An herbal formulation "Shugan Xiaozhi decoction" ameliorates methionine/choline deficiency-induced nonalcoholic steatohepatitis through regulating inflammation and apoptosis-related pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Shugan Xiaozhi (SGXZ) decoction is a traditional Chinese medicine used for treating nonalcoholic steatohepatitis (NASH). It has been used clinically for over 20 years and proved to be effective; however, the molecular mechanism underlying the effects of SGXZ decoction remains unclear. AIM OF THE STUDY: We analyzed the chemical components, core targets, and molecular mechanisms of SGXZ decoction to improve NASH through network pharmacology and in vivo experiments. MATERIALS AND METHODS: The chemical components, core targets, and related signaling pathways of SGXZ decoction intervention in NASH were predicted using network pharmacology. Molecular docking was performed to verify chemical components and their core targets. The results were validated in the NASH model treated with SGXZ decoction. Mouse liver function was assessed by measuring ALT and AST levels. TC and TG levels were determined to evaluate lipid metabolism, and lipid deposition was assessed via oil red O staining. Mouse liver damage was determined via microscopy following hematoxylin and eosin staining. Liver fibrosis was assessed via Masson staining. Western blot (WB) and immunohistochemical (IHC) analyses were performed to detect inflammation and the expression of apoptosis-related proteins, including IL-1ß, IL-6, IL-18, TNF-α, MCP1, p53, FAS, Caspase-8, Caspase-3, Caspase-9, Bax, Bid, Cytochrome c, Bcl-2, and Bcl-XL. In addition, WB and IHC were used to assess protein expression associated with the TLR4/MyD88/NF-κB pathway. RESULTS: Quercetin, luteolin, kaempferol, naringenin, and nobiletin in SGXZ decoction were effective chemical components in improving NASH, and TNF-α, IL-6, and IL-1ß were the major core targets. Molecular docking indicated that these chemical components and major core targets might interact. KEGG pathway analysis showed that the pathways affected by SGXZ decoction, primarily including apoptosis and TLR4/NF-κB signaling pathways, interfere with NASH. In vivo experiments indicated that SGXZ decoction considerably ameliorated liver damage, fibrosis, and lipid metabolism disorder in MCD-induced NASH mouse models. In addition, WB and IHC verified the underlying molecular mechanisms of SGXZ decoction as predicted via network pharmacology. SGXZ decoction inhibited the activation of apoptosis-related pathways in MCD-induced NASH mice. Moreover, SGXZ decoction suppressed the activation of TLR4/MyD88/NF-κB pathway in MCD-induced NASH mice. CONCLUSION: SGXZ decoction can treat NASH through multiple targets and pathways. These findings provide new insights into the effective treatment of NASH using SGXZ decoction.

Osteosarcoma PDX-Derived Cell Line Models for Preclinical Drug Evaluation Demonstrate Metastasis Inhibition by Dinaciclib through a Genome-Targeted Approach.

PURPOSE: Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes. EXPERIMENTAL DESIGN: Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model. RESULTS: PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden. CONCLUSIONS: The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.

[Distribution Characteristics and Environmental Driving Factors of Cyanobacteria Community in Impounded Lakes and Reservoirs in Shandong on the East Route of South-to-North Water Diversion Project].

