Search

Parasitic helminths continue to pose problems in human and veterinary medicine, as well as in agriculture. Semen pharbitidis, the seeds of Pharbitis nil (Linn.) Choisy (Convolvulaceae), is a well-known traditional Chinese medicinal botanical preparation widely used for treating intestinal parasites in China owing to its desirable efficacy. However, the anthelmintic compounds in Semen pharbitidis and their mechanism of action have not been investigated yet. This study aimed to identify the compounds active against helminths from Semen pharbitidis, and to establish the mechanism of action of these active compounds. Bioassay-guided fractionation was used to identify the anthelmintic compounds from Semen pharbitidis. The anthelmintic assay was performed by monitoring Caenorhabditis elegans (C. elegans) motility with a WMicrotracker instrument. Active compounds were identified by high-resolution mass spectrometry. Several (analogues of) fragments of the anthelmintic compounds were purchased and tested to explore the structure–activity relationship, and to find more potent compounds. A panel of C. elegans mutant strains resistant to major currently used anthelmintic drugs was used to explore the mechanism of action of the active compounds. The bioassay-guided isolation from an ethanol extract of Semen pharbitidis led to a group of glycosides, namely pharbitin (IC50: 41.0 ± 9.4 μg/mL). Hit expansion for pharbitin fragments yielded two potent analogues: 2-bromohexadecanoic acid (IC50: 1.6 ± 0.7 μM) and myristoleic acid (IC50: 35.2 ± 7.6 μM). One drug-resistant mutant ZZ37 unc-63 (x37) demonstrated a ~17-fold increased resistance to pharbitin compared with wild-type worms. Collectively, we provide further experimental scientific evidence to support the traditional use of Semen pharbitidis for the treatment of intestinal parasites. The anthelmintic activity of Semen pharbitidis is due to pharbitin, whose target could be UNC-63 in C. elegans. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-expressing macrophages (CAR-M) have a great potential to improve cancer therapy, as shown from several recent preclinical studies. However, unlike CAR-T cell therapy, which has been widely studied, the efficacy and limitations of CAR-M cells remain to be established. To address this issue, in the present study, we compared three intracellular signaling domains (derived from common γ subunit of Fc receptors (FcRγ), multiple EGF-like-domains protein 10 (Megf10), and the CD19 cytoplasmic domain that recruits the p85 subunit of phosphoinositide-3 kinase (PI3K), respectively) for their ability to promote primary CAR-M functions, and investigated the potential synergistic effect between CAR-M and CAR-T cells in their ability to kill tumor cells. We found that CAR-MFcRγ exerted more potent phagocytic and tumor-killing capacity than CAR-MMegf10 and CAR-MPI3K. CAR-M and CAR-T demonstrated synergistic cytotoxicity against tumor cells in vitro. Mechanistically, the inflammatory factors secreted by CAR-T increased the expression of costimulatory ligands (CD86 and CD80) on CAR-M and augmented the cytotoxicity of CAR-M by inducing macrophage M1 polarization. The upregulated costimulatory ligands may promote the fitness and activation of CAR-T cells in turn, achieving significantly enhanced cytotoxicity. Taken together, our study demonstrated for the first time that CAR-M could synergize with CAR-T cells to kill tumor cells, which provides proof-of-concept for a novel combinational immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Semen Pharbitidis , the seeds of Pharbitis nil (Linn.) Choisy (Convolvulaceae) is a well-known traditional Chinese medicinal plant used for treating helminthiasis and epilepsy in China. Aim of the study This study aims to identify the anti-seizure components from Semen Pharbitidis. Methods A bioassay-guided isolation of anti-seizure compounds from Semen Pharbitidis was performed using a zebrafish pentylenetetrazol seizure model. The structures of active compounds were elucidated by high resolution mass spectrometry. The fragments of active compounds were tested for anti-seizure activity as well. Results The bioassay-guided isolation of ethanol extract of Semen Pharbitidis led to a group of resin glucosides, namely pharbitin. One of the fragments of pharbitin, 2-methylbutyric acid, also showed anti-seizure activity. Conclusions We provided further experimental scientific evidence to support the traditional use of Semen Pharbitidis for the treatment of epilepsy. Pharbitin was identified to be the main anti-seizure component in Semen Pharbitidis. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A practical, automated and low-cost whole-organism motility assay was established using a WMicroTracker. • A repurposing library comprising 2745 molecules was screened. • All known anthelmintics in this library were picked up as well as four novel hits. • One hit (EVP4593) demonstrated a potent and broad anthelmintic activity, and a high selectivity index. Abstract Parasitic nematodes continue to cause significant economic losses in livestock globally. Given the limited number of anthelmintic drugs on the market and the currently increasing drug resistance, there is an urgent need for novel anthelmintics. Most motility assays of anthelmintic activity for parasitic nematodes are laborious and low throughput, and therefore not suitable for screening large compound libraries. Cooperia oncophora accounts for a large proportion of reports on the drug-resistance development of parasites globally. Therefore, using a WMicroTracker instrument, we established a practical, automated and low-cost whole-organism motility assay against exsheathed L3 stages (xL3s) of the ruminant parasite Cooperia oncophora , and screened a repurposing library comprising 2745 molecules. Fourteen known anthelmintics contained in this library were picked up in this blind screen, as well as four novel hits: thonzonium bromide, NH125, physostigmine sulfate, and EVP4593. The four hits were also active against xL3s of Ostertagia ostertagi , Haemonchus contortus and Teladorsagia circumcincta using the same assay. Cytotoxicity testing showed that thonzonium bromide and NH125 (1-Benzyl-3-cetyl-2-methylimidazolium iodide) have significant cytotoxicity. EVP4593 (N(4)-(2-(4-phenoxyphenyl)ethyl)-4,6-quinazolinediamine) demonstrated a potent and broad anthelmintic activity, and a high selectivity index. Moreover, given its novel and unexplored chemical scaffold for anthelmintic activity, EVP4593 is an interesting anthelmintic hit for further optimization. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Semen Torreyae , the seeds of Torreya grandis Fortune ex Lindley (Cephalotaxaceae) is a well-known traditional Chinese medicinal plant recorded in the Chinese Pharmacopeia (2010 version). It is widely used for treating intestinal parasites in China, owing to its desirable efficacy and safety. However, the anthelmintic compounds in Semen Torreyae have not yet been identified. Aim of the study This study aims to identify the compounds active against helminths from Semen Torreyae . In addition, we tested whether C. elegans strains resistant to currently-used anthelmintic drugs showed cross-resistance to these compounds. Methods A bioassay-guided isolation of anthelmintic compounds from Semen Torreyae was performed using a Caenorhabditis elegans ( C. elegans ) testing model. The structures of active compounds were elucidated by a combination of GC-MS, high resolution MS, and NMR. The median-effect method was employed to generate a combination index (CI) to evaluate the synergistic effect of the anthelmintic compounds. A panel of C. elegans mutant strains resistant against the major anthelmintic drug classes was used to study the cross-resistance to currently-used anthelmintic drugs. A panel of transient receptor potential (TRP) channel mutant strains was also tested to explore the possible mechanisms of action of the anthelmintic compounds. Results The bioassay-guided isolation led to two active compounds, i.e . galangal acetate (IC 50 : 58.5 ± 8.9 μM) and miogadial (IC 50 : 25.1 ± 5.4 μM). The combination of galangal acetate and miogadial resulted in a synergistic effect at IC 50 , IC 70 , and IC 90 levels (CIs < 1). Galangal acetate and miogadial demonstrated similar activity against drug-resistant C. elegans strains compared to the wild-type strain. In addition, none of the TRP mutants was significantly resistant to galangal acetate or miogadial compared to wild type worms. Conclusions We identified the bioactive compounds from Semen Torreyae responsible for its anthelmintic activity: galangal acetate and miogadial. The two anthelmintic compounds demonstrated a synergistic effect against C. elegans . Galangal acetate and miogadial are unlikely to act on the targets of currently-used anthelmintics (ivermectin, levamisole, benomyl and aldicarb), and an action on TRP channels appears to be ruled out as well. In summary, galangal acetate and miogadial are promising anthelmintic hits worth further investigation. