Mendelian randomization of stroke risk after total hip and knee replacements.

Objective: Previous epidemiological studies have indicated an increased risk of neurovascular diseases in patients following total hip and knee replacements. However, definitive conclusions regarding the increased risk of stroke post-replacement remain elusive. Therefore, we conducted a two-sample Mendelian randomization study to investigate the causal relationship between total hip and knee replacements and stroke. Methods: We utilized summary data from publicly available genome-wide association studies (GWAS). Data concerning total hip replacements (THR, N = 319,037) and total knee replacements (TKR, N = 252,041) were sourced from the Genetics of Osteoarthritis (GO) Consortium. Stroke-related data were obtained from the International Stroke Genetics Consortium, encompassing any stroke (AS), any ischemic stroke (AIS), large vessel ischemic stroke (LV-IS), cardioembolic ischemic stroke (CE-IS), and small vessel ischemic stroke (SV-IS). Our primary causal inference method was the inverse variance weighted (IVW) approach, supplemented by weighted median and MR-Egger regression as secondary inference methods. We utilized the MR-PRESSO global test for outlier detection, Cochran's Q statistic to assess heterogeneity, and assessed the multiplicity and stability of our findings using p-values from MR-PRESSO and MR-Egger regressions, and the leave-one-out method, respectively. Results: We identified significant genetic associations between THR and both AS (IVW p = 0.0001, OR = 1.08, 95% CI = 1.04-1.12) and AIS (IVW p = 0.0016, OR = 1.07, 95% CI = 1.03-1.12). Significant associations were also observed between TKR and AS (IVW p = 0.0002, OR = 1.08, 95% CI = 1.04-1.12), as well as AIS (IVW p = 0.0005, OR = 1.15, 95% CI = 1.06-1.24). Conclusion: Our findings genetically support an increased risk of stroke following total hip and knee replacements. However, further studies are necessary to elucidate the specific mechanisms underlying stroke episodes post-replacement.

Plastic Events of the Vestibular Nucleus: the Initiation of Central Vestibular Compensation.

Vestibular compensation is a physiological response of the vestibular organs within the inner ear. This adaptation manifests during consistent exposure to acceleration or deceleration, with the vestibular organs incrementally adjusting to such changes. The molecular underpinnings of vestibular compensation remain to be fully elucidated, yet emerging studies implicate associations with neuroplasticity and signal transduction pathways. Throughout the compensation process, the vestibular sensory neurons maintain signal transmission to the central equilibrium system, facilitating adaptability through alterations in synaptic transmission and neuronal excitability. Notable molecular candidates implicated in this process include variations in ion channels and neurotransmitter profiles, as well as neuronal and synaptic plasticity, metabolic processes, and electrophysiological modifications. This study consolidates the current understanding of the molecular events in vestibular compensation, augments the existing research landscape, and evaluates contemporary therapeutic strategies. Furthermore, this review posits potential avenues for future research that could enhance our comprehension of vestibular compensation mechanisms.

Enhanced VEGF secretion and blood-brain barrier disruption: Radiation-mediated inhibition of astrocyte autophagy via PI3K-AKT pathway activation.

Radiation-induced damage to the blood-brain barrier (BBB) is the recognized pathological basis of radiation-induced brain injury (RBI), a side effect of head and neck cancer treatments. There is currently a lack of therapeutic approaches for RBI due to the ambiguity of its underlying mechanisms. Therefore, it is essential to identify these mechanisms in order to prevent RBI or provide early interventions. One crucial factor contributing to BBB disruption is the radiation-induced activation of astrocytes and oversecretion of vascular endothelial growth factor (VEGF). Mechanistically, the PI3K-AKT pathway can inhibit cellular autophagy, leading to pathological cell aggregation. Moreover, it acts as an upstream pathway of VEGF. In this study, we observed the upregulation of the PI3K-AKT pathway in irradiated cultured astrocytes through bioinformatics analysis, we then validated these findings in animal brains and in vitro astrocytes following radiation exposure. Additionally, we also found the inhibition of autophagy and the oversecretion of VEGF in irradiated astrocytes. By inhibiting the PI3K-AKT pathway or promoting cellular autophagy, we observed a significant amelioration of the inhibitory effect on autophagy, leading to reductions in VEGF oversecretion and BBB disruption. In conclusion, our study suggests that radiation can inhibit autophagy and promote VEGF oversecretion by upregulating the PI3K-AKT pathway in astrocytes. Blocking the PI3K pathway can alleviate both of these effects, thereby mitigating damage to the BBB in patients undergoing radiation treatment.