To investigate the distribution characteristics of the cyanobacteria community and the driving factors in impounded lakes and reservoirs in Shandong on the east route of the South-to-North Water Diversion Project, monthly samples of phytoplankton and the aquatic environment from Nansi Lake, Dongping Lake, Datun Reservoir, Donghu Reservoir, and Shuangwangcheng Reservoir were collected from May to November during 2010 to 2019. A total of 44 planktonic cyanobacteria taxa were identified with 23 filamentous cyanobacteria taxa. Pseudanabaena limnetica, Cylindrospermopsis raciborskii, Microcystis aeruginosa, and Microcystis wesenbergii were the dominant harmful cyanobacteria species, with a high detection frequency and abundance in all lakes and reservoirs. By analyzing the distribution characteristics of the cyanobacteria community in impounded lakes and reservoirs, we found that filamentous cyanobacteria had growth advantages in the water with large hydraulic disturbances, which should be the key points of cyanobacteria prevention and control in the future. Pearson correlation analysis and generalized linear fitting curve results showed that total nitrogen, total phosphorus, water temperature, and water depth played a key role in affecting the growth of P. limnetica, C. raciborskii, M. aeruginosa, and M. wesenbergii. The nitrogen and phosphorus nutrients could promote the growth of harmful cyanobacteria. Due to the good temperature adaptability, P. limnetica could still become the dominant species in early summer and late autumn, and C. raciborskii, M. aeruginosa, and M. wesenbergii had growth advantages when the water temperature was higher than 25℃. In addition, shallow water was more conducive to the growth of C. raciborskii. It was suggested that based on strengthening of the control of nitrogen and phosphorus nutrient input in lakes and reservoirs, the key monitoring of P. limnetica in lakes should be conducted in early summer and late autumn, and the growth of C. raciborskii in shallow water areas should be paid close attention in the high temperature period to ensure the safety of water quality.

Astragaloside IV Protects Against IL-1ß-Induced Chondrocyte Damage via Activating Autophagy.

BACKGROUND: Osteoarthritis (OA) is a chronic inflammatory condition that affects the articular cartilage. Astragaloside IV (AS-IV) constitutes the primary active component of the Chinese herbal medicine Huangqi (Radix Astragali Mongolici). AS-IV demonstrates anti-inflammatory and anti-apoptotic attributes, exhibiting therapeutic potential across various inflammatory and apoptosis-related disorders. Nevertheless, its pharmaceutical effects in OA are yet to be fully defined. OBJECTIVES: This study aimed to investigate the protective impact of AS-IV on rat chondrocytes treated with IL-1ß and ascertain whether autophagy plays a role in this effect. METHODS: Chondrocytes were isolated and cultivated from the knee joints of neonatal SD mice. The study included the blank control group, the model group, and the AS-IV concentration gradient group (50, 100, 200 µmol/L) to intervene with chondrocytes. The MTT assay was employed to assess cell viability at varying culture periods, enabling the determination of suitable concentration and duration. Subsequently, chondrocytes were treated with the optimal AS-IV concentration and divided into three groups: the model group replicated IL-1ß-induced inflammatory chondrocyte injury, the AS-IV group received a co-culture of AS-IV and IL-1ß, and a blank control group was established. Changes in cell morphology and structure were observed using ghost pen cyclic peptide staining. ELISA was used to measure TNF-α and GAG levels in cell supernatants. RT-qPCR assessed p62 and LC3 mRNA expression, while Western Blot evaluated p62 and LC3Ⅱ/Ⅰ protein expression. RESULTS: AS-IV promoted chondrocyte proliferation and concurrently inhibited cell apoptosis. An optimal AS-IV dose of 200 µmol/L and a suitable reaction time of 48 h were identified. Ghost pen cyclic peptide staining indicated that the model group's cytoskeleton exhibited fusiform changes with reduced immunofluorescence intensity, as opposed to the blank control group. The AS-IV group displayed more polygonal cytoskeletal morphology with increased immunofluorescence intensity. AS-IV reduced TNF-α levels and elevated GAG levels in the culture supernatant. Additionally, AS-IV lowered p62 mRNA and protein expression while increasing LC3 mRNA expression in cultured chondrocytes. CONCLUSION: Our findings suggest that AS-IV mitigates inflammatory chondrocyte injury, safeguarding chondrocytes through a potential autophagy suppression mechanism. These results imply that AS-IV could offer preventive advantages for OA.

Progress in the mechanism of autophagy and traditional Chinese medicine herb involved in alcohol-related liver disease.

