting SARS-CoV-2 viruses and microplastics. Its SERS signal can be enhanced by the temperature gradient created between a body heat source (∼37 °C) and a cold environment. The suitability of this method for virus detection was also examined using a reverse transcription-polymerase chain reaction and SARS-CoV-2 virus antigen detection. This work offers new horizons for research of E-SERS, and its application potential for rapid detection of the SARS-CoV-2 virus and microplastics was also studied.

Combined exposure of MAHs and PAHs enhanced amino acid and lipid metabolism disruption in epithelium leading asthma risk.

Monoaromatic hydrocarbons (MAHs) and polycyclic aromatic hydrocarbons (PAHs) are ubiquitous air pollutants from industry, with multiple adverse effects on respiratory system. However, the underlying mechanisms of their mixture to induce asthma is still unclear. Here, we examined mixture of 8 MAHs, mixture of 16 PAHs and a total mixture (MIX) on human bronchial epithelial (16-HBE) cells. Exposure to MIX resulted in increased expressions of asthma alarm cytokines (TSLP, IL-25 and IL-33), indicating potential asthma risk. Exposure to MIX led to significant upregulation of transcriptional level of oxidative stress and inflammation biomarkers through aryl hydrocarbon receptor activation, including SOD-2, NQO-1, IL-1ß, IL-6 and IL-8 with 3.1, 19.9, 3.5, 23.4, 18.7, 28.1-fold change, indicated asthma related epithelial cell lesions. A total of 25, 49 and 59 differential metabolites were identified in cells response to MAH, PAH and MIX exposure, respectively, and enrichment analysis demonstrated MIX exposure disturbing alanine, aspartate and glutamate metabolism, glutathione metabolism, methionine metabolism and sphingolipid metabolism, involved in antioxidative defense and inflammation response. Combined exposure of MAHs and PAHs may result in increased toxic risks, and provide evidence to asthma onset and deterioration.

Lithium impacts the function of hematopoietic stem cells via disturbing the endoplasmic reticulum stress and Hsp90 signaling.

Lithium (Li) has been widely used in clinical therapy and new Li-ion battery industry. To date, the impact of Li on the development of immune cells is largely unknown. The aim of this study was to investigate the impact of Li on hematopoiesis. C57BL/6 (B6) mice were treated with 50 ppm LiCl, 200 ppm LiCl, or the control via drinking water for 3 months, and thereafter the hematopoiesis was evaluated. Treatment with Li increased the number of mature lymphoid cells while suppressing the number of mature myeloid cells in mice. In addition, a direct action of Li on hematopoietic stem cells (HSC) suppressed endoplasmic reticulum (ER) stress to reduce the proliferation of HSC in the bone marrow (BM), thus leading to fewer HSC in mice. On the other hand, the suppression of ER stress by Li exposure increased the expression of Hsp90, which promoted the potential of lymphopoiesis but did not impact that for myelopoiesis in HSC in the BM of mice. Moreover, in vitro treatment with Li also likely disturbed the ER stress-Hsp90 signaling, suppressed the proliferation, and increased the potential for lymphopoiesis in human HSC. Our study reveals a previously unrecognized toxicity of Li on HSC and may advance our understanding for the immunotoxicology of Li.

Mercury chloride activates the IFNγ-IRF1 signaling in myeloid progenitors and promotes monopoiesis in mice.