The impact of nurses' experiences of hospital violence on resilience: A mediated moderation model.

AIMS: This study aims to investigate the impact of nurses' experiences of hospital violence on resilience, the mediating effect of trust in patients and the moderating effect of organizational trust. BACKGROUND: Despite belonging to the central part of health care worldwide and being the leading provider of medical services, nurses are often subjected to hospital violence, which affects their physical and mental well-being. Trust is a high-order mechanism that encourages positive thinking and personal and professional development. However, research into the impact of trust on resilience concerning nurses' experiences of hospital violence is limited. METHODS: The participants were 2331 nurses working in general hospitals in China. A cross-sectional survey was conducted, and data were collected via questionnaires from July to October 2022 and analysed using SPSS 25.0 and SPSS PROCESS 3.3 macros. This study was prepared and reported according to the STROBE checklist. RESULTS: Mean trust in patients was 48.00 ± 10.86 (12-60), mean organizational trust was 56.19 ± 8.90 (13-65) and mean resilience was 78.63 ± 19.26 (0-100). Nurses' experience of hospital violence had a direct negative effect on resilience (ß = -.096, p = .871), a significant adverse effect on trust in patients (ß = -3.022, p < .001) and a significant positive effect on trust in patients on resilience (ß = 1.464, p < .001). Trusting patients played a mediating role. The significant moderating effect of organizational trust between experience of hospital violence and trust in patients was moderated by a mediating effect index of -0.1867 (95% CI = [-0.3408, -0.0345]). CONCLUSIONS: Nurses' experience of hospital violence exerted a negative effect on resilience, trust in patients had a fully mediated effect and organizational trust had a significant moderating influence in the pathway from nurses' experience of hospital violence to patients' trust-mediated resilience. IMPLICATIONS FOR NURSING AND HEALTH POLICY: This study highlights the impact of nurses' experiences of hospital violence on resilience and explores the importance of trust from the nurses' perspective. Measures taken by managers to provide nurses with a safe, trusting and positive work environment can be highly beneficial in enhancing nurse resilience.

The impact of resilience on clinical nurses' moral courage during COVID-19: A moderated mediation model of ethical climate and moral distress.

AIM: The purpose of this study was to explore whether clinical ethical climate mediates the relationship between resilience and moral courage in a population of clinical nurses during COVID-19, and if moral distress faced by nurses is a moderating factor. BACKGROUND: Resilience can help nurses maintain their personal health during COVID-19 when they face great physical and psychological shock and are prone to health problems. Moral courage, as an ethical competency, helps nursing staff in adhering to the principles and values of professional ethics. There is a strong correlation between resilience and moral courage, but the mechanism by which resilience contributes to moral courage is unclear. METHOD: A cross-sectional study research is designed. Three hundred thirty clinical nurses from six hospitals in Beijing, Sichuan, and Fujian of China were included between August 2021 and March 2022. The survey instruments include the Nurses' Moral Courage Scale (NMCS), Connor-Davidson Resilience Scale (CD-RISC), Moral Distress Scale-Revised (MDS-R), and Hospital Ethical Climate Scale (HECS). RESULTS: Ethical climate mediates 15% of the relationship between resilience and moral courage. The association between resilience and ethical climate, as well as the indirect relationship between resilience and moral courage, was modified by moral distress. DISCUSSION: This study investigated the mechanisms by which resilience affects moral courage in clinical nurses in the context of COVID-19, suggesting that moral courage can be increased by alleviating moral distress and increasing ethical climate. IMPLICATIONS FOR NURSING AND HEALTH POLICY: This study confirms the mediating effect of moral climate on the relationship between resilience and moral courage, as well as the moderating effect of moral distress. Hospital policymakers should value nurses' psychological resilience and moral courage, develop effective policies to prevent and manage stressors, build social support systems, and create a positive ethical climate.

