Triptolide regulates neutrophil function through the Hippo signaling pathway to alleviate rheumatoid arthritis disease progression.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammatory changes in the joints, the etiology of which is unclear. It is now well established that regulated cell death (RCD) and migration of neutrophils play an important role in the pathogenesis of RA. Tripterygium wilfordii Hook.f (TwHF) is a total saponin extracted from the root of Tripterygium wilfordii Hook.f, a plant of the family Wesleyanaceae, which has strong anti-inflammatory and immunomodulatory effects and has been used as a basic drug in the clinical treatment of RA. Despite the good efficacy of TwHF treatment, the mechanism of action of TwHF remains unclear. Several studies have demonstrated that the drug tripterygium glycosides, in which TwHF is the main ingredient, has achieved excellent efficacy in the clinical treatment of RA. Investigations have also found that TwHF can affect cellular RCD, cell migration, cell proliferation, and the apoptosis-related Hippo signaling pathway. In this study, we first analyzed the RCD and migration differences of neutrophils in patients with RA through network pharmacology and transcriptome analysis. Subsequently, we used electron microscopy, immunofluorescence, and other methods to identify the RCD phenotype of neutrophils. In collagen-induced arthritis (CIA) model, we demonstrated that Triptolide (the main active ingredient in TwHF) could alleviate the progression of arthritis by reducing the bone destruction and the infiltration of neutrophils. Furthermore, in vitro experiments showed that Triptolide induced neutrophil apoptosis, inhibited the formation of neutrophil extracellular traps (NETs), and impeded the neutrophil migration process in a Hippo pathway-dependent manner. Taken together, these findings indicate that Triptolide has potential for treating RA and provide theoretical support for the clinical application of TwHF, as a traditional Chinese medicine, in RA.

The therapeutic value of bifidobacteria in cardiovascular disease.

There has been an increase in cardiovascular morbidity and mortality over the past few decades, making cardiovascular disease (CVD) the leading cause of death worldwide. However, the pathogenesis of CVD is multi-factorial, complex, and not fully understood. The gut microbiome has long been recognized to play a critical role in maintaining the physiological and metabolic health of the host. Recent scientific advances have provided evidence that alterations in the gut microbiome and its metabolites have a profound influence on the development and progression of CVD. Among the trillions of microorganisms in the gut, bifidobacteria, which, interestingly, were found through the literature to play a key role not only in regulating gut microbiota function and metabolism, but also in reducing classical risk factors for CVD (e.g., obesity, hyperlipidemia, diabetes) by suppressing oxidative stress, improving immunomodulation, and correcting lipid, glucose, and cholesterol metabolism. This review explores the direct and indirect effects of bifidobacteria on the development of CVD and highlights its potential therapeutic value in hypertension, atherosclerosis, myocardial infarction, and heart failure. By describing the key role of Bifidobacterium in the link between gut microbiology and CVD, we aim to provide a theoretical basis for improving the subsequent clinical applications of Bifidobacterium and for the development of Bifidobacterium nutritional products.

Molecular mechanisms of rapid-acting antidepressants: New perspectives for developing antidepressants.

Major depressive disorder (MDD) is a chronic relapsing psychiatric disorder. Conventional antidepressants usually require several weeks of continuous administration to exert clinically significant therapeutic effects, while about two-thirds of the patients are prone to relapse of symptoms or are completely ineffective in antidepressant treatment. The recent success of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine as a rapid-acting antidepressant has propelled extensive research on the action mechanism of antidepressants, especially in relation to its role in synaptic targets. Studies have revealed that the mechanism of antidepressant action of ketamine is not limited to antagonism of postsynaptic NMDA receptors or GABA interneurons. Ketamine produces powerful and rapid antidepressant effects by affecting α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, adenosine A1 receptors, and the L-type calcium channels, among others in the synapse. More interestingly, the 5-HT2A receptor agonist psilocybin has demonstrated potential for rapid antidepressant effects in depressed mouse models and clinical studies. This article focuses on a review of new pharmacological target studies of emerging rapid-acting antidepressant drugs such as ketamine and hallucinogens (e.g., psilocybin) and briefly discusses the possible strategies for new targets of antidepressants, with a view to shed light on the direction of future antidepressant research.