Alcohol-related liver disease (ALD) is chronic liver damage caused by long-term heavy drinking with, extremely complicated pathogenesis. The current studies speculated that excessive alcohol and its metabolites are the major causes of liver cell toxicity. Autophagy is evolutionarily conserved in eukaryotes and aggravates alcoholic liver damage, through various mechanisms, such as cellular oxidative stress, inflammation, mitochondrial damage and lipid metabolism disorders. Therefore, autophagy plays an critical role in the occurrence and development of ALD. Some studies have shown that traditional Chinese medicine extracts improve the histological characteristics of ALD, as reflected in the improvement of oxidative stress and lipid droplet clearance, which might be achieved by inducing autophagy. This article reviews the mechanisms of quercetin, baicalin, glycycoumarin, salvianolic acid A, resveratrol, ginsenoside rg1, and dihydromyricetin inducing autophagy and their participation in the inhibition of ALD. The regulation of autophagy in ALD by these traditional Chinese medicine extracts provides novel ideas for the treatment of the disease; however, its molecular mechanism needs to be elucidated further.

An Alternative Mechanism of Subcellular Iron Uptake Deficiency in Cardiomyocytes.

BACKGROUND: Systemic defects in intestinal iron absorption, circulation, and retention cause iron deficiency in 50% of patients with heart failure. Defective subcellular iron uptake mechanisms that are independent of systemic absorption are incompletely understood. The main intracellular route for iron uptake in cardiomyocytes is clathrin-mediated endocytosis. METHODS: We investigated subcellular iron uptake mechanisms in patient-derived and CRISPR/Cas-edited induced pluripotent stem cell-derived cardiomyocytes as well as patient-derived heart tissue. We used an integrated platform of DIA-MA (mass spectrometry data-independent acquisition)-based proteomics and signaling pathway interrogation. We employed a genetic induced pluripotent stem cell model of 2 inherited mutations (TnT [troponin T]-R141W and TPM1 [tropomyosin 1]-L185F) that lead to dilated cardiomyopathy (DCM), a frequent cause of heart failure, to study the underlying molecular dysfunctions of DCM mutations. RESULTS: We identified a druggable molecular pathomechanism of impaired subcellular iron deficiency that is independent of systemic iron metabolism. Clathrin-mediated endocytosis defects as well as impaired endosome distribution and cargo transfer were identified as a basis for subcellular iron deficiency in DCM-induced pluripotent stem cell-derived cardiomyocytes. The clathrin-mediated endocytosis defects were also confirmed in the hearts of patients with DCM with end-stage heart failure. Correction of the TPM1-L185F mutation in DCM patient-derived induced pluripotent stem cells, treatment with a peptide, Rho activator II, or iron supplementation rescued the molecular disease pathway and recovered contractility. Phenocopying the effects of the TPM1-L185F mutation into WT induced pluripotent stem cell-derived cardiomyocytes could be ameliorated by iron supplementation. CONCLUSIONS: Our findings suggest that impaired endocytosis and cargo transport resulting in subcellular iron deficiency could be a relevant pathomechanism for patients with DCM carrying inherited mutations. Insight into this molecular mechanism may contribute to the development of treatment strategies and risk management in heart failure.