Inorganic mercury (Hg2+) is a highly toxic heavy metal in the environment. To date, the impacts of Hg2+ on the development of monocytes, or monopoiesis, have not been fully addressed. The aim of the present study was to investigate the impact of Hg2+ on monopoiesis. In this study, we treated B10.S mice and DBA/2 mice with 10 µM or 50 µM HgCl2 via drinking water for 4 wk, and we then evaluated the development of monocytes. Treatment with 50 µM HgCl2, but not 10 µM HgCl2, increased the number of monocytes in the blood, spleen and bone marrow (BM) of B10.S mice. Accordingly, treatment with 50 µM HgCl2, but not 10 µM HgCl2, increased the number of common myeloid progenitors (CMP) and granulocyte-macrophage progenitors (GMP) in the BM. Functional analyses indicated that treatment with 50 µM HgCl2 promoted the differentiation of CMP and GMP to monocytes in the BM of B10.S mice. Mechanistically, treatment with 50 µM HgCl2 induced the production of IFNγ, which activated the Jak1/3-STAT1/3-IRF1 signaling in CMP and GMP and enhanced their differentiation potential for monocytes in the BM, thus likely leading to increased number of mature monocytes in B10.S mice. Moreover, the increased monopoiesis by Hg2+ was associated with the increased inflammatory status in B10.S mice. In contrast, treatment with 50 µM HgCl2 did not impact the monopoiesis in DBA/2 mice. Our study reveals the impact of Hg on the development of monocytes.

CRISPR/Cas9 Disruption of MYB134 and MYB115 in Transgenic Poplar Leads to Differential Reduction of Proanthocyanidin Synthesis in Roots and Leaves.

Proanthocyanidins (PAs) are common specialized metabolites and particularly abundant in trees and woody plants. In poplar (Populus spp.), PA biosynthesis is stress-induced and regulated by two previously studied transcription factors MYB115 and MYB134. To determine the relative contribution of these regulators to PA biosynthesis, we created single- and double-knockout (KO) mutants for both genes in transgenic poplars using CRISPR/Cas9. Knocking out either MYB134 or MYB115 showed reduced PA accumulation and downregulated flavonoid genes in leaves, but MYB134 disruption had the greatest impact and reduced PAs to 30% of controls. In roots, by contrast, only the MYB134/MYB115 double-KOs showed a significant change in PA concentration. The loss of PAs paralleled the lower expression of PA biosynthesis genes and concentrations of flavan-3-ol PA precursors catechin and epicatechin. Interestingly, salicinoids were also affected in double-KOs, with distinct patterns in roots and shoots. We conclude that the regulatory pathways for PA biosynthesis differ in poplar leaves and roots. The residual PA content in the double-KO plants indicates that other transcription factors must also be involved in control of the PA pathway.

Lead exposure suppresses the Wnt3a/ß-catenin signaling to increase the quiescence of hematopoietic stem cells via reducing the expression of CD70 on bone marrow-resident macrophages.

Lead (Pb) is a heavy metal highly toxic to human health in the environment. The aim of this study was to investigate the mechanism of Pb impact on the quiescence of hematopoietic stem cells (HSC). WT C57BL/6 (B6) mice treated with 1250 ppm Pb via drinking water for 8 weeks had increased the quiescence of HSC in the bone marrow (BM), which was caused by the suppressed activation of the Wnt3a/ß-catenin signaling. Mechanically, a synergistic action of Pb and IFNγ on BM-resident macrophages (BM-Mφ) reduced their surface expression of CD70, which thereby dampened the Wnt3a/ß-catenin signaling to suppress the proliferation of HSC in mice. In addition, a joint action of Pb and IFNγ also suppressed the expression of CD70 on human Mφ to impair the Wnt3a/ß-catenin signaling and reduce the proliferation of human HSC purified from umbilical cord blood of healthy donors. Moreover, correlation analyses showed that the blood Pb concentration was or tended to be positively associated with the quiescence of HSC, and was or tended to be negatively associated with the activation of the Wnt3a/ß-catenin signaling in HSC in human subjects occupationally exposed to Pb. Collectively, these data indicate that an occupationally relevant level of Pb exposure suppresses the Wnt3a/ß-catenin signaling to increase the quiescence of HSC via reducing the expression of CD70 on BM-Mφ in both mice and humans.

Benzo [a] pyrene-loaded aged polystyrene microplastics promote colonic barrier injury via oxidative stress-mediated notch signalling.