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Bioassay-guided isolation of anthelmintic compounds from Warburgia ugandensis leaves using Caenorhabditis elegans model. • Anthelmintic activity of W. ugandensis is mainly ascribable to warburganal, polygodial and alpha-linolenic acid (ALA) • Polygodial and ALA, as well as warburganal and ALA, have synergistic effects against C. elegans. • The underlying mechanism of anthelmintic action of polygodial is probably inhibition of mitochondrial ATP synthesis. Abstract Parasitic helminths continue to pose problems in human and veterinary medicine, as well as in agriculture. Resistance to current anthelmintics has prompted the search for new drugs. Anthelmintic metabolites from medicinal plants could be good anthelmintic drug candidates. However, the compounds active against nematodes have not been identified in most medicinal plants with anthelmintic activity. In this study, we aimed to identify the active compounds against helminths in Warburgia ugandensis Sprague subspecies ugandensis (Canellaceae) and study the underlying mechanism of action. A bioassay-guided isolation of anthelmintic compounds from the plant was performed using a Caenorhabditis elegans (C. elegans) test model with a WMicrotracker instrument to monitor motility. Three active compounds were purified and identified by nuclear magnetic resonance and high resolution MS: warburganal (IC 50 : 28.2 ± 8.6 μM), polygodial (IC 50 : 13.1 ± 5.3 μM) and alpha-linolenic acid (ALA, IC 50 : 70.1 ± 17.5 μM). A checkerboard assay for warburganal and ALA as well as polygodial and ALA showed a fractional inhibitory concentration index of 0.41 and 0.37, respectively, suggesting that polygodial and ALA, as well as warburganal and ALA, have a synergistic effect against nematodes. A preliminary structure–activity relationship study for polygodial showed that the α,β-unsaturated 1,4-dialdehyde structural motif is essential for the potent activity. None of a panel of C. elegans mutant strains, resistant against major anthelmintic drug classes, showed significant resistance to polygodial, implying that polygodial may block C. elegans motility through a mechanism which differs from that of currently marketed drugs. Further measurements showed that polygodial inhibits mitochondrial ATP synthesis of C. elegans in a dose-dependent manner (IC 50 : 1.8 ± 1.0 μM). Therefore, we believe that the underlying mechanism of action of polygodial is probably inhibition of mitochondrial ATP synthesis. In conclusion, polygodial could be a promising anthelmintic drug candidate worth considering for further development. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Tetradenia (T.) riparia (Hochst.) Codd (Lamiaceae), formerly known as Iboza riparia (Hochst.) N.E.Br., is one of the most frequently used medicinal plants in traditional Rwandese medicine. It was used as a remedy against a wide range of diseases including malaria, angina, yaws, dental abscesses, headache, worm infections and several kinds of fevers and aches. Aim of the study This study aims to identify the compounds active against helminths from Tetradenia riparia . Methods A bioassay-guided isolation of anthelmintic compounds from the leaves of Tetradenia riparia was performed using a Caenorhabditis elegans ( C. elegans ) testing model. Results The bioassay-guided isolation led to one active compound, i.e. 8(14),15-sandaracopimaradiene-7α,18-diol. Its IC 50 value was 5.4 ± 0.9 µg/mL (17.8 ± 2.9 µM). Conclusions We identified the bioactive compound from Tetradenia riparia responsible for its anthelmintic activity: 8(14),15-sandaracopimaradiene-7α,18-diol. Although the compound and several of its bioactivities have been described before, this is the first report of its