The therapeutic potential of arctigenin against multiple human diseases: A mechanistic review.

BACKGROUND: Arctigenin (ATG), a dibenzyl butyrolactone lignan compound, is one of the major bioactive components from the medicinal plant Arctium lappa. ATG possesses remarkable therapeutic potential against a wide range of human diseases, such as cancers, immune disorders and chronical diseases. The molecular mechanisms behind the biological effects of ATG have been intensively studied. PURPOSE: This review aims to systematically summarize the updated knowledge of the proteins and signaling pathways behind the curative property of ATG, and further analyze the potential connections between them. METHOD: SciFinder, Pubmed, Web of Science and Cochrane Library databases were queried for publications reporting the therapeutic properties of ATG. "Arctigenin", "disease", "cancer", "inflammation", "organ damage", "infection", "toxicity" and "pharmacokinetics" were used as the searching titles. RESULT: 625 publications were identified and 95 met the inclusion criteria and exclusion criteria. 42 studies described the molecular mechanisms implicated in ATG treatments. Several proteins including phosphodiesterase subtype 4D (PDE4D), estrogen receptor (ER) ß, protein phosphatase 2A (PP2A), phosphoinositide 3-kinase (PI3K) and transmembrane protein 16A (TMEM16A) are targeted by ATG in different settings. The frequently described signaling pathways are TLR4/NF-κB, PI3K/AKT/mTOR, AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf-2) signalings. CONCLUSION: Inhibition of PI3K/AKT pathway and activation of AMPK signaling play the pivotal roles in the therapeutic effects of ATG. PI3K/AKT and AMPK signaling widely link to other signaling pathways, modulating various biological processes such as anti-inflammation, anti-oxidative stress, anti-fibrosis, anti-ER stress, anti-steatosis and pro-apoptosis, which constitute the curative mechanisms of ATG against multiple human diseases.

Clinical nurse adherence to professional ethics: A grounded theory.

BACKGROUND: Professional ethics is the regulation and discipline of nurses' daily nursing work. Nurses often encounter various ethical challenges and problems in their clinical work, but there are few studies on nurses' adherence to professional ethics. RESEARCH AIM: An analysis of nursing adherence to nursing ethics from the perspective of clinical nurses in the Chinese public health system. RESEARCH DESIGN: This study adopts the grounded theory approach proposed by Strauss and Corbin. PARTICIPANTS AND RESEARCH CONTEXT: Between July 2021 and January 2022, Clinical nurses were recruited for online video interviews using purposive and theoretical sampling methods in seven hospitals in Beijing, Tianjin, Shanxi, Henan, Guangdong, and Fujian, China. Data analysis was conducted using Strauss and Corbin's coding approach. ETHICAL CONSIDERATIONS: This study was approved by the Ethics Committee of Sanming First Hospital (MingYiLun 71/2021). FINDINGS: A total of 27 participants were included. A theoretical model of nursing staff adherence to professional ethics was constructed. The main core was adherence to professional ethics and the other cores were (1) causal conditions: professional ethics code, individual conscience; (2) intervening conditions: personal growth, social support system, matching career compensation, prediction of adverse consequences; (3) action strategies: sticking to professional values, self-regulation, flexible response, post-event improvement; and (4) outcomes: self-harmony, reduced medical disputes. CONCLUSIONS: This study provides an interpretive understanding of why clinical nurses adhere to professional ethics in China and describes the challenges and issues posed by nurses' use of strategies to cope with ethical adversity. The findings can be used to develop future complex studies.