Construction of Curcumin and Paclitaxel Co-Loaded Lipid Nano Platform and Evaluation of Its Anti-Hepatoma Activity in vitro and Pharmacokinetics in vivo.

Purpose: The present study aimed to construct a co-loading platform encapsulating curcumin and paclitaxel at ratios of 2:1-80:1 (w/w) designated "CU-PTX-LNP" and explored the synergistic effects of CU-PTX at different composite proportions on liver cancer cells using the combination index (CI) method. Methods: The CU lipid nanoplatform (CU-LNP) formulation was optimized via single-factor and orthogonal experiments. Various concentrations of PTX were added to the optimal formulation of CU-LNP to generate CU-PTX-LNP and the nanoplatform characterized via differential scanning calorimetry (DSC), transmission electron microscope (TEM), X-ray diffraction (XRD), zeta potential, polydispersity index (PDI), and size analyses. The cumulative release, stability, and cytotoxicity of CU-PTX-LNP in LO2, HepG2, and SMMC-7221 cells were assessed in vitro, followed by safety investigation and pharmacokinetic studies in vivo. The anti-tumor activity of CU-PTX-LNP was also evaluated using nude mice. Results: CU-PTX-LNP formulations containing CU:PTX at a range of proportions (2:1-80:1; w/w) appeared as uniformly dispersed nanosized spherical particles with high entrapment efficiency (EE> 90%), sustained release and long-lasting stability. Data from in vitro cytotoxicity assays showed a decrease in the IC50 value of PTX of CU-PTX-LNP (by 5.47-332.7 times in HepG2 and 4.29-143.21 times in SMMC-7221 cells) compared to free PTX. In vivo, CU-PTX-LNP displayed excellent biosafety, significant anti-tumor benefits and enhanced pharmacokinetic behavior with longer mean residence time (MRT(0-t); CU: 4.31-fold, PTX: 4.61-fold) and half-life (t1/2z; CU: 1.83-fold, PTX: 2.28-fold) relative to free drugs. Conclusion: The newly designed CU-PTX-LNP platform may serve as a viable technological support system for the successful production of CU-PTX composite preparations.

The role of NLRP3 inflammasome in hepatocellular carcinoma.

Inflammasomes play an important role in innate immunity. As a signal platform, they deal with the excessive pathogenic products and cellular products related to stress and injury. So far, the best studied and most characteristic inflammasome is the NLR-family pyrin domain-containing protein 3(NLRP3) inflammasome, which is composed of NLRP3, apoptosis associated speck like protein (ASC) and pro-caspase-1. The formation of NLRP3 inflammasome complexes results in the activation of caspase-1, the maturation of interleukin (IL)-1ß and IL-18, and pyroptosis. Many studies have demonstrated that NLRP3 inflammasome not only participates in tumorigenesis, but also plays a protective role in some cancers. Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Currently, due to the lack of effective treatment methods for HCC, the therapeutic effect of HCC has not been ideal. Therefore, it is particularly urgent to explore the pathogenesis of HCC and find its effective treatment methods. The increasing evidences indicate that NLRP3 inflammasome plays a vital role in HCC, however, the related mechanisms are not fully understood. Hence, we focused on the recent progress about the role of NLRP3 inflammasome in HCC, and analyzed the relevant mechanisms in detail to provide reference for the future in-depth researches.

The application of extracellular vesicles in colorectal cancer metastasis and drug resistance: recent advances and trends.

Colorectal cancer (CRC) has high incidence and mortality rates and is one of the most common cancers of the digestive tract worldwide. Metastasis and drug resistance are the main causes of cancer treatment failure. Studies have recently suggested extracellular vesicles (EVs) as a novel mechanism for intercellular communication. They are vesicular particles, which are secreted and released into biological fluids, such as blood, urine, milk, etc., by a variety of cells and carry numerous biologically active molecules, including proteins, nucleic acids, lipids, metabolites, etc. EVs play a crucial part in the metastasis and drug resistance of CRC by delivering cargo to recipient cells and modulating their behavior. An in-depth exploration of EVs might facilitate a comprehensive understanding of the biological behavior of CRC metastasis and drug resistance, which might provide a basis for developing therapeutic strategies. Therefore, considering the specific biological properties of EVs, researchers have attempted to explore their potential as next-generation delivery systems. On the other hand, EVs have also been demonstrated as biomarkers for the prediction, diagnosis, and presumed prognosis of CRC. This review focuses on the role of EVs in regulating the metastasis and chemoresistance of CRC. Moreover, the clinical applications of EVs are also discussed.

