Effect of amino acids on cryopreservation of cynomolgus monkey (Macaca fascicularis) sperm

The effects of three amino acids (proline, glutamine, and glycine) added to the freezing medium Tes-Tris-egg yolk (TTE) for cryopreservation of cynomolgus monkey (Macaca fascicularis) spermatozoa were studied. This is the first report on the effects of amino acids on nonhuman primate sperm cryopreservation. The addition of 5mM proline, 10mM glutamine, and 10 or 20mM glycine each significantly improved post-thaw sperm motility and membrane and acrosome integrity compared with the control (TTE alone). However, a significant decrease in motility and membrane/acrosome integrity was observed when amino acid concentrations increased to 60mM for proline and glutamine, and 80 mM for glycine. The results suggest that adding a limited amount of amino acids to the freezing media is beneficial for freezing cynomolgus monkey sperm.     

Mutation on Gly115 and Tyr205 of the cyclic dipeptide C2-prenyltransferase FtmPT1 increases its catalytic activity toward hydroxynaphthalenes

Applied Microbiology and Biotechnology - The fungal cyclic dipeptide prenyltransferase FtmPT1 from Aspergillus fumigatus catalyzes a regular C2-prenylation of brevianamide F (cyclo-l-Trp-l-Pro) and...     

Subcellular Distribution and Chemical Forms of Cadmium in the Medicine Food Homology Plant <i>Platycodon grandiflorum</i> (Jacq.) A.DC.

Although Platycodon grandiflorum (Jacq.) A.DC. is a renowned medicine food homology plant, reports of excessive cadmium (Cd) levels are common, which affects its safety for clinical use and food consumption. To enable its Cd levels to be regulated or reduced, it is necessary to first elucidate the mechanism of Cd uptake and accumulation in the plant, in addition to its detoxification mechanisms. This present study used inductively couple plasma-mass-spectrometry to analyze the subcellular distribution and chemical forms of Cd in different tissues of P. grandiflorum. The experimental results showed that Cd was mainly accumulated in the roots [predominantly in the cell wall (50.96%–61.42%)], and it was found primarily in hypomobile and hypotoxic forms. The proportion of Cd in the soluble fraction increased after Cd exposure, and the proportion of insoluble phosphate Cd and oxalate Cd increased in roots and leaves, with a higher increase in oxalate Cd. Therefore, it is likely that root retention mechanisms, cell wall deposition, vacuole sequestration, and the formation of low mobility and low toxicity forms are tolerance strategies for Cd detoxification used by P. grandiflorum. The results of this study provide a theoretical grounding for the study of Cd accumulation and detoxification mechanisms in P. grandiflorum, and they can be used as a reference for developing Cd limits and standards for other medicine food homology plants.     

南亚热带10种造林树种的水力结构和水力安全

南亚热带地区人工纯林面积大, 但是结构简单, 对气候变化响应敏感。在区域气候干旱化的背景下, 造林树种的生理生态策略及其对季节性干旱的响应亟待研究。该研究选择南亚热带地区10种造林树种(包括6种乡土种和4种外来种), 测定这些树种的平均生长速率、水力学性状以及经济学性状, 分析性状与生长速率之间的相关关系, 并比较水力安全边际和气孔安全边际的种间差异。结果发现: (1)造林树种的生长速率与木质部导水率显著正相关, 但与木材密度、比叶面积以及水力安全性指标无显著相关性。(2)造林树种的水分传导效率性和安全性之间没有权衡关系, 外来树种Acacia crassicarpa和Eucalyptus grandis × urophylla同时具有较高的木质部导水率和较强的抗栓塞能力。(3)造林树种的水力安全边际和气孔安全边际的种间差异显著, 大叶相思(Acacia auriculiformis)、红锥(Castanopsis hystrix)、壳菜果(Mytilaria laosensis)和阴香(Cinnamomum burmannii)在干季发生水力失败的风险较高。建议南亚热带人工林的生态监测指标体系中应包括树木水力学性状, 进而为人工林的可持续经营管理提供重要参考。     