Effect of arctigenin on neurological diseases: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Arctium lappa L. is a common specie of Asteraceae. Its main active ingredient, Arctigenin (AG), in mature seeds exerts pharmacological effects on the Central Nervous System (CNS). AIM OF THE STUDY: To review studies on the specific effects of the AG mechanism on various CNS diseases and elucidate signal transduction mechanisms and their pharmacological actions. MATERIALS AND METHODS: This investigation reviewed the essential role of AG in treating neurological disorders. Basic information on Arctium lappa L. was retrieved from the Pharmacopoeia of the People's Republic of China. The related articles from 1981 to 2022 on the network database (including CNKI, PubMed, and Wan Fang and so on) were reviewed using AG and CNS diseases-related terms such as Arctigenin and Epilepsy. RESULTS: It was confirmed that AG has a therapeutic effect on Alzheimer's disease, Glioma, infectious CNS diseases (such as Toxoplasma and Japanese Encephalitis Virus), Parkinson's disease, Epilepsy, etc. In these diseases, related experiments such as a Western blot analysis revealed that AG could alter the content of some key factors (such as the reduction of Aß in Alzheimer's disease). However, in-vivo AG's metabolic process and possible metabolites are still undetermined. CONCLUSION: Based on this review, the existing pharmacological research has indeed made objective progress to elucidate how AG prevents and treats CNS diseases, especially senile degenerative disease such as Alzheimer's diseases. It was revealed that AG could be used as a potential nervous system drug as it has a wide range of effects in theory with markedly high application value, especially in the elder group. However, the existing studies are limited to in-vitro experiments; therefore, little is known about how AG metabolizes and functions in-vivo, limiting its clinical application and requiring further research.

Botanical characteristics, chemical components, biological activity, and potential applications of mangosteen.

Garcinia mangostana L. (Mangosteen), a functional food, belongs to the Garcinaceae family and has various pharmacological effects, including anti-oxidative, anti-inflammatory, anticancer, antidiabetic, and neuroprotective effects. Mangosteen has abundant chemical constituents with powerful pharmacological effects. After searching scientific literature databases, including PubMed, Science Direct, Research Gate, Web of Science, VIP, Wanfang, and CNKI, we summarized the traditional applications, botanical features, chemical composition, and pharmacological effects of mangosteen. Further, we revealed the mechanism by which it improves health and treats disease. These findings provide a theoretical basis for mangosteen's future clinical use and will aid doctors and researchers who investigate the biological activity and functions of food.

The Therapeutic Potential of Antioxidants in Chemotherapy-Induced Peripheral Neuropathy: Evidence from Preclinical and Clinical Studies.

As cancer therapies advance and patient survival improves, there has been growing concern about the long-term adverse effects that patients may experience following treatment, and concerns have been raised about such persistent, progressive, and often irreversible adverse effects. Chemotherapy is a potentially life-extending treatment, and chemotherapy-induced peripheral neuropathy (CIPN) is one of its most common long-term toxicities. At present, strategies for the prevention and treatment of CIPN are still an open problem faced by medicine, and there has been a large amount of previous evidence that oxidative damage is involved in the process of CIPN. In this review, we focus on the lines of defense involving antioxidants that exert the effect of inhibiting CIPN. We also provide an update on the targets and clinical prospects of different antioxidants (melatonin, N-acetylcysteine, vitamins, α-lipoic acid, mineral elements, phytochemicals, nutritional antioxidants, cytoprotectants and synthetic compounds) in the treatment of CIPN with the help of preclinical and clinical studies, emphasizing the great potential of antioxidants as adjuvant strategies to mitigate CIPN.

[Effect of acupotomy on the fat infiltration degree of lumbar multifidus muscle in patients with lumbar disc herniation after percutaneous transforaminal endoscopic discectomy].