The adsorption of toxic substances on polystyrene microplastics (PSMPs) can modify their biological toxicity and exacerbate the threat to human health. The effects of benzo [a] pyrene (B (a) P)-loaded aged PSMPs on colonic barrier integrity remains unclear. Here, we showed that binding environmentally relevant concentrations of B (a) P alteredl̥ the physicochemical features and markedly enhanced the toxicity of PSMPs. Compared to pristine PSMP, PSMP@B (a) P promoted colonic barrier degradation, body weight loss, colon length shortening, oxidative stress (OS), autophagy, inflammation, and bacterial translocation. Microplastic (MP) exposure induced injury to the colon barrier, including tight junction (TJ) and mucosal barriers, via overactivation of the Notch signalling pathway under increased OS in mice and intestinal organoids. Notably, PSMP@B (a) P exposure exacerbated damage to TJ and the mucosal barrier via the overproduction of reactive oxygen species (ROS), which could be related to the release of B (a) P from PSMP@B (a) P induced by the acidic environment of autophagosomes, which in turn exert synergistic toxic effects with PSMPs. Our study elucidates some of the potential molecular mechanisms by which B (a) P enhances PSMP-related intestinal toxicity, which provides a potential therapeutic approach for diseases caused by PSMP@B (a)P and PSMP pollution.

Impact of the COVID-19 lockdown on typical ambient air pollutants: Cyclical response to anthropogenic emission reduction.

Preliminary studies have confirmed that ambient air pollutant concentrations are significantly influenced by the COVID-19 lockdown measures, but little attention focus on the long term impacts of human countermeasures in cities all over the world during the period. Still, fewer have addressed their other essential properties, especially the cyclical response to concentration reduction. This paper aims to fill the gaps with combined methods of abrupt change test and wavelet analysis, research areas were made of five cities, Wuhan, Changchun, Shanghai, Shenzhen and Chengdu, in China. Abrupt changes in contaminant concentrations commonly occurred in the year prior to the outbreak. The lockdown has almost no effect on the short cycle below 30 d (days) for both pollutants, and a negligible impact on the cycle above 30 d. PM2.5 (fine particulate matter) has a stable short-cycle nature, which is greatly influenced by anthropogenic emissions. The analysis revealed that the sensitivity of PM2.5 to climate is increased along with the concentrations of PM2.5 were decreasing by the times when above the threshold (30-50 µg m-3), and which could lead to PM2.5 advancement relative to the ozone phase over a period of 60 d after the epidemic. These results suggest that the epidemic may have had an impact earlier than when it was known. And significant reductions in anthropogenic emissions have little impact on the cyclic nature of pollutants, but may alter the inter-pollutant phase differences during the study period.

National Institute of Health Stroke Scale was associated with the immediate and long-term prognosis of patients with acute ischemic stroke treated with intravenous thrombolysis.

OBJECTIVE: The objective of this study was to examine whether the National Institute of Health Stroke Scale was associated with the short- and long-term prognosis of patients with acute ischemic stroke treated with intravenous thrombolysis. METHODS: A total of 247 patients with acute ischemic stroke admitted to the hospital from April 2019 to October 2020 were retrospectively selected as study subjects, and the immediate and long-term prognosis after thrombolysis was assessed using the modified Rankin Scale and divided into good prognosis group (119 cases) and poor prognosis group (128 cases) based on the effect of thrombolysis. Both groups were treated with alteplase, the National Institute of Health Stroke Scale of the two groups was compared, and the factors affecting the prognosis of acute ischemic stroke were analyzed. RESULTS: After intravenous thrombolysis, 24 h, and 7 days of treatment, the National Institute of Health Stroke Scale in the poor prognosis group was higher than those of patients in the good prognosis group, and the differences were statistically significant (p<0.05). The results of the multivariate analysis suggested that National Institute of Health Stroke Scale before treatment was an independent factor associated with the 3-month (OR: 1.068, 95%CI 1.015-1.123, p=0.011) and long-term poor prognosis (OR: 1.064, 95%CI 1.012-1.119, p=0.015) in patients with acute ischemic stroke receiving intravenous thrombolysis after adjustment of age, gender, body mass index, smoking, alcohol consumer, onset-to-door time, door-to-needle time, and imaging score. CONCLUSION: The National Institute of Health Stroke Scale could be a promising indicator for the prognosis, and active intervention is needed to improve the quality of life in patients with acute ischemic stroke.