Numerical Investigation of Interlaminar Stress of CRTS II Slab Ballastless Track Induced by Creep and Shrinkage of Concrete.

The secondary development of ABAQUS was carried out to calculate the shrinkage and creep of concrete, and a finite element model of the China Railway Track System (CRTS) II slab ballastless track was established. Then, the interlaminar stress of CRTS II slab ballastless track at different ages of the track slab during laying (AOTSL) caused by concrete shrinkage and creep was studied. The obtained results showed that the stress redistribution occurred in the sliding layer, which resulted in the generation of a gap. Although the gap length was slightly reduced due to the shear cogging, the sliding layer at the slab edge is more prone to produce gaps. Under the effect of shrinkage and creep of the ballastless track, large additional shear stress, up to 0.676 MPa, was induced at the interface between CA mortar and the track slab. Meanwhile, the appearance of additional vertical and lateral forces of the shear cogging was caused by the shrinkage and creep of the ballastless track. Additionally, by further analysis, the recommended AOTSL ranges from 120 days to 180 days.

Reliability and validity of the Mandarin version of the Trust in Nurses Scale.

AIMS: This study aimed to translate and validate the Trust in Nurses Scale (TINS) and then test and implement the tool. BACKGROUND: Trust is the core feature of the nurse-patient relationship, and a simple and universal instrument to measure patients' trust in nurses in China is lacking. METHODS: Exploratory and confirmatory factor analyses (EFA and CFA) were performed to verify structural validity. Content validity and reliability analyses were also conducted. RESULTS: The Cronbach's alpha of the TINS was .817, and the test-retest reliability coefficient was .852. EFA revealed two factors and explained 59.702% of the total variation. CFA proved that all the goodness-of-fit indicators were acceptable. CONCLUSION: The TINS exhibited satisfactory reliability and validity, and it can be universally applied to survey Chinese patients' trust in nurses. IMPLICATIONS FOR NURSING MANAGEMENT: The TINS can be used by nursing managers to assess patients' trust in nurses, and appropriate programmes can be developed to improve patients' trust.

Perceptions of pelvic floor dysfunction and rehabilitation care amongst women in southeast China after radical hysterectomy: a qualitative study.

OBJECTIVE: To investigate the perceptions of pelvic floor dysfunction (PFD) and rehabilitation care amongst women after radical hysterectomy and to explore ways to improve quality of care. METHODS: Thirty-six women who underwent radical hysterectomy at a hospital in southeast China were enrolled via purposive sampling. Semi-structured in-depth interviews were conducted. The texts were analysed via qualitative content analysis. RESULTS: Four themes were obtained: serious lack of knowledge, heavy psychological burden, different coping strategies and great eagerness to receive multiparty support on PFD rehabilitation care. CONCLUSION: The society and professional staff should strengthen health education on PFD. Professionals should offer education before and after surgery and actively provide rehabilitation consultation to promote the availability of rehabilitation to support women with PFD rehabilitation care. In addition, family-centred care is an important way to support women to return to normal life, and women's need for family support should be more actively expressed. Moreover, knowledge of medical insurance should be popularised, especially in rural areas in China.

Design, synthesis, biological evaluation and molecular dynamics simulation studies of imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) is a member of the phosphotyrosine phosphatase family and plays an important role in the signal transduction of diabetes. Inhibition of PTP1B activity can increase insulin sensitivity and reduce blood sugar levels. Therefore, it is urgent to find compounds with novel structures that can inhibit PTP1B. This study designed imidazolidine-2,4-dione derivatives through the computer-aided drug design (CADD) strategy, and the Comp#10 showed outstanding inhibitory ability. (IC50 = 2.07 µM) and selectivity. The inhibitory mechanism at molecular level of Comp#10 on PTP1B was studied by molecular dynamics simulation. The results show that the catalytic region of PTP1B protein is more stable, which makes the catalytic sites unsuitable for exposure. Interestingly, the most obvious changes in the interaction between residues in the P-loop region (such as: His214, Cys215, and Ser216). In short, this study reported for the first time that imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors had good inhibitory activity and selectivity, providing new ideas for the development of small molecule PTP1B inhibitors.

