Leonurus japonicus Houtt. Modulates Neuronal Apoptosis in Intracerebral Hemorrhage: Insights from Network Pharmacology and Molecular Docking.

ETHNOPHARMACOLOGICAL RELEVANCE: Leonurus japonicus Houtt. (Labiatae), commonly known as Chinese motherwort, is a herbaceous flowering plant that is native to Asia. It is widely acknowledged in traditional medicine for its diuretic, hypoglycemic, antiepileptic properties and neuroprotection. Currently, Leonurus japonicus (Leo) is included in the Pharmacopoeia of the People's Republic of China. Traditional Chinese Medicine (TCM) recognizes Leo for its myriad pharmacological attributes, but its efficacy against ICH-induced neuronal apoptosis is unclear. AIMS OF THE STUDY: This study aimed to identify the potential targets and regulatory mechanisms of Leo in alleviating neuronal apoptosis after ICH. MATERIALS AND METHODS: The study employed network pharmacology, UPLC-Q-TOF-MS technique,molecular docking, pharmacodynamic studies, western blotting, and immunofluorescence techniques to explore its potential mechanisms. RESULTS: Leo was found to assist hematoma absorption, thus improving the neurological outlook in an ICH mouse model. Importantly, molecular docking highlighted JAK as Leo's potential therapeutic target in ICH scenarios. Further experimental evidence demonstrated that Leo adjusts JAK1 and STAT1 phosphorylation, curbing Bax while augmenting Bcl-2 expression. CONCLUSION: Leo showcases potential in mitigating neuronal apoptosis post-ICH, predominantly via the JAK/STAT mechanism.

Enhanced CO Adsorption by Modulating the Electron Density Distribution of Graphite-Copper Porphyrin Sorbents with Light.

The photo-responsive adsorption has emerged as a vibrant area, but its current methodology is limited by the well-defined photochromic units and their molecular deformation driven by photo-stimuli. Herein, a methodology of nondeforming photo-responsiveness is successfully exploited. With the exploiting agent of Cu-TCPP framework assembled on the graphite and strongly interacted with it, the sorbent generates two kinds of adsorption sites, over which the electron density distribution of the graphite layer can be modulated at the c-axis direction, which can further evolve due to photo-stimulated excited states. The excited states are stable enough to meet the timescale of microscopic adsorption equilibrium. Independent of the ultra-low specific surface area of the sorbent (20 m2 g-1 ), the CO adsorption capability can be improved from 0.50 mmol g-1 at the ground state to 1.24 mmol g-1 (0 °C, 1 bar) with the visible light radiation, rather than the photothermal desorption.

High-efficiency catalyst CuSO4/SBA-15 toward butylated hydroxytoluene synthesis in a heterogeneous system.

An SBA-15 loaded CuSO4 catalyst was designed and prepared for the highly selective production of 2,6-di-tert-butyl-p-cresol (BHT) from p-cresol and isobutylene. The acidity of solid acid catalysts was altered by varying the loading amount of CuSO4. Among them, 10% CuSO4/SBA-15 exhibited the greatest catalytic performance in the alkylation reaction with a BHT yield of 85.5%. After four cycles, the yield of BHT exceeded 70%. Overall, the catalyst has excellent catalytic performance and can be utilized as a catalyst for efficient BHT production.

Hierarchically hollow N-doped carbon-cobalt nanoparticle heterointerface for efficient bifunctional oxygen electrocatalysis.

The rational design and fabrication of high-performance and durable bifunctional non-noble-metal electrocatalysts for both the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are still a great challenge in the practical applications of rechargeable zinc-air (Zn-air) batteries. Herein, we report a simple yet robust route to synthesize cobalt nanoparticles rooted in the hierarchically hollow nitrogen-doped carbon frameworks (Co@HNCs). This strategy employs the pyrolysis of nanostructured hollow Co-based metal-organic framework (ZIF-67) precursors produced by selective linker cleaving with pyrazino(2,3-f)(1,10)phenanthroline-2,3-dicarboxylic acid molecules (H2PPDA). The designed hierarchically architecture is favorable for the accessibility of the active sites in the catalyst, which affords enhanced bifunctional performance for ORR and OER. Moreover, when used as a cathode in liquid and all-solid-state Zn-air batteries, the resultant Co@HNCs delivers high efficiency and outstanding durability, even outperforming the benchmark Pt/C + RuO2. This work provides a feasible design avenue to achieve advanced dual-phasic oxygen electrocatalyst and promotes the development of rechargeable Zn-air batteries.