The enormous repetitive Antarctic krill genome reveals environmental adaptations and population insights.

Antarctic krill (Euphausia superba) is Earth's most abundant wild animal, and its enormous biomass is vital to the Southern Ocean ecosystem. Here, we report a 48.01-Gb chromosome-level Antarctic krill genome, whose large genome size appears to have resulted from inter-genic transposable element expansions. Our assembly reveals the molecular architecture of the Antarctic krill circadian clock and uncovers expanded gene families associated with molting and energy metabolism, providing insights into adaptations to the cold and highly seasonal Antarctic environment. Population-level genome re-sequencing from four geographical sites around the Antarctic continent reveals no clear population structure but highlights natural selection associated with environmental variables. An apparent drastic reduction in krill population size 10 mya and a subsequent rebound 100 thousand years ago coincides with climate change events. Our findings uncover the genomic basis of Antarctic krill adaptations to the Southern Ocean and provide valuable resources for future Antarctic research.

Clinical Efficacy of Chemotherapy Regimen Combined with Levofloxacin in Patients with Pulmonary Tuberculosis Complicated with Type-2 Diabetes.

Objective: To evaluate the clinical efficacy of a chemotherapy regimen combined with levofloxacin in patients with pulmonary tuberculosis complicated with Type-2 diabetes. Methods: Total 80 patients with pulmonary tuberculosis complicated with Type-2 diabetes admitted to Baoding People's Hospital from January, 2019 to January, 2022 were randomly divided into two groups: the experimental group and the control group, with 40 cases in each group. Patients in the control group were given the conventional 2HRZE/10HRE regimen, while those in the experimental group were given the chemotherapy regimen 2HRZEL/6HRE combined with levofloxacin. Sixty four slice spiral CT was used for chest plain scan before and after treatment, respectively, to evaluate the absorption of lesions based on the range of lung lesions; Venous blood was drawn to detect the changes of oxidative stress indicators, the incidence of adverse drug reactions and the negative conversion rate of sputum tuberculosis bacteria in the two groups. Results: After treatment, the efficacy of the experimental group was 90%, which was significantly higher than that of the control group (67.5%), with a statistically significant difference (p=0.01). After treatment, CD3+, CD4+, CD4+/CD8+ and other indicators in the experimental group were significantly higher than those in the control group, with a statistically significant difference (CD3+, p=0.01; CD4+, p=0.01; CD4+/CD8+, p=0.00), while CD8+ did not change significantly (p=0.92); The incidence of adverse reactions was 52.5% in the experimental group and 47.5% in the control group, with no statistically significant difference (p=0.66); The negative conversion rate of patients in the experimental group was significantly higher than that in the control group at one month, three months and six months after treatment, with a statistically significant difference (p<0.05). Conclusion: Chemotherapy combined with levofloxacin is a safe and effective regimen for patients' pulmonary tuberculosis complicated with Type-2 diabetes, boasting a variety of benefits such as improved clinical efficacy, ameliorated cellular immune status, a high negative conversion rate of sputum tuberculosis bacteria, and no significant increase in adverse reactions.

Multifunctional nanoparticle-VEGF modification for tissue-engineered vascular graft to promote sustained anti-thrombosis and rapid endothelialization.