OBJECTIVE: To observe the effect of acupotomy on the fat infiltration degree of lumbar multifidus muscle (LMM) in patients with lumbar disc herniation after percutaneous transforaminal endoscopic discectomy (PTED). METHODS: A total of 104 patients with lumbar disc herniation treated with PTED were randomly divided into an observation group (52 cases, 3 cases dropped off) and a control group (52 cases, 4 cases dropped off). Patients of both groups received rehabilitation training of two weeks 48 h after PTED treatment. The observation group was treated with acupotomy (L3-L5 Jiaji [EX-B 2]) once within 24 h after PTED. In the two groups, the fat infiltration cross sectional area (CSA) of LMM was compared before and 6 months after PTED, the visual analogue scale (VAS) score and Oswestry disability index (ODI) score were observed before and 1, 6 months after PTED. The correlation between fat infiltration CSA of LMM in each segment and VAS score was analyzed. RESULTS: Six months after PTED, the fat infiltration CSA of LMM in L4/L5 and the total L3-S1 segments of the observation group was lower than that before PTED (P<0.05), and the fat infiltration CSA of LMM in L4/L5 of the observation group was lower than the control group (P<0.01). One month after PTED, the ODI and VAS scores of the two groups were lower than those before PTED (P<0.01), and those in the observation group were lower than the control group (P<0.05). Six months after PTED, the ODI and VAS scores of the two groups were lower than those before PTED and 1 month after PTED (P<0.01), and those in the observation group were lower than the control group (P<0.01). There was a positive correlation between the fat infiltration CSA of LMM in the total L3-S1 segments and VAS scores in the two groups before PTED (r = 0.64, P<0.01). Six months after PTED, there was no correlation between the fat infiltration CSA of LMM in each segment and VAS scores in the two groups (P>0.05). CONCLUSION: Acupotomy can improve the fat infiltration degree of LMM, pain symptoms and activities of daily living in patients with lumbar disc herniation after PTED.

New insight into fate and transport of organic compounds from pollution sources to aquatic environment using non-targeted screening: A wastewater treatment plant case study.

A variety of chemicals discharged into the aquatic environment by the wastewater treatment plant (WWTP), which is a potential source of hazard to the ecological environment and human health. This study established a novel analytical method for all compounds using non-targeted screening to comprehensively explore the fate and transport of organic compounds from WWTP to aquatic environment. 3967 and 3636 features were detected in WWTP samples and river samples, respectively. Multi-level classification was applied to all identified compounds, and results showed that aliphatics were dominant in both abundance and response, accounting for an average of 35.49 % and 74.10 %, respectively. A total of 88 Emerging Contaminants (ECs), including 22 endocrine disrupting chemicals (EDCs), 12 pharmaceuticals and personal care products (PPCPs), 12 pesticides, 10 volatile organic compounds (VOCs), 5 persistent organic pollutants (POPs) and 27 chemicals with other uses, were identified from all compounds, and their traceability analysis was performed. Furthermore, the contribution rate of organic compounds from WWTP effluent to river was calculated to be 33.60 % by the analysis of source-sink relationship. An in-depth and comprehensive exploration of the fate and transport of all organic compounds will help to provide guidelines for the treatment technologies and achieve the traceability of pollutants.

Network-Based Elaboration of the Efficacy of the Dachangshu (BL25) and Tianshu (ST25) Points in the Treatment of Functional Constipation in Children through Inflammation, Adipocytokine, or Leptin Pathways.

Constipation commonly occurs during childhood, and more than 95% of cases are classified as functional constipation. If not effectively treated, 20% of patients with childhood constipation can continue to exhibit symptoms into adulthood, which seriously affects their mental health and quality of life. The main feature of acupuncture or acupoint stimulation, a special branch of traditional Chinese medicine, is the selection of different acupoints for different diseases, and many worthy guidelines have been established for matching acupoints. The back-shu and front-mu point combination adheres to an important acupoint compatibility law that has been used since its proposal 2,500 years ago but has not yet been verified by the modern evidence-based experiments. This study focused on the back-shu and front-mu point combination using the Dachangshu (BL25) and Tianshu (ST25) points as examples to explore possible research methods for network acupoint-based stimulation based on existing evidence and to elucidate the mechanisms induced by BL25 and ST25 in the treatment of functional constipation in children (FCC). The study found that BL25 and ST25 have 20 common targets, namely, AQP8, DRD2, VIP, TAC1, IL6R, TNF, FOS, KIT, CHAT, HTR3A, GAS8, SOD3, TRPV1, MPO, CALCA, IL1B, P2RX7, NPY2R, IL10RA, and TPH1, and these targets may provide a strategy for the combined usage of BL25 and ST25. In addition, BL25 and ST25 can affect FCC treatment through inflammation-relatedTh17-cell differentiation, the NF-kappa B signaling pathway, and the Toll-like receptor signaling pathway. Adipocytokines or leptin may also comprise the mechanism through which BL25 and ST25 regulate FCC. In addition, BL25 and ST25 regulate FCC through 13 core targets, namely, NFKBIA, RELA, TNF, IKBKB, IRAK1, TLR4, MYD88, TNFRSF1A, IL1R1, TLR2, IL1B, TRAF6, and TNFRSF1B. In short, this study provides new ideas and methods for studying the mechanism of acupuncture points.