α7 Nicotinic acetylcholine receptor: a key receptor in the cholinergic anti-inflammatory pathway exerting an antidepressant effect.

Depression is a common mental illness, which is related to monoamine neurotransmitters and the dysfunction of the cholinergic, immune, glutamatergic, and neuroendocrine systems. The hypothesis of monoamine neurotransmitters is one of the commonly recognized pathogenic mechanisms of depression; however, the drugs designed based on this hypothesis have not achieved good clinical results. A recent study demonstrated that depression and inflammation were strongly correlated, and the activation of alpha7 nicotinic acetylcholine receptor (α7 nAChR)-mediated cholinergic anti-inflammatory pathway (CAP) in the cholinergic system exhibited good therapeutic effects against depression. Therefore, anti-inflammation might be a potential direction for the treatment of depression. Moreover, it is also necessary to further reveal the key role of inflammation and α7 nAChR in the pathogenesis of depression. This review focused on the correlations between inflammation and depression as well-discussed the crucial role of α7 nAChR in the CAP.

Bromide-mediated, C2-selective, and oxygenative alkylation of pyridinium salts using alkenes and molecular oxygen.

Herein, we report a bromide-mediated, C2-selective, and oxygenative alkylation of pyridinium salts using alkenes and O2 for the synthesis of important ß-2-pyridyl ketones. Notably, a quaternary carbon center was successfully installed at the C2-position of pyridine and the resulting C2-substituents were highly functionalized. The intermediary cycloadduct was isolated and further transformed into the desired product, which indicated that this three-component reaction underwent a reaction cascade including dearomative cycloaddition and rearomative ring-opening oxygenation. Finally, the bromide-mediated mechanism was discussed and active Br(I) species were proposed to be generated in situ and promote the rearomative ring-opening oxygenation by halogen bond-assisted electron transfer.

Study on the ozonation degradation of methylene blue enhanced by microchannel and ultrasound.

Azo dye-containing wastewater poses serious risks of environmental pollution because it is generally biologically toxic and resistant to conventional wastewater treatment methods. A novel degradation system integrating ozone, microchannel, and ultrasound was designed to effectively degrade azo dye-contaminated wastewater. The effects of discharge voltage of dielectric barrier discharge (DBD) reactor, liquid flow rate, microchannel width, ultrasonic power, initial pH, and reaction temperature on methylene blue (MB) decolorization were studied. A maximum MB decolorization efficiency of 92.7% was obtained in the ozone/microchannel/ultrasound (O3/MC/US) system with 14 min of treatment. In addition, the 14-min decolorization efficiency and TOC removal efficiency obtained in O3/MC/US system were increased by 12.6 and 6.5%, respectively, compared to those obtained in the pure O3 system. Based on the results of scavenging experiments, the combined effects of microchannel and ultrasound were proved to improve the contribution rate of hydroxyl radicals, thus improving the decolorization efficiency. The present work clearly illustrates that ozonation degradation can be effectively enhanced by microchannel and ultrasound, and also provides a feasible method for the treatment of organic wastewater.

Preparation and Evaluation of Curcumin Derivatives Nanoemulsion Based on Turmeric Extract and Its Antidepressant Effect.