Purpose: The absence of a complete endothelial cell layer is a well-recognized reason leading to small-diameter tissue-engineered vascular graft failure. Here we reported a multifunctional system consisting of chitosan (CS), Arg-Glu-Asp-Val (REDV) peptide, heparin, and vascular endothelial growth factor (VEGF) to achieve sustained anti-thrombosis and rapid endothelialization for decellularized and photo-oxidized bovine internal mammary arteries (DP-BIMA). Methods: CS-REDV copolymers were synthesized via a transglutaminase (TGase) catalyzed reaction. CS-REDV-Hep nanoparticles were formed by electrostatic self-assembly and loaded on the DP-BIMA. The quantification of released heparin and vascular endothelial growth factor was detected. Hemolysis rate, platelets adhesion, endothelial cell (EC) adhesion and proliferation, and MTT assay were performed in vitro. The grafts were then tested in a rabbit abdominal aorta interposition model for 3 months. The patency rates were calculated and the ECs regeneration was investigated by immunofluorescence staining of CD31, CD144, and eNOS antibodies. Results: The nanoparticle-VEGF system (particle size: 61.8 ± 18.3 nm, zeta-potential: +13.2 mV, PDI: .108) showed a sustained and controlled release of heparin and VEGF for as long as 1 month and exhibited good biocompatibility, a lower affinity for platelets, and a higher affinity for ECs in vitro. The nanoparticle-VEGF immobilized BIMA achieved 100% and 83.3% patency in a rabbit abdominal interposition model during 1 and 3 months, respectively, without any thrombogenicity and showed CD31, CD144, eNOS positive cell adhesion as early as 1 day. After 3 months, CD31, CD144, and eNOS positive cells covered almost the whole luminal surface of the grafts. Conclusion: The results demonstrated that the multifunctional nanoparticle-VEGF system can enhance the anti-thrombosis property and promote rapid endothelialization of small-diameter tissue-engineered vascular grafts. Utilizing nanoparticles to combine different kinds of biomolecules is an appropriate technology to improve the long-term patency of small-diameter tissue-engineered vascular grafts.

Dynamic changes of inulin utilization associated with longitudinal development of gut microbiota.

Inulin is a typical kind of fermentable polysaccharide and has emerged as a promising dietary supplement due to its multiple health-promoting effects. This study aimed to unveil the dynamic change pattern of inulin utilizability as a fermentation substrate during gut microbiota development and illuminate its potential association with gut microbiota in Chinese Jinhua native pig models via longitudinal analyses. Herein, fresh feces were collected at one week pre- and post-weaning as well as 3rd month post-weaning, respectively. Targeted metabolomics and in vitro simulated fermentation revealed increasing concentrations of fecal short-chain fatty acids (SCFAs) and elevating utilizability of inulin as a fermentation substrate. Microbiomic analyses demonstrated the conspicuous longitudinal alteration in gut microbial composition and a significant rise in microbial community diversity during gut microbiota development. Furthermore, gut microbial functional analyses showed a remarkable increase in the relative abundances of carbohydrate metabolism pathways, including pentose phosphate pathway, galactose metabolism pathway, butanoate metabolism pathway as well as fructose and mannose metabolism pathway. Notably, relative abundances of bacterial genera Bifidobacterium, Roseburia, Faecalibacterium and Enterococcus displayed significantly positive correlations with the production of microbial fermentation-derived SCFAs. Collectively, these findings offer novel insights into understanding inulin utilizability variations from the perspective of gut microbiota development.

Cadmium impairs the development of natural killer cells and bidirectionally modifies their capacity for cytotoxicity.

Cadmium (Cd) is a highly toxic heavy metal in the environment. The aim of this study was to investigate the impact of Cd on natural killer (NK) cells. C57BL/6 mice were treated with 10 ppm Cd via drinking water for 3 months, and the development of NK cells in the bone marrow (BM) and the cytotoxicity of mature NK (mNK) cells in the peripheral immune organs were evaluated thereafter; the impact of Cd on the cytotoxicity of mNK cells from human peripheral blood mononuclear cells (PBMC) was also investigated. Whereas Cd treatment impaired the differentiation of NK progenitors in the BM, Cd treatment activated the JAK3/STAT5 signaling to drive the proliferation of mNK cells and thereby lead to a compensation increase of mNK cells in the peripheral immune organs of mice. Additionally, Cd treatment bidirectionally regulated the cytotoxicity of mouse mNK cells to differential tumor cells, dependent on the levels of Fas expression in the tumor cells; mechanically, Cd treatment activated the JAK3/STAT5 signaling to promote the expression of FasL in mNK cells to increase their cytotoxicity, while Cd treatment reduced the expression of granzyme B in mNK cells to impair their cytotoxicity in the peripheral immune organs of mice. Likewise, in vitro assays indicated that Cd treatment also activated the JAK3/STAT5 signaling to increase the expression of FasL, whereas Cd treatment reduced the expression of granzyme B in human mNK cells. Thus Cd treatment impaired the development of NK cells in the BM and bidirectionally regulated the cytotoxicity of mNK cells in the peripheral immune organs, which may extend our current understanding for the immunotoxicity of Cd.