Activation of SIRT1 Alleviates Ferroptosis in the Early Brain Injury after Subarachnoid Hemorrhage.

Ferroptosis is a regulated cell death that characterizes the lethal lipid peroxidation and iron overload, which may contribute to early brain injury (EBI) pathogenesis after subarachnoid hemorrhage (SAH). Although Sirtuin 1 (SIRT1), a class III histone deacetylase, has been proved to have endogenous neuroprotective effects on the EBI following SAH, the role of SIRT1 in ferroptosis has not been studied. Hence, we designed the current study to determine the role of ferroptosis in the EBI and explore the correlation between SIRT1 and ferroptosis after SAH. The pathways of ferroptosis were examined after experimental SAH in vivo (prechiasmatic cistern injection mouse model) and in HT-22 cells stimulated by oxyhemoglobin (oxyHb) in vitro. Then, ferrostatin-1 (Fer-1) was used further to determine the role of ferroptosis in EBI. Finally, we explored the correlation between SIRT1 and ferroptosis via regulating the expression of SIRT1 by resveratrol (RSV) and selisistat (SEL). Our results showed that ferroptosis was involved in the pathogenesis of EBI after SAH through multiple pathways, including acyl-CoA synthetase long-chain family member 4 (ACSL4) activation, iron metabolism disturbance, and the downregulation of glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Inhibition of ferroptosis by Fer-1 significantly alleviated oxidative stress-mediated brain injury. SIRT1 activation could suppress SAH-induced ferroptosis by upregulating the expression of GPX4 and FSP1. Therefore, ferroptosis could be a potential therapeutic target for SAH, and SIRT1 activation is a promising method to inhibit ferroptosis.

Placental Immune Tolerance and Organ Transplantation: Underlying Interconnections and Clinical Implications.

The immune system recognizes and attacks non-self antigens, making up the cornerstone of immunity activity against infection. However, during organ transplantation, the immune system also attacks transplanted organs and leads to immune rejection and transplantation failure. Interestingly, although the embryo and placenta are semi-allografts, like transplanted organs, they can induce maternal tolerance and be free of a vigorous immune response. Also, embryo or placenta-related antibodies might adversely affect subsequent organ transplantation despite the immune tolerance during pregnancy. Therefore, the balance between the immune tolerance in maternal-fetal interface and normal infection defense provides a possible desensitization and tolerance strategy to improve transplantation outcomes. A few studies on mechanisms and clinical applications have been performed to explore the relationship between maternal-fetal immune tolerance and organ transplantation. However, up to now, the mechanisms underlying maternal-fetal immune tolerance remain vague. In this review, we provide an overview on the current understanding of immune tolerance mechanisms underlying the maternal-fetal interface, summarize the interconnection between immune tolerance and organ transplantation, and describe the adverse effect of pregnancy alloimmunization on organ transplantation.

Gut Microbiota and Acute Central Nervous System Injury: A New Target for Therapeutic Intervention.

Acute central nervous system (CNS) injuries, including stroke, traumatic brain injury (TBI), and spinal cord injury (SCI), are the common causes of death or lifelong disabilities. Research into the role of the gut microbiota in modulating CNS function has been rapidly increasing in the past few decades, particularly in animal models. Growing preclinical and clinical evidence suggests that gut microbiota is involved in the modulation of multiple cellular and molecular mechanisms fundamental to the progression of acute CNS injury-induced pathophysiological processes. The altered composition of gut microbiota after acute CNS injury damages the equilibrium of the bidirectional gut-brain axis, aggravating secondary brain injury, cognitive impairments, and motor dysfunctions, which leads to poor prognosis by triggering pro-inflammatory responses in both peripheral circulation and CNS. This review summarizes the studies concerning gut microbiota and acute CNS injuries. Experimental models identify a bidirectional communication between the gut and CNS in post-injury gut dysbiosis, intestinal lymphatic tissue-mediated neuroinflammation, and bacterial-metabolite-associated neurotransmission. Additionally, fecal microbiota transplantation, probiotics, and prebiotics manipulating the gut microbiota can be used as effective therapeutic agents to alleviate secondary brain injury and facilitate functional outcomes. The role of gut microbiota in acute CNS injury would be an exciting frontier in clinical and experimental medicine.

Efficient, green, and rapid strategy for separating actinomycin D and X2 using supercritical fluid chromatography.