Design, synthesis and antifungal activities of novel triazole derivatives with selenium-containing hydrophobic side chains.

In this work, a series of novel 1,2,4-triazole derivatives with selenium-containing hydrophobic side chains were designed and synthesized based on the structure of lanosterol 14α-demethylase (CYP51). All compounds were characterized by HRMS, 1H NMR and 13C NMR. Then, their antifungal activities against eight human pathogenic fungi were evaluated in vitro by testing the minimal inhibitory concentrations. The results showed that nearly all tested compounds were found to be more potent against all tested fungal strains than control drug fluconazole. Further mechanism study demonstrated that the target compounds had fungal CYP51 inhibitory activity. Meanwhile, representative compounds revealed low cytotoxic effects toward mammalian cell lines. In addition, the docking results showed that the target compounds bound to Candida albicans CYP51 in a better pattern than fluconazole, especially in the narrow hydrophobic cleft. Overall, the novel 1,2,4-triazole derivatives with selenium-containing hydrophobic side chains can be further developed for the potential treatment of invasive fungal infections.

Discovery of novel selenium-containing azole derivatives as antifungal agents by exploiting the hydrophobic cleft of CYP51.

Herein, we report the design, synthesis and evaluation of a novel series of diselenide and selenide derivatives as potent antifungal agents by exploiting the hydrophobic cleft of CYP51. Among all synthesized compounds, the most potent compound B01 with low cytotoxic and hemolysis effect exhibited excellent activity against C.alb., C.gla., C.par. and C.kru., as well as selected fluconazole-resistant strains. Moreover, compound B01 could reduce the biofilm formation of the FCZ-resistant C.alb. Subsequently, metabolic stability assays using liver microsomes demonstrated that compound B01 showed good profiles of metabolic stability. With superior pharmacological profile, compound B01 was advanced into in vivo bioactivity evaluation. In a murine model of systemic C.alb. infection, compound B01 significantly reduced fungal load of kidneys. Furthermore, compound B01 revealed relatively low acute toxicity and subacute toxicity in mice. In addition, docking study performed into C.alb. CYP51, showed the binding mode between C.alb. CYP51 and compound B01. Collectively, diselenides compound B01 can be further developed for the potential treatment of invasive fungal infections.

Strong Penetration-Induced Effective Photothermal Therapy by Exosome-Mediated Black Phosphorus Quantum Dots.

Nanocancer medicine, such as photothermal therapy (PTT), as a promising way to solve cancer without side effects, faces a huge biological barrier during the circulation of nanoparticles in the body, including nanobiological interactions in the blood, isolation of nanoparticles in the macrophage system, tumor spillover effect, and especially uneven intratumoral distribution of nanoparticles, which cast a shadow over the hope. To address the problem of intratumoral distribution, an effective photothermal agent is introduced by packaging the black phosphorus quantum dots (BPQDs) into exosome vector (EXO) through electroporation method. With the improving and proper stability for better therapy, the resulting BPQDs@EXO nanospheres (BEs) exhibit good biocompatibility, long circulation time, and excellent tumor targeting ability, hence impressive PTT efficiency evidenced by highly efficient tumor ablation in vivo. Importantly, great permeability on organoids contributed by EXO appears with BEs, which strongly promotes the efficient killing ability. These BP-based nanospheres must promise high clinical potential due to the high PTT efficiency and minimal side effects.

