Baicalin ameliorates heat stress-induced hepatic injury and intestinal microecology dysbiosis in late gestational mice.

Heat stress (HS) disrupts intestinal microbiota, glycolipid metabolism, and hepatic mitochondrial function in late gestational mice. Baicalin (BAI), a Chinese herbal medicine known for its heat-clearing and anti-inflammatory properties, has shown promise in modulating intestinal microecology and mitigating inflammation in various organs. This study investigates whether baicalin attenuates HS-induced intestinal microbial dysbiosis and liver damage in pregnant mice during late gestation. Twenty-four pregnant mice were randomly assigned to four groups, including thermoneutral (TN) (24 ± 1 ℃), HS (35 ± 1 ℃), HS+BAI200 (oral gavaged with 200 mg/kg BW of BAI), and HS+BAI400 (oral gavaged with 400 mg/kg BW of BAI). 400 mg/kg BAI treatment markedly decreased the rectal temperature and increased fetal weight in HS pregnant mice. Furthermore, 400 mg/kg BAI administration effectively ameliorated HS-induced hepatic damage and lipid disorders, reducing HSP70, AST, and ALT levels while increasing TG concentration. Notably, it activated a network of genes involved in lipid synthesis, including fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and oxidation, such as peroxisome proliferator-activated receptor alpha (PPARα), carnitine palmityl transferase 1 beta (CPT1ß). Moreover, BAI intervention restored the intestinal morphology and barrier function, evidenced by increased intestinal villus height, the ratio of villus height to crypt depth, and colonic goblet cells numbers. 400 mg/kg of BAI treatment up-regulated the expression of tight junction proteins, such as claudin-1 and Zonula Occludens-1 (ZO-1), in the jejunum and ileum, counteracting HS-induced downregulation. High-throughput sequencing showed that BAI treatment altered cecal microbial composition, increasing the relative abundance of beneficial Bacteroidota and decreasing Deferribacterota, Turicibacter, and Akkermansia. Spearman's correlation analysis highlighted significant correlations between differential cecal microbiota and physiological indexes. In conclusion, BAI administration alleviated adverse impacts in heat-exposed mice during late gestation, improving maternal physiological parameters, and ameliorating hepatic damage with altered cecal microbial composition. The findings suggest that BAI may regulate the gut-liver axis by modulating intestinal morphology, microecology, and hepatic function.

Resveratrol protects against ox-LDL-induced endothelial dysfunction in atherosclerosis via depending on circ_0091822/miR-106b-5p-mediated upregulation of TLR4.

BACKGROUND: Atherosclerosis (AS) is the most common inducer of cardiovascular diseases, and resveratrol (RSV) has played a protective function in the endothelial injury of AS. This study was to explore the molecular mechanism of RSV in oxidized low-density lipoprotein (ox-LDL)-mediated endothelial dysfunction. METHODS: Circ_0091822, microRNA-106b-5p (miR-106b-5p) or toll-like receptor (TLR4) levels were examined using reverse transcription-quantitative polymerase chain reaction assay. Cell viability was detected via Cell Counting Kit-8 assay and angiogenesis was assessed by tube formation assay. Cell apoptosis was determined through flow cytometry. The protein analysis was conducted via western blot. Inflammatory cytokines were measured by enzyme-linked immunosorbent assay. The oxidative injury was evaluated using the commercial kits. The binding detection was performed via dual-luciferase reporter assay and RNA pull-down assay. RESULTS: Circ_0091822 was downregulated by RSV in ox-LDL-treated endothelial cells. RSV promoted cell viability and angiogenesis while inhibiting apoptosis, inflammation, and oxidative stress after exposure to ox-LDL. The circ_0091822 knockdown relieved the ox-LDL-induced cell damages. RSV suppressed the ox-LDL-caused endothelial dysfunction via inducing the downregulation of circ_0091822. Circ_0091822 could target miR-106b-5p, and the reversal of circ_0091822 for RSV function was achieved by sponging miR-106b-5p. Circ_0091822 absorbed miR-106b-5p to elevate the level of TLR4. RSV impeded ox-LDL-induced damages by regulating miR-106b-5p/TLR4 axis. CONCLUSION: All these findings suggested that RSV acted as an inhibitory factor in ox-LDL-induced endothelial injury via downregulating circ_0091822 to upregulate miR-106b-5p-related TLR4.