Actinomycin D has long been used as a first-line antitumor drug in clinical practice. Actinomycin X2, a new drug lead, is often isolated along with actinomycin D. The minor differences between the two actinomycin analogs pose a daunting challenge in separation. In this study, supercritical fluid chromatography (SFC) was successfully utilized for the purification of actinomycin X2 and actinomycin D from a marine derived Streptomyces sp. DQS-5. After one-step SFC purification, the purities of these two compounds were determined to be 97.3 % and 97.8 %, respectively. This method provides a green alternative for the separation of these pharmacologically important actinomycin antibiotics. This study also demonstrated the development of a simple and rapid method for the separation of natural products based on SFC.

Management of patients with intermediate stage hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) causes a significant health burden globally and its impact is expected to increase in the coming years. Intermediate stage HCC, as defined by the Barcelona Clinic Liver Cancer (BCLC) system stage B, represents up to 30% of patients at diagnosis and encompasses a broad spectrum of tumor burden. Several attempts have been made to further subclassify this heterogenous group. The current standard of care recommended by BCLC for intermediate stage HCC patients is transarterial chemoembolization (TACE), with modest outcomes reported. While refinements have been made to TACE technique and patient selection, it remains non-curative. In the real-world setting, only 60% of patients with intermediate stage HCC receive TACE, with the remainder deviating to a range of other therapies that have shown promise in select patient subgroups. These include curative treatments (resection, ablation, and liver transplantation), radiotherapy (stereotactic and radioembolization), systemic therapies, and their combination. In this review, we summarize the classifications and current management for patients with intermediate stage HCC as well as highlight recent key developments in this space.

FibroBox: a novel noninvasive tool for predicting significant liver fibrosis and cirrhosis in HBV infected patients.

BACKGROUND: China is a highly endemic area of chronic hepatitis B (CHB). The accuracy of existed noninvasive biomarkers including TE, APRI and FIB-4 for staging fibrosis is not high enough in Chinese cohort. METHODS: Using liver biopsy as a gold standard, a novel noninvasive indicator was developed using laboratory tests, ultrasound measurements and liver stiffness measurements with machine learning techniques to predict significant fibrosis and cirrhosis in CHB patients in north and east part of China. We retrospectively evaluated the diagnostic performance of the novel indicator named FibroBox, Fibroscan, aspartate transaminase-to-platelet ratio index (APRI), and fibrosis-4 index (FIB-4) in CHB patients from Jilin and Huai'an (training sets) and also in Anhui and Beijing cohorts (validation sets). RESULTS: Of 1289 eligible HBV patients who had liver histological data, 63.2% had significant fibrosis and 22.5% had cirrhosis. In LASSO logistic regression and filter methods, fibroscan results, platelet count, alanine transaminase (ALT), prothrombin time (PT), type III procollagen aminoterminal peptide (PIIINP), type IV collagen, laminin, hyaluronic acid (HA) and diameter of spleen vein were finally selected as input variables in FibroBox. Consequently, FibroBox was developed of which the area under the receiver operating characteristic curve (AUROC) was significantly higher than that of TE, APRI and FIB-4 to predicting significant fibrosis and cirrhosis. In the Anhui and Beijing cohort, the AUROC of FibroBox was 0.88 (95% CI, 0.72-0.82) and 0.87 (95% CI, 0.83-0.91) for significant fibrosis and 0.87 (95% CI, 0.82-0.92) and 0.90 (95% CI, 0.85-0.94) for cirrhosis. In the validation cohorts, FibroBox accurately diagnosed 81% of significant fibrosis and 84% of cirrhosis. CONCLUSIONS: FibroBox has a better performance in predicting liver fibrosis in Chinese cohorts with CHB, which may serve as a feasible alternative to liver biopsy.

Resistance to PD-1/PD-L1 blockade cancer immunotherapy: mechanisms, predictive factors, and future perspectives.

PD-1/PD-L1 blockade therapy is a promising cancer treatment strategy, which has revolutionized the treatment landscape of malignancies. Over the last decade, PD-1/PD-L1 blockade therapy has been trialed in a broad range of malignancies and achieved clinical success. Despite the potentially cure-like survival benefit, only a minority of patients are estimated to experience a positive response to PD-1/PD-L1 blockade therapy, and the primary or acquired resistance might eventually lead to cancer progression in patients with clinical responses. Accordingly, the resistance to PD-1/PD-L1 blockade remains a significant challenge hindering its further application. To overcome the limitation in therapy resistance, substantial effort has been made to improve or develop novel anti-PD-1/PD-L1 based immunotherapy strategies with better clinical response and reduced immune-mediated toxicity. In this review, we provide an overview on the resistance to PD-1/PD-L1 blockade and briefly introduce the mechanisms underlying therapy resistance. Moreover, we summarize potential predictive factors for the resistance to PD-1/PD-L1 blockade. Furthermore, we give an insight into the possible solutions to improve efficacy and clinical response. In the following research, combined efforts of basic researchers and clinicians are required to address the limitation of therapy resistance.