Antiviral effect of fufang yinhua jiedu (FFYH) granules against influenza A virus through regulating the inflammatory responses by TLR7/MyD88 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang-Yinhua-Jiedu Granules (FFYH) optimized from a Yin-Qiao-San, as traditional Chinese medicine (TCM), was used to treat influenza and upper respiratory tract infection and was recommended for the prevention and treatment of SARS in 2003 and current COVID-19 in Anhui Province in 2020. AIM OF STUDY: In the clinical studies, FFYH was very effective for the treatment of influenza, but the mechanism of action against influenza A virus remains unclear. In the present study, we investigated the antiviral effect of FFYH against influenza A virus in vitro and vivo. Moreover, the potential mechanism of FFYH against influenza A virus in vivo was investigated for the first time. MATERIALS AND METHODS: CPE inhibition assay and HA assay were used to evaluate the in vitro antiviral effects of FFYH against influenza A virus H1N1, H3N2, H5N1, H7N9 and H9N2. Mice were used to evaluate the antiviral effect of FFYH in vivo with ribavirin and lianhuaqingwen as positive controls. RT-PCR was used to quantify the mRNA transcription of TNF-α, IL-6, IFN-γ, IP10, and IL-1ß mRNA. ELISA was used to examine the expression of inflammatory factors such as TNF-α, IL-6, IFN-γ, IP10, and IL-1ß in sera. The blood parameters were analyzed with auto hematology analyzer. Moreover, the potential mechanism of FFYH against influenza A virus in vivo was also investigated. RESULTS: FFYH showed a broad-spectrum of antiviral activity against H1N1, H3N2, H5N1, H7N9, and H9N2 influenza A viruses. Furthermore, FFYH dose-dependently increased the survival rate, significantly prolonged the median survival time of mice, and markedly reduced lung injury caused by influenza A virus. Also, FFYH significantly improve the sick signs, food taken, weight loss, blood parameters, lung index, and lung pathological changes. Moreover, FFYH could markedly inhibit the inflammatory cytokine expression of TNF-α, IL-6, IFN-γ, IP10, IL-10, and IL-1ß mRNA or protein via inhibition of the TLR7/MyD88/NF-κB signaling pathway in vivo. CONCLUSION: FFYH not only showed a broad-spectrum of anti-influenza virus activity in vitro, but also exhibited a significant protective effect against lethal influenza virus infection in vivo. Furthermore, our results indicated that the in vivo antiviral effect of FFYH against influenza virus may be attributed to suppressing the expression of inflammatory cytokines via regulating the TLR7/MyD88/NF-κB signaling pathway. These findings provide evidence for the clinical treatment of influenza A virus infection with FFYH.

Comparative genomics and transcriptomics analyses provide insights into the high yield and regulatory mechanism of Norvancomycin biosynthesis in Amycolatopsis orientalis NCPC 2-48.