A Case of Central Nervous System Post-Transplant Lymphoproliferative Disorder Following Haploidentical Stem Cell Transplantation in a Patient With Acute Lymphoblastic Leukemia.

We present a differential diagnosis of an intracranial lesion following haploidentical stem cell transplantation (haplo-SCT) in a female patient with acute lymphoblastic leukemia (ALL). This patient received an anti-CD19-chimeric antigen receptor (CAR) T-cell therapy for refractory B-cell ALL and obtained minimal residual disease (MRD)-positive (0.03%) complete remission (CR). Then the patient received a bridging therapy of haplo-SCT. After bridging therapy, the patient maintained MRD-negative and full donor chimerism in bone marrow (BM) and was negative for Epstein-Barr virus (EBV)-DNA copy in peripheral blood. At 91 days after haplo-SCT, the patient presented with dizziness and fatigue and magnetic resonance imaging (MRI) demonstrated an intracranial lesion. The diagnosis of isolated extramedullary relapse (IEMR) was temporarily considered. Then next-generation sequencing (NGS) identified positive EBV-DNA in the cerebrospinal fluid, although EBV-DNA in the peripheral blood was negative. Furthermore, the positive EBV-DNA by NGS and complete donor chimerism in the brain tissue confirmed the diagnosis of central nervous system post-transplant lymphoproliferative disorder (CNS-PTLD). However, the EBV-encoded small RNAs (EBERs) in situ hybridization was sparsely positive. The patient was subsequently treated with anti-CD22-CAR T cells in combination with Zanubrutinib, but the disease progressed quickly and died. Donor chimerism examination of focal biopsy provides important evidence for diagnosing PTLD. Furthermore, NGS detection of EBV-DNA in local lesions is more valuable for diagnosing PTLD than detection of EBV-DNA in the peripheral blood.Trial registration: The patient was enrolled in a clinical trial of ChiCTR1800019622 and ChiCTR1800019298.

[Advances of Kunitz-type serine protease inhibitors].

Kunitz-type serine protease inhibitors are a class of ubiquitous protease inhibitors, which play important roles in various life activities. The structures of such inhibitors are generally stable, and are usually characterized by the presence of one or several Kunitz domains in tandem, which are able to bind to serine proteases in a manner similar to substrate binding, thereby inhibiting enzyme activity. In terms of function, Kunitz-type serine protease inhibitors are involved in processes such as blood coagulation and fibrinolysis, tumor immunity, inflammation regulation, and resistance to bacterial and fungal infections. This article summarizes the advances of Kunitz-type serine protease inhibitors and provides new ideas for the development of novel Kunitz-type serine protease inhibitors.

DAKS1, a Kunitz Scaffold Peptide from the Venom Gland of Deinagkistrodon acutus Prevents Carotid-Artery and Middle-Cerebral-Artery Thrombosis via Targeting Factor XIa.