Neuroprotective effects of macamide from maca (Lepidium meyenii Walp.) on corticosterone-induced hippocampal impairments through its anti-inflammatory, neurotrophic, and synaptic protection properties.

The present study aims to investigate the protective effects of N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (M 18:3) on corticosterone-induced neurotoxicity. A neurotoxic model was established by subcutaneous injection of corticosterone (40 mg per kg bw) for 21 days. Depressive behaviors (the percentage of sucrose consumption, the immobility time in the forced swimming test, and the total distance in the open field test) were observed. The levels of the brain-derived neurotrophic factor, the contents of tumor necrosis factor-α and interleukin-6, and the numbers of positive cells of doublecortin and bromodeoxyuridine in the hippocampus were measured. The density of hippocampal neurons was calculated. The morphological changes of hippocampal neurons (the density of dendritic spines, the dendritic length, and the area and volume of dendritic cell bodies) were observed. The expression levels of synaptophysin, synapsin I, and postsynaptic density protein 95 were measured. Behavioral experiments showed that M 18:3 (5 and 25 mg per kg bw) could remarkably improve the depressive behaviors. The enzyme-linked immunosorbent assay showed that M 18:3 could considerably reduce hippocampal neuroinflammation and increase hippocampal neurotrophy. Nissl staining showed that M 18:3 could remarkably improve the corticosterone-induced decrease in the hippocampal neuron density. Immunofluorescence analysis showed that M 18:3 could considerably promote hippocampal neurogenesis. Golgi staining showed that M 18:3 could remarkably improve the corticosterone-induced changes in the hippocampal dendritic structure. Western blotting showed that M 18:3 could considerably increase the expression levels of synaptic-structure-related proteins in the hippocampus. In conclusion, the protective effects of M 18:3 may be attributed to the anti-inflammatory, neurotrophic, and synaptic protection properties.

Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections.

A series of selenium-containing miconazole derivatives were identified as potent antifungal drugs in our previous study. Representative compound A03 (MIC = 0.01 µg/mL against C.alb. 5314) proved efficacious in inhibiting the growth of fungal pathogens. However, further study showed lead compound A03 exhibited potential hemolysis, significant cytotoxic effect and unfavorable metabolic stability and was therefore modified to overcome these drawbacks. In this article, the further optimization of selenium-containing miconazole derivatives resulted in the discovery of similarly potent compound B17 (MIC = 0.02 µg/mL against C.alb. 5314), exhibiting a superior pharmacological profile with decreased rate of metabolism, cytotoxic effect and hemolysis. Furthermore, compound B17 showed fungicidal activity against Candida albicans and significant effects on the treatment of resistant Candida albicans infections. Meanwhile, compound B17 not only could reduce the ergosterol biosynthesis pathway by inhibiting CYP51, but also inhibited biofilm formation. More importantly, compound B17 also shows promising in vivo efficacy after intraperitoneal injection and the PK study of compound B17 was evaluated. In addition, molecular docking studies provide a model for the interaction between the compound B17 and the CYP51 protein. Overall, we believe that these selenium-containing miconazole compounds can be further developed for the potential treatment of fungal infections.

Comparison of Short-Term Outcomes between Button-Type Bipolar Plasma Vaporization and Transurethral Resection for the Prostate: A Systematic Review and Meta-Analysis.