Purpose: The early stage of this study verified that a turmeric extract (TUR) including 59% curcumin (CU), 22% demethoxycurcumin (DMC), and 18% bisdemethoxycurcumin (BDMC), could enhance the stability of CU and had greater antidepressant potential in vitro. The objective of the study was to develop a nano-delivery system containing TUR (TUR-NE) to improve the pharmacokinetic behavior of TUR and enhance its antidepressant effect. Methods: The antidepressant potential of TUR was explored using ABTS, oxidative stress-induced cell injury, and a high-throughput screening model. TUR-NE was fabricated, optimized and characterized. The pharmacokinetic behaviors of TUR-NE were evaluated following oral administration to normal rats. The antidepressant effect of TUR-NE was assessed within chronic unpredictable mild stress model (CUMS) mice. The behavioral and biochemical indexes of mice were conducted. Results: The results depicted that TUR had 3.18 and 1.62 times higher antioxidant capacity than ascorbic acid and CU, respectively. The inhibition effect of TUR on ASP+ transport was significantly enhanced compared with fluoxetine and CU. TUR-NE displayed a particle size of 116.0 ± 0.31 nm, polydispersity index value of 0.121 ± 0.007, an encapsulation rate of 98.45%, and good release and stability in cold storage. The results of pharmacokinetics indicated the AUC(0-t) of TUR-NE was 8.436 and 4.495 times higher than that of CU and TUR, while the Cmax was 9.012 and 5.452 times higher than that of CU and TUR, respectively. The pharmacodynamic study confirmed that the superior antidepressant effect of TUR-NE by significantly improving the depressant-like behaviors and elevating the content of 5-hydroxytryptamine in plasma and brain in CUMS mice. TUR-NE showed good safety with repeated administration. Conclusion: TUR-NE, which had small and uniform particle size, enhanced the bioavailability and antidepressant effect of TUR. It could be a promising novel oral preparation against depression.

Endothelial cell protein C receptor regulates neutrophil extracellular trap-mediated rheumatoid arthritis disease progression.

Endothelial cell protein C receptor (EPCR) is a 46 kDa transmembrane protein receptor, expressed in most immune cells (T cells, monocytes, dendritic cells, polymorphonuclear neutrophils [PMN]). EPCR reportedly plays a vital role in rheumatoid arthritis (RA). Our results confirmed that EPCR expression exists in the PMN of RA patients, and animal experiments demonstrated that down-regulation of EPCR expression affects disease progression in collagen-induced arthritis (CIA) mice. PMN is the immune cell type that first enters the site of inflammation in the early stages of inflammation. In the early stage of RA, PMN cells migrate into the joint cavity and function in the process of RA synovial inflammation, aggravating the bone destruction found in RA and mediating the progression of RA disease progression. We verified the differences in EPCR expression in PMN cells between RA and osteoarthritis (OA) patients by Western blot and then confirmed this difference in animals. We found that CIA mice treated with PMN-neutralizing antibody intervention had reduced disease performance. On this basis, EPCR was knocked down at the same time. The therapeutic effect of PMN-neutralizing antibody treatment was subsequently diminished. To explore the relationship between EPCR and PMN in RA, we used immunofluorescence to detect the expression of PMN-neutrophil extracellular traps (NETs) in RA patients and used EPCR neutralizing antibodies as an intervention. The results showed that the formation of PMN-NETs in RA patients increased. Finally, through in vitro intervention experiments involving EPCR and PMN transcriptome analysis of the peripheral blood of RA patients, we concluded that EPCR may regulate the formation of PMN-NETs in RA patients through the activated protein C (APC)-EPCR signaling pathway, thereby affecting the progression of disease in RA patients.

The Role of Hydrogen Sulfide Targeting Autophagy in the Pathological Processes of the Nervous System.

Autophagy is an important cellular process, involving the transportation of cytoplasmic contents in the double membrane vesicles to lysosomes for degradation. Autophagy disorder contributes to many diseases, such as immune dysfunction, cancers and nervous system diseases. Hydrogen sulfide (H2S) is a volatile and toxic gas with a rotten egg odor. For a long time, it was considered as an environmental pollution gas. In recent years, H2S is regarded as the third most important gas signal molecule after NO and CO. H2S has a variety of biological functions and can play an important role in a variety of physiological and pathological processes. Increasingly more evidences show that H2S can regulate autophagy to play a protective role in the nervous system, but the mechanism is not fully understood. In this review, we summarize the recent literatures on the role of H2S in the pathological process of the nervous system by regulating autophagy, and analyze the mechanism in detail, hoping to provide the reference for future related research.