Scaffold-based peptides (SBPs) are fragments of large proteins that are characterized by potent bioactivity, high thermostability, and low immunogenicity. Some SBPs have been approved by the FDA for human use. In the present study, we developed SBPs from the venom gland of Deinagkistrodon acutus (D. acutus) by combining transcriptome sequencing and Pfam annotation. To that end, 10 Kunitz peptides were discovered from the venom gland of D. acutus, and most of which peptides exhibited Factor XIa (FXIa) inhibitory activity. One of those, DAKS1, exhibiting strongest inhibitory activity against FXIa, was further evaluated for its anticoagulant and antithrombotic activity. DAKS1 prolonged twofold APTT at a concentration of 15 µM in vitro. DAKS1 potently inhibited thrombosis in a ferric chloride-induced carotid-artery injury model in mice at a dose of 1.3 mg/kg. Furthermore, DAKS1 prevented stroke in a transient middle cerebral-artery occlusion (tMCAO) model in mice at a dose of 2.6 mg/kg. Additionally, DAKS1 did not show significant bleeding risk at a dose of 6.5 mg/kg. Together, our results indicated that DAKS1 is a promising candidate for drug development for the treatment of thrombosis and stroke disorders.

WPK5, a Novel Kunitz-Type Peptide from the Leech Whitmania pigra Inhibiting Factor XIa, and Its Loop-Replaced Mutant to Improve Potency.

Kunitz-type proteins or peptides have been found in many blood-sucking animals, but the identity of them in leeches remained elusive. In the present study, five Kunitz-type peptides named WPK1-WPK5 were identified from the leech Whitmania pigra. Recombinant WPK1-WPK5 were expressed in Pichia pastoris GS115, and their inhibitory activity against Factor XIa (FXIa) was tested. WPK5 showed inhibitory activity against FXIa with an IC50 value of 978.20 nM. To improve its potency, the loop replacement strategy was used. The loop 1 (TGPCRSNLER) and loop 2 (QYGGC) in WPK5 were replaced by loop 1 (TGPCRAMISR) and loop 2 (FYGGC) in PN2KPI, respectively, and the resulting peptide named WPK5-Mut showed an IC50 value of 8.34 nM to FXIa, which is about 100-fold the potency of FXIa compared to that of WPK5. WPK5-Mut was further evaluated for its extensive bioactivity in vitro and in vivo. It dose-dependently prolonged APTT on both murine plasma and human plasma, and potently inhibited FeCl3-induced carotid artery thrombosis in mice at a dose of 1.5 mg/kg. Additionally, WPK5-Mut did not show significant bleeding risk at a dose of 6 mg/kg. Together, these results showed that WPK5-Mut is a promising candidate for the development of an antithrombotic drug.

Serum ROCK1 mRNA is of great diagnostic value for glioma patients.

The study aimed to measure the presence of rho-associated protein kinase 1 (ROCK1) mRNA in serum samples collected from glioma and investigate its diagnostic significance in glioma.The presence of ROCK1 mRNA was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between ROCK1 mRNA and clinical characteristics was analyzed via Chi-square test. The criteria of diagnosis evaluation, including sensitivity, specificity, optimal cutoff point, and area under the curve (AUC) were determined through the receiver operating characteristic (ROC) curve analysis.ROCK1 mRNA was significantly increased in serum samples collected from glioma patients compared to the controls (P <.05). Besides, high ROCK1 mRNA expression was tightly related with Karnofsky Performance Status (KPS) score (P = .024) and World Health Organization (WHO) grade (P = .029). However, there was no association between ROCK1 expression and gender, neurological disorders, family history and cigarette smoking (all, P >.05). In addition, the optimal cutoff point was 3.025, with the sensitivity and specificity of 88.89% and 79.25%, respectively. The AUC was 0.881, indicating that ROCK1 was a diagnostic biomarker for glioma patients (P <.0001, 95% CI = 0.829-0.933).Serum ROCK1 mRNA is significantly up-regulated in glioma cases compared to healthy controls. ROCK1 may be a potential diagnostic biomarker in glioma.

The dynamic links between CO2 emissions, energy consumption and economic development in the countries along "the Belt and Road".