BACKGROUND: Norvancomycin has been widely used in clinic to treat against MRSA (Methicillin-resistant Staphylococcus aureus) and MRSE (Methicillin-resistant Staphylococcus epidermidis) infections in China. Amycolatopsis orientalis NCPC 2-48, a high yield strain derived from A. orientalis CPCC 200066, has been applied in industrial large-scale production of norvancomycin by North China Pharmaceutical Group. However, the potential high-yield and regulatory mechanism involved in norvancomycin biosynthetic pathway has not yet been addressed. RESULTS: Here we sequenced and compared the genomes and transcriptomes of A. orientalis CPCC 200066 and NCPC 2-48. These two genomes are extremely similar with an identity of more than 99.9%, and no duplication and structural variation was found in the norvancomycin biosynthetic gene cluster. Comparative transcriptomic analysis indicated that biosynthetic genes of norvancomycin, as well as some primary metabolite pathways for the biosynthetic precursors of norvancomycin were generally upregulated. AoStrR1 and AoLuxR1, two cluster-situated regulatory genes in norvancomycin cluster, were 23.3-fold and 5.8-fold upregulated in the high yield strain at 48 h, respectively. Over-expression of AoStrR1 and AoLuxR1 in CPCC 200066 resulted in an increase of norvancomycin production, indicating their positive roles in norvancomycin biosynthesis. Furthermore, AoStrR1 can regulate the production of norvancomycin by directly interacting with at least 8 promoters of norvancomycin biosynthetic genes or operons. CONCLUSION: Our results suggested that the high yield of NCPC 2-48 can be ascribed to increased expression level of norvancomycin biosynthetic genes in its cluster as well as the genes responsible for the supply of its precursors. The norvancomycin biosynthetic genes are presumably regulated by AoStrR1 and AoLuxR1, of them AoStrR1 is possibly the ultimate pathway-specific regulator for the norvancomycin production. These results are helpful for further clarification of the holistic and pathway-specific regulatory mechanism of norvancomycin biosynthesis in the industrial production strain.

Inducing secondary metabolite production of Aspergillus sydowii through microbial co-culture with Bacillus subtilis.

BACKGROUND: The co-culture strategy which mimics natural ecology by constructing an artificial microbial community is a useful tool to activate the biosynthetic gene clusters to generate new metabolites. However, the conventional method to study the co-culture is to isolate and purify compounds separated by HPLC, which is inefficient and time-consuming. Furthermore, the overall changes in the metabolite profile cannot be well characterized. RESULTS: A new approach which integrates computational programs, MS-DIAL, MS-FINDER and web-based tools including GNPS and MetaboAnalyst, was developed to analyze and identify the metabolites of the co-culture of Aspergillus sydowii and Bacillus subtilis. A total of 25 newly biosynthesized metabolites were detected only in co-culture. The structures of the newly synthesized metabolites were elucidated, four of which were identified as novel compounds by the new approach. The accuracy of the new approach was confirmed by purification and NMR data analysis of 7 newly biosynthesized metabolites. The bioassay of newly synthesized metabolites showed that four of the compounds exhibited different degrees of PTP1b inhibitory activity, and compound N2 had the strongest inhibition activity with an IC50 value of 7.967 µM. CONCLUSIONS: Co-culture led to global changes of the metabolite profile and is an effective way to induce the biosynthesis of novel natural products. The new approach in this study is one of the effective and relatively accurate methods to characterize the changes of metabolite profiles and to identify novel compounds in co-culture systems.

Mycotoxins as inhibitors of protein tyrosine phosphatases from the deep-sea-derived fungus Aspergillus puniceus SCSIO z021.

Nine new xanthone-type and anthraquinone-type mycotoxins including austocystins J-N (1-5), 7-chloro versicolorin A (6), 3'-hydroxy-8-O-methyl versicolorin B (7), 8-O-methyl versiconol (8) and 2',3'-dihydroxy versiconol (9), together with 17 known analogues (10-26) were isolated from an extract of the deep-sea-derived fungus Aspergillus puniceus SCSIO z021. Their structures were elucidated by detailed analysis of spectroscopic data, and their absolute configurations were further determined by quantum chemical calculations of ECD spectra or comparison of the experimental ECD spectra. Eleven hydrogenated austocystins were synthesized from 1-2, 10-15 and 17 by catalytic hydrogenation for bioactivities evaluation. Totally, 18 of the all 37 compounds showed strong toxicity against brine shrimps or Vero cell, and the toxicity of 8-O-methyldemethylsterigmatocystin (18) (LC50 = 0.020 µM) against brine shrimps was higher than those of three positive controls. In addition, 22 of the isolated compounds also exhibited significant inhibitory activity against seven different protein tyrosine phosphatases (PTPs), among them austocystin H (15) and methyl-averantin (24) were the most potent inhibitors with IC50 values of 0.20-3.0 µM. Their structure-bioactivity relationship was also discussed.