Lung transplantation as therapeutic option in acute respiratory distress syndrome for coronavirus disease 2019-related pulmonary fibrosis.

BACKGROUND: Critical patients with the coronavirus disease 2019 (COVID-19), even those whose nucleic acid test results had turned negative and those receiving maximal medical support, have been noted to progress to irreversible fatal respiratory failure. Lung transplantation (LT) as the sole therapy for end-stage pulmonary fibrosis related to acute respiratory distress syndrome has been considered as the ultimate rescue therapy for these patients. METHODS: From February 10 to March 10, 2020, three male patients were urgently assessed and listed for transplantation. After conducting a full ethical review and after obtaining assent from the family of the patients, we performed three LT procedures for COVID-19 patients with illness durations of more than one month and extremely high sequential organ failure assessment scores. RESULTS: Two of the three recipients survived post-LT and started participating in a rehabilitation program. Pearls of the LT team collaboration and perioperative logistics were summarized and continually improved. The pathological results of the explanted lungs were concordant with the critical clinical manifestation, and provided insight towards better understanding of the disease. Government health affair systems, virology detection tools, and modern communication technology all play key roles towards the survival of the patients and their rehabilitation. CONCLUSIONS: LT can be performed in end-stage patients with respiratory failure due to COVID-19-related pulmonary fibrosis. If confirmed positive-turned-negative virology status without organ dysfunction that could contraindicate LT, LT provided the final option for these patients to avoid certain death, with proper protection of transplant surgeons and medical staffs. By ensuring instant seamless care for both patients and medical teams, the goal of reducing the mortality rate and salvaging the lives of patients with COVID-19 can be attained.

Hsa_circ_0070963 inhibits liver fibrosis via regulation of miR-223-3p and LEMD3.

Previous circular RNA (circRNA) microarray analyses have uncovered an abnormal expression of hsa_circ_0070963 in hepatic stellate cells (HSCs). However, the specific role of hsa_circ_0070963 in liver fibrosis remains unknown. Here, we show that hsa_circ_0070963 inhibits liver fibrosis via regulation of miR-223-3p and LEMD3. Moreover, we demonstrated that hsa_circ_0070963 levels were reduced during liver fibrosis while restoring hsa_circ_0070963 levels abolished HSC activation, with a reduction in α-SMA and type I collagen levels both in vitro and in vivo. Furthermore, hsa_circ_0070963 overexpression suppressed both cell proliferation and the cell cycle of HSCs. MiR-223-3p was confirmed as a target of hsa_circ_0070963 and was shown to be involved in the effects of hsa_circ_0070963 on HSC activation. Furthermore, LEMD3 was confirmed as a target of miR-223-3p and was shown to be responsible for the activation of HSCs. The interactions between hsa_circ_0070963, miR-223-3p, and LEMD3 were validated via bioinformatic analysis, luciferase reporter assays, and rescue experiments. Collectively, hsa_circ_0070963 appeared to function as a miR-223-3p sponge that inhibited HSC activation in liver fibrosis via regulation of miR-223-3p and LEMD3. Therefore, hsa_circ_0070963 may serve as a potential therapeutic target for liver fibrosis.

Gut microbiome and cancer immunotherapy.

Gut microbiome has received significant attention for its influences on a variety of host functions, especially immune modulation. With the next-generation sequencing methodologies, more knowledge is gathered about gut microbiome and its irreplaceable role in keeping the balance between human health and diseases is figured out. Immune checkpoint inhibitors (ICIs) are one of the most innovational cancer immunotherapies across cancer types and significantly expand the therapeutic options of cancer patients. However, a proportion of patients show no effective responses or develop immune-related adverse events when responses do occur. More important, it is demonstrated that the therapeutic response or treatment-limiting toxicity of cancer immunotherapy can be ameliorated or diminished by gut microbiome modulation. In this review, we first introduce the relationship between gut microbiome and cancer immunotherapy. And then, we expound the impact of gut microbiome on efficacy and toxicity of cancer immunotherapy. Further, we review approaches to manipulating gut microbiome to regulate response to ICIs. Finally, we discuss the current challenges and propose future directions to improve cancer immunotherapy via gut microbiome manipulation.