Experimental study on tailings cementation by MICP technique with immersion curing.

The filling mining method is an effective method for controlling ground stress and preventing surface subsidence in the mining field during exploitation of underground resources. Tailings can be utilized as the filling material, so as to realize the reuse of industrial waste. However, utilization of the traditional Portland cement as the cementing material for tailings leads to groundwater pollution. In addition, production of Portland cement results in consumption of a great amount of ore and air pollution. In this paper, a tailings cementation method by using the microbial induced calcite precipitation (MICP) technique with immersion curing is proposed. Tailings are cemented by the MICP technique with aerobic bacteria (Sporosarcina pasteurii) under a soaked curing environment. The variable control method is applied to investigate the factors influencing the cementation effects by the MICP technique with Sporosarcina pasteurii, including the bacterial solution concentration, the cementing solution concentration, the particle size of tailings, and the curing temperature. The results indicate that: when OD600 of the Sporosarcina pasteurii solution is 1.6, the urea concentration in the cementing solution is 0.75 mol/L, the tailings are raw materials without grinding, and the curing temperature is 30°C, the cementation effect is the best. In view of uneven calcification during MICP with Sporosarcina pasteurii, mixed Sporosarcina pasteurii and Castellaniella denitrificans are used for tailings cementation. Higher strength of cemented tailings is achieved. It is proved that the MICP technique with mixed aerobic bacteria and facultative anaerobes is an effective method for tailings cementation.

Hydrogen Sulfide Plays an Important Role by Regulating Endoplasmic Reticulum Stress in Diabetes-Related Diseases.

Endoplasmic reticulum (ER) plays important roles in protein synthesis, protein folding and modification, lipid biosynthesis, calcium storage, and detoxification. ER homeostasis is destroyed by physiological and pharmacological stressors, resulting in the accumulation of misfolded proteins, which causes ER stress. More and more studies have shown that ER stress contributes to the pathogenesis of many diseases, such as diabetes, inflammation, neurodegenerative diseases, cancer, and autoimmune diseases. As a toxic gas, H2S has, in recent years, been considered the third most important gas signal molecule after NO and CO. H2S has been found to have many important physiological functions and to play an important role in many pathological and physiological processes. Recent evidence shows that H2S improves the body's defenses to many diseases, including diabetes, by regulating ER stress, but its mechanism has not yet been fully understood. We therefore reviewed recent studies of the role of H2S in improving diabetes-related diseases by regulating ER stress and carefully analyzed its mechanism in order to provide a theoretical reference for future research.

The Role of Pyroptosis and Autophagy in Ischemia Reperfusion Injury.

Pyroptosis is a process of programmed cell death mediated by gasdermin (GSDM) found in recent years. In the process of pyroptosis, caspase-1 or caspase-11/4/5 is activated, which cleaves gasdermin D and separates its N-terminal pore-forming domain (PFD). The oligomers of PFD bind to the cell membrane and form macropores on the membrane, resulting in cell swelling and membrane rupture. Increasing evidence indicates that pyroptosis is involved in many diseases, including ischemia reperfusion injury. Autophagy is a highly conserved catabolic process in eukaryotic cells. It plays an important role in the survival and maintenance of cells by degrading organelles, proteins, and macromolecules in the cytoplasm and recycling degradation products. Increasing evidence shows that dysfunctional autophagy participates in many diseases. Recently, autophagy and pyroptosis have been reported to play a vital role in the process of ischemia/reperfusion injury, but the related mechanisms are not completely clear. Therefore, this article reviews the role of autophagy and pyroptosis in ischemia-reperfusion injury and analyzes the related mechanisms to provide a basis for future research.

The Role of Autophagy and Pyroptosis in Liver Disorders.