Meranzin Hydrate Improves Depression-Like Behaviors and Hypomotility via Ghrelin and Neurocircuitry.

OBJECTIVE: To investigate whether meranzin hydrate (MH) can alleviate depression-like behavior and hypomotility similar to Chaihu Shugan Powder (CSP), and further explore the potential common mechanisms. METHODS: Totally 120 Spraque-Dawley rats were randomly divided into 5-8 groups including sham, vehicle, fluoxetine (20 mg/kg), mosapride (10 mg/kg), CSP (30 g/kg), MH (9.18 mg/kg), [D-Lys3]-GHRP-6 (Dlys, 0.5 mg/kg), and MH+Dlys groups by a random number table, 8 rats in each group. And 32 mice were randomly divided into wild-type, MH (18 mg/kg), growth hormone secretagogue receptor-knockout (GHSR-KO), and GHSR+MH groups, 8 mice in each group. The forced swimming test (FST), open field test (OFT), tail suspension test (TST), gastric emptying (GE) test, and intestinal transit (IT) test were used to assess antidepressant and prokinetic (AP) effects after drug single administration for 30 min with absorbable identification in rats and mice, respectively. The protein expression levels of brain-derived neurotrophic factor (BDNF) and phosphorylated mammalian target of rapamycin (p-mTOR) in the hippocampus of rats were evaluated by Western blot. The differences in functional brain changes were determined via 7.0 T functional magnetic resonance imaging-blood oxygen level-dependent (fMRI-BOLD). RESULTS: MH treatment improved depression-like behavior (FST, OFT) and hypomotility (GE, IT) in the acute forced swimming (FS) rats (all P<0.05), and the effects are similar to the parent formula CSP. The ghrelin antagonist [D-Lys3]-GHRP-6 inhibited the effect of MH on FST and GE (P<0.05). Similarly, MH treatment also alleviated depression-like behavior (FST, TST) in the wild-type mice, however, no effects were found in the GHSR KO mice. Additionally, administration of MH significantly stimulated BDNF and p-mTOR protein expressions in the hippocampus (both P<0.01), which were also prevented by [D-Lys3]-GHRP-6 (P<0.01). Besides, 3 main BOLD foci following acute FS rats implicated activity in hippocampus-thalamus-basal ganglia (HTB) circuits. The [D-Lys3]-GHRP-6 synchronously inhibited BOLD HTB foci. As expected, prokinetic mosapride only had effects on the thalamus and basal ganglia, but not on the hippocampus. Within the HTB, the hippocampus is implicated in depression and FD. CONCLUSIONS: MH accounts for part of AP effects of parent formula CSP in acute FS rats, mainly via ghrelin-related shared regulation coupled to BOLD signals in brain areas. This novel functionally connection of HTB following acute stress, treatment, and regulation highlights anti-depression unified theory.