Design, synthesis, biological evaluation, common feature pharmacophore model and molecular dynamics simulation studies of ethyl 4-(phenoxymethyl)-2-phenylthiazole-5-carboxylate as Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors.

SHP2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell death pathway (PD-1/PD-L1) and cell growth and differentiation pathway (MAPK). Moreover, mutations in SHP2 have been implicated in Leopard syndrome (LS), Noonan syndrome (NS), juvenile myelomonocytic leukemia (JMML) and several types of cancer and solid tumors. Thus, SHP2 inhibitors are much needed reagents for evaluation of SHP2 as a therapeutic target. A series of novel ethyl 4-(phenoxymethyl)-2-phenylthiazole-5-carboxylate derivatives were designed and synthesized, and their SHP2 inhibitory activities (IC50) were determined. Among the desired compounds, 1d shares the highest inhibitory activity (IC50 = 0.99 µM) against SHP2. Additionally, a common feature pharmacophore model was established to explain the structure activity relationship of the desired compounds. Finally, molecular dynamics simulation was carried out to explore the most likely binding mode of compound 1d with SHP2. In brief, the findings reported here may at least provide a new strategy or useful insights in discovering novel effective SHP2 inhibitors.Communicated by Ramaswamy H. Sarma.

Penicimeroterpenoids A-C, Meroterpenoids with Rearrangement Skeletons from the Marine-Derived Fungus Penicillium sp. SCSIO 41512.

Three novel andrastin-type meroterpenoids, penicimeroterpenoids A-C (1-3), possessing two unprecedented skeletons consisting of fused 6/5/6/6/7 and 6/5/6/6/4 polycyclic systems, were obtained from the marine-derived fungus Penicillium sp. SCSIO 41512. Their structures were determined by spectroscopic methods, and the absolute configurations were further determined by single-crystal X-ray diffraction analysis for 1 and quantum chemical calculations of ECD spectra for 2 and 3, respectively. A plausible biosynthetic pathway for 1-3 was proposed.

Naphthacemycins from a Streptomyces sp. as Protein-Tyrosine Phosphatase Inhibitors.

Nine new naphthacemycins (1-9), along with one known naphthacemycin (10) were isolated from the culture of Streptomyces sp. N12W1565. Their structures were elucidated on the basis of spectroscopic analysis, including UV, NMR, and HRESIMS. All the compounds showed significant activity, with IC50 values less than 10 µM against protein-tyrosine phosphatase 1B (PTP1B). The anti-PTP1B structure-activity relationship of naphthacemycins (1-10) is discussed. These findings provide a promising starting point for the development of naphthacemycins as potential anti-PTP1B agents.

Identification of potential leukocyte antigen-related protein (PTP-LAR) inhibitors through 3D QSAR pharmacophore-based virtual screening and molecular dynamics simulation.

Owing to its negative regulatory role in insulin signaling, protein tyrosine phosphatase of leukocyte antigen-related protein (PTP-LAR) was widely thought as a potential drug target for diabetes. Now, it was urgent to search for potential LAR inhibitors targeting diabetes. Initially, the pharmacophore models of LAR inhibitors were established with the application of the HypoGen module. The cost analysis, test set validation, as well as Fischer's test was used to verify the efficiency of pharmacophore model. Then, the best pharmacophore model (Hypo-1-LAR) was applied for the virtual screening of the ZINC database. And 30 compounds met the Lipinski's rule of five. Among them, 10 compounds with better binding affinity than the known LAR inhibitor (BDBM50296375) were discovered by docking studies. Finally, molecular dynamics simulations and post-analysis experiments (RMSD, RMSF, PCA, DCCM and RIN) were conducted to explore the effect of ligands (ZINC97018474 and Compound 1) on LAR and preliminary understand why ZINC97018474 had better inhibitory activity than Compound 1 (BDBM50296375). Communicated by Ramaswamy H. Sarma.