Pyroptosis is a programmed cell death caused by inflammasomes, which can detect cell cytosolic contamination or disturbance. In pyroptosis, caspase-1 or caspase-11/4/5 is activated, cleaving gasdermin D to separate its N-terminal pore-forming domain (PFD). The oligomerization of PFD forms macropores in the membrane, resulting in swelling and membrane rupture. According to the different mechanisms, pyroptosis can be divided into three types: canonical pathway-mediated pyroptosis, non-canonical pathway-mediated pyroptosis, and caspase-3-induced pyroptosis. Pyroptosis has been reported to play an important role in many tissues and organs, including the liver. Autophagy is a highly conserved process of the eukaryotic cell cycle. It plays an important role in cell survival and maintenance by degrading organelles, proteins and macromolecules in the cytoplasm. Therefore, the dysfunction of this process is involved in a variety of pathological processes. In recent years, autophagy and pyroptosis and their interactions have been proven to play an important role in various physiological and pathological processes, and have gradually attracted more and more attention to become a research hotspot. Therefore, this review summarized the role of autophagy and pyroptosis in liver disorders, and analyzed the related mechanism to provide a basis for future research.

The Protective Role of 4-Acetylarylquinolinol B in Different Pathological Processes.

Antrodia cinnamomea is a traditional plant and a unique fungus native to Taiwan that has been reported to have many biological functions, including anti-inflammatory and anticancer activities. The compound 4-acetylarylquinolinol B (4-AAQB) is one of the main bioactive compounds in the stamens of Antrodia cinnamomea, and has many biological functions, such as anti-inflammatory, antiproliferative, blood sugar reduction, antimetastasis, and vascular tone relaxation. In recent years, the increasing evidences have shown that 4-AAQB is involved in many diseases; however, the relevant mechanisms have not been fully clarified. This review aimed to clarify the improvement by 4-AAQB in different pathological processes, as well as the compound's molecular mechanisms, in order to provide a theoretical reference for future related research.

The Emerging Role of EVA1A in Different Types of Cancers.

Eva-1 homolog A (EVA1A), also known as transmembrane protein 166 (TMEM166) and regulator of programmed cell death, is an endoplasmic reticulum associated protein, which can play an important role in many diseases, including a variety of cancers, by regulating autophagy/apoptosis. However, the related mechanism, especially the role of EVA1A in cancers, has not been fully understood. In this review, we summarize the recent studies on the role of EVA1A in different types of cancers, including breast cancer, papillary thyroid cancer, non-small cell lung cancer, hepatocellular carcinoma, glioblastoma and pancreatic cancer, and analyze the relevant mechanisms to provide a theoretical basis for future related research.

The Role of H2S Regulating NLRP3 Inflammasome in Diabetes.

Nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) is a recently discovered cytoplasmic multiprotein complex involved in inflammation. The NLRP3 inflammasome contains NLRP3, apoptosis-related specific protein (ASC) and precursor caspase-1. The NLRP3 inflammasome is involved in many diseases, including diabetes. H2S is a harmful gas with a rotten egg smell. Recently, it has been identified as the third gas signal molecule after nitric oxide and carbon monoxide. It has many biological functions and plays an important role in many diseases, including diabetes. In recent years, it has been reported that H2S regulation of the NLRP3 inflammasome contributes to a variety of diseases. However, the mechanism has not been fully understood. In this review, we summarized the recent role and mechanism of H2S in regulating the NLRP3 inflammasome in diabetes, in order to provide a theoretical basis for future research.

The Role of Endoplasmic Reticulum Stress and NLRP3 Inflammasome in Liver Disorders.

The endoplasmic reticulum (ER) is a key organelle responsible for the synthesis, modification, folding and assembly of proteins; calcium storage; and lipid synthesis. When ER homeostatic balance is disrupted by a variety of physiological and pathological factors-such as glucose deficiency, environmental toxins, Ca2+ level changes, etc.-ER stress can be induced. Abnormal ER stress can be involved in many diseases. NOD-like receptor family pyrin domain-containing 3 (NLRP3), an intracellular receptor, can perceive internal and external stimuli. It binds to apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 to assemble into a protein complex called the NLRP3 inflammasome. Evidence indicates that ER stress and the NLRP3 inflammasome participate in many pathological processes; however, the exact mechanism remains to be understood. In this review, we summarized the role of ER stress and the NLRP3 inflammasome in liver disorders and analyzed the mechanisms, to provide references for future related research.