Jinhua Qinggan granules attenuates acute lung injury by promotion of neutrophil apoptosis and inhibition of TLR4/MyD88/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is one of the fatal complications of respiratory virus infections such as influenza virus and coronavirus, which has high clinical morbidity and mortality. Jinhua Qinggan granules (JHQG) has been approved by China Food and Drug Administration in the treatment of H1N1 influenza and mild or moderate novel coronavirus disease 2019 (COVID-19), which is an herbal formula developed based on Maxingshigan decoction and Yinqiao powder that have been used to respiratory diseases in China for thousands of years. However, the underlying mechanism of JHQG in treating infectious diseases remains unclear. AIM OF THE STUDY: This study investigated the effects of JHQG on neutrophil apoptosis and key signaling pathways in lipopolysaccharide (LPS) -induced ALI mice in order to explore its mechanism of anti-inflammation. MATERIALS AND METHODS: The effect of JHQG on survival rate was observed in septic mouse model by intraperitoneal injection of LPS (20 mg/kg). To better pharmacological evaluation, the mice received an intratracheal injection of 5 mg/kg LPS. Lung histopathological changes, wet-to-dry ratio of the lungs, and MPO activity in the lungs and total protein concentration, total cells number, TNF-α, IL-1ß, IL-6, and MIP-2 levels in BALF were assessed. Neutrophil apoptosis rate was detected by Ly6G-APC/Annexin V-FITC staining. Key proteins associated with apoptosis including caspase 3/7 activity, Bcl-xL and Mcl-1 were measured by flow cytometry and confocal microscope, respectively. TLR4 receptor and its downstream signaling were analyzed by Western blot assay and immunofluorescence, respectively. RESULTS: JHQG treatment at either 6 or 12 g/kg/day resulted in 20% increase of survival in 20 mg/kg LPS-induced mice. In the model of 5 mg/kg LPS-induced mice, JHQG obviously decreased the total protein concentration in BALF, wet-to-dry ratio of the lungs, and lung histological damage. It also attenuated the MPO activity and the proportion of Ly6G staining positive neutrophils in the lungs, as well as the MIP-2 levels in BALF were reduced. JHQG inhibited the expression of Mcl-1 and Bcl-xL and enhanced caspase-3/7 activity, indicating that JHQG partially acted in promoting neutrophil apoptosis via intrinsic mitochondrial apoptotic pathway. The levels of TNF-α, IL-1ß, and IL-6 were significantly declined in LPS-induced mice treated with JHQG. Furthermore, JHQG reduced the protein expression of TLR4, MyD88, p-p65 and the proportion of nuclei p65, suggesting that JHQG treatment inhibited TLR4/MyD88/NF-κB pathway. CONCLUSION: JHQG reduced pulmonary inflammation and protected mice from LPS-induced ALI by promoting neutrophil apoptosis and inhibition of TLR4/MyD88/NF-κB pathway, suggesting that JHQG may be a promising drug for treatment of ALI.

National Institute of Health Stroke Scale was associated with the immediate and long-term prognosis of patients with acute ischemic stroke treated with intravenous thrombolysis

OBJECTIVE: The objective of this study was to examine whether the National Institute of Health Stroke Scale was associated with the short- and long-term prognosis of patients with acute ischemic stroke treated with intravenous thrombolysis. METHODS: A total of 247 patients with acute ischemic stroke admitted to the hospital from April 2019 to October 2020 were retrospectively selected as study subjects, and the immediate and long-term prognosis after thrombolysis was assessed using the modified Rankin Scale and divided into good prognosis group (119 cases) and poor prognosis group (128 cases) based on the effect of thrombolysis. Both groups were treated with alteplase, the National Institute of Health Stroke Scale of the two groups was compared, and the factors affecting the prognosis of acute ischemic stroke were analyzed. RESULTS: After intravenous thrombolysis, 24 h, and 7 days of treatment, the National Institute of Health Stroke Scale in the poor prognosis group was higher than those of patients in the good prognosis group, and the differences were statistically significant (p<0.05). The results of the multivariate analysis suggested that National Institute of Health Stroke Scale before treatment was an independent factor associated with the 3-month (OR: 1.068, 95%CI 1.015-1.123, p=0.011) and long-term poor prognosis (OR: 1.064, 95%CI 1.012-1.119, p=0.015) in patients with acute ischemic stroke receiving intravenous thrombolysis after adjustment of age, gender, body mass index, smoking, alcohol consumer, onset-to-door time, door-to-needle time, and imaging score. CONCLUSION: The National Institute of Health Stroke Scale could be a promising indicator for the prognosis, and active intervention is needed to improve the quality of life in patients with acute ischemic stroke.