China has proposed the Belt and Road Initiative to promote the cooperation of energy production and trade between the relevant countries. This paper investigates the relationship between the energy consumption and economic growth of the countries along the Belt and Road using a panel of data for 69 countries during the period between 1970 and 2013. Both of the renewable and traditional fossil energy consumptions are investigated in this study. By employing vector error correction model (VECM), fully modified OLS (FMOLS) and dynamic OLS (DOLS) approaches, the estimation results indicate that the nexuses of the energy consumption and economic developments vary across different subgroups. For the entire group, there is evidence of long-run bidirectional causalities among carbon emissions, energy use, industry value added and GDP per capita. For the energy-importing countries along the Belt and Road, there exists unidirectional short-run causality running from GDP to renewable energy and long-run causality in the reverse direction. In contrast, for the energy-exporting countries, there is a bidirectional causality between the energy use and GDP per capita in the long run. These findings suggest significant cooperation potential in the economies and trades of China and the Belt and Road countries.

Retrospective Clinical Study of Eighty-One Cases of Intracranial Mucormycosis.

BACKGROUND: Fungal infections of the central nervous system, especially cerebral mucormycosis or brain abscess are very rare.Cerebral mucormycosis is a rare disease. It is not an independent disease, but a secondary opportunistic infectious disease. MATERIALS AND METHODS: This study has collected the data of 81 cases of intracranial mucormycosis from 28 Chinese hospitals, within 37 years, as well as reviewed the literatures and retrospectively analyzed and summarized this disease's background, clinical classifications, risk factors, pathology, clinical manifestations, diagnosis, treatment, and prognosis. RESULTS: The 81 IM cases were aged between 15 days (the youngest) and 79 years (oldest), with a mean age of 41.6 years. Among them, 12 cases were <1 year old (the infant group), six cases were within one to 13 years old (the children group), and 63 cases were >14 years old (the adult group ). 45 cases were male and 36 were female, with a male/female ratio of 1.25:1.0. The shortest duration of the disease was three days, and the longest was 248 days. CONCLUSIONS: This study helped to realize an early diagnosis and treatment, improve the cure rate, and reduce mortality.

Effects of atorvastatin on expression of ICAM-1 in atherosclerotic rabbits.

AIMS: Lipid accumulation and inflammatory response are major events in the progression of atherosclerosis. This research was performed to determine if atorvastatin could prevent atherosclerosis and its underlying mechanisms. METHODS: An atherosclerotic model was established in rabbits. Atorvastatin was administrated by gavage. Blood samples were collected to measure plasma total cholesterol, total triglyceride and low-density lipoprotein (LDL)-cholesterol. After the high-cholesterol diet with or without atorvastatin treatment, the morphological changes of the rabbits were examined with hematoxylin and eosin staining of tissues, and the expression of intercellular adhesion molecule 1 (ICAM-1) was determined by immuno-staining and reverse transcriptase-PCR (RT-PCR). RESULTS: Atorvastatin significantly reduced plasma levels of total cholesterol (41.7%) and LDL-cholesterol (34.6%). Neither the hypercholesterol diet nor atorvastatin treatment had any significant impact on body weight and plasma triglycerides. Treatment with atorvastatin significantly restored 40.9% of the widened intima and even down-regulated the ratio of intima/media by 55.5%. The inhibitory effects of atorvastatin on the expression of ICAM-1 showed a decrease of up to 37.6% (P < 0.01). The diseased rabbits showed a 167.3% increase in ICAM-1 mRNA expression (P < 0.01), which was reversed by nearly 46.4% by treatment with atorvastatin. CONCLUSION: Atorvastatin significantly prevents atherosclerotic changes in rabbits with a high-cholesterol diet, possibly by lowering plasma lipids and decreasing over-expressed ICAM-1.

Rapid synthesis of zeolitic imidazolate framework-8 (ZIF-8) nanocrystals in an aqueous system.

We report here the first example of ZIF materials synthesized in aqueous solution. The synthesis was performed at room temperature and typically took several minutes compared to hours and days in non-aqueous conditions. The obtained product were ZIF-8 nanocrystals having size of ~85 nm and showed excellent thermal, hydrothermal and solvothermal stabilities.