The combination therapy of oncolytic HSV-1 armed with anti-PD-1 antibody and IL-12 enhances anti-tumor efficacy

Cancer immunotherapy is a new therapeutic strategy for cancer treatment that targets tumors by improving or restoring immune system function. Therapies targeting immune checkpoint molecules have exerted potent anti-tumor effects and prolonged the overall survival rate of patients. However, only a small number of patients benefit from the treatment. Oncolytic viruses exert anti-tumor effects by regulating the tumor microenvironment and affecting multiple steps of tumor immune circulation. In this study, we engineered two oncolytic viruses that express mouse anti-PD-1 antibody (VT1093M) or mouse IL-12 (VT1092M). We found that both oncolytic viruses showed significant anti-tumor effects in a murine CT26 colon adenocarcinoma model. Importantly, the intratumoral combined injection with VT1092M and VT1093M inhibited growth of the primary tumor, prevented growth of the contralateral untreated tumor, produced a vaccine-like response, activated antigen-specific T cell responses and prolonged the overall survival rate of mice. These results indicate that combination therapy with the engineered oncolytic virus may represent a potent immunotherapy strategy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.     

Human Organoids as a Promising Platform for Fighting COVID-19

The coronavirus disease 2019 (COVID-19) global pandemic evoked by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a major public health problem with significant morbidity and mortality. Understanding the pathogenesis and molecular mechanisms underlying this novel virus is crucial for both fundamental research and clinical trials in order to devise effective therapies and vaccination regimens. Basic research on SARS-CoV-2 largely depends on ex vivo models that allow viral invasion and replication. Organoid models are now emerging as a valuable tool to investigate viral biology and disease progression, serving as an efficient platform to investigate potential therapies for COVID-19. Here, we summarize various human stem cell-derived organoid types employed in SARS-CoV-2 studies. We highlight key findings from these models, including cell tropisms and molecular mechanisms in viral infection. We also describe their use in identifying potential therapeutic agents against SARS-CoV-2. As more and more advanced organoids emerge, they will facilitate the understanding of disease pathogenesis for drug development in this dreaded pandemic.     

BMP-2 promotes osteogenic differentiation of mesenchymal stem cells by enhancing mitochondrial activity

Objectives:Mesenchymal stem cells (MSCs) have become seed cells and basic elements for bone regeneration and bone tissue engineering. The aim of the present study was to investigate the roles and mechanisms of bone morphogenetic protein 2 (BMP-2) on osteogenic differentiation of MSCs.Methods:Primary MSCs were isolated from the femur and tibia bone of rats and then transfected with BMP-2 and PGC-1α adenovirus vectors. Alkaline phosphatase (ALP) activity and alizarin red staining were used to measure osteogenic differentiation of MSCs. Real-time PCR and western blot assays were performed to assess osteogenic differentiation-related proteins levels. The activities of mitochondrial respiratory chain complexes I and II and mitochondrial fluorescence intensity were used to explore mitochondria status during osteogenic differentiation of MSCs.Results:We found that the ability of BMP-2 overexpressed (OE) group osteogenic differentiation was significantly improved, compared with the negative control (NC) group. The results also indicated that BMP-2 can promote the activity of mitochondria. We further used the gain- and loss-of-function approaches to demonstrate that BMP-2 promotes mitochondrial activity by up-regulating PGC-1α to promote osteogenic differentiation of MSCs.Conclusions:These results explored the important role of BMP-2 in the osteoblast differentiation of MSCs from a new perspective, providing a theoretical and experimental basis for bone defect and repair.     

Discovery of 3-(4-sulfamoylnaphthyl)pyrazolo[1,5-a]pyrimidines as potent and selective ALK2 inhibitors

The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties.     

Design,synthesis and evaluation of 4′-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer’s disease treatment

A series of 4′-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ_1–42 aggregation (60.0% and 78.2%, respectively) and Cu²⁺-induced Aβ_1–42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.