Background: Previous meta-analysis evaluated a limited number of parameters regarding the comparison of BTPV and TURP for BPH. Method: PubMed, Embase and Cochrane Library were searched for literature comparing BTPV with TURP. Data of efficacy (IPSS, Qmax, PVR and QoL) and safety were extracted and evaluated using either SMD or OR with 95% CI. All analyses were performed by RevMan 5.3. Results: Eleven trials with 1690 patients were selected. Compare to BTPV, TURP had better 6-month IPSS (SMD=0.36, 95% CI 0.08 to 0.63), better 1- (SMD=-0.38, 95% CI -0.63 to -0.12), 6- (SMD=-0.73, 95% CI -0.99 to -0.46) and 12-month Qmax (SMD=-0.47, 95% CI -0.85 to -0.10), better 6-month PVR (SMD=1.18, 95% CI 0.87 to 1.48), as well as better 3- (SMD=-0.24, 95% CI -0.48 to -0.01) and 6-month QoL (SMD=-0.62, 95% CI -0.91 to -0.33). However, BTPV had shorter catheterization time (SMD=-0.96, 95% CI -1.12 to -0.79) and hospital stay (SMD=-0.71, 95% CI -0.89 to -0.53), less hemoglobin decrease (SMD=-1.09, 95% CI -1.27 to -0.91) and virtually shorter operation time (SMD=-0.15, 95% CI -0.31 to 0.01). Moreover, BTPV had fewer occurrence of overall complications (OR=0.52, 95% CI 0.40 to 0.69), Clavien III-IV complications (OR=0.61, 95% CI 0.37 to 1.02), blood transfusion (OR=0.25, 95% CI 0.09 to 0.69), hematuria (OR=0.27, 95% CI 0.13 to 0.56) and capsular perforation (OR=0.19, 95% CI 0.08 to 0.48). Subgroup analysis indicated BTPV and bipolar TURP had similar total complications (OR 1.08, 95% CI 0.40-2.88, P=0.88) and Clavien III-IV complications (OR 1.42, 95% CI 0.36-5.57, P=0.61) and blood transfusion rate (OR 0.28, 95% CI 0.04-1.73, P=0.17). Conclusion: Both TURP and BTPV could significantly improve IPPS, Qmax, PVR and QoL. TURP had slightly better short-term efficacy, while BTPV had better safety. However, subgroup analysis found bipolar TURP and BTPV had similar safety.

The ameliorative effect of the Pyracantha fortuneana (Maxim.) H. L. Li extract on intestinal barrier dysfunction through modulating glycolipid digestion and gut microbiota in high fat diet-fed rats.

Pyracantha fortuneana fruits are consumed as a dietary supplement in China and attenuate obesity and metabolic disorders. Obesity is known to be associated with intestinal barrier dysfunction driven by hyperglycemia and gut dysbiosis. However, whether the health benefits of P. fortuneana fruits are linked with the intestinal barrier function (IBF) remains unknown. This study aimed to evaluate the restorative effects of P. fortuneana fruit extract (PFE) on the IBF. Sprague Dawley rats were fed with a chow, a high-fat diet (HFD), or a PFE-supplemented diet for 8 weeks. Results showed that PFE intervention ameliorated HFD-induced intestinal barrier dysfunction by attenuating impaired structural integrity, reducing the elevated lactulose/mannitol ratio, and improving the mRNA and protein expression levels of tight junction proteins in HFD-fed rats. The ameliorations were associated with a beneficial effect on glycolipid homeostasis, as evidenced from the PFE decreasing intestinal absorptive capacity based on the d-xylose excretory rate, lowering the expression of GLUT2 and inhibiting digestive enzyme activities. The proanthocyanidins in the PFE showed greater in vitro inhibition on α-amylase, α-glucosidase, and lipase compared with triterpenoid saponins. Furthermore, the ameliorations on the IBF were also associated with effects on the microbial composition based on 16S rRNA gene sequence analysis. Several bacterial groups, which were linked with gut barrier integrity, were modulated after PFE administration, that is, Actinobacteria, Bacteroidaceae, Corynebacteriaceae, Lactobacillaceae, and S24-7 were elevated and the HFD-induced increase in Clostridia, Ruminococcaceae, Oscillospira, and Flexispira was restored. These data provide evidence for the ameliorative effect of the PFE on diet-induced intestinal barrier functional alternations in association with its capacity to modulate glycolipid digestion and gut microbiota in HFD-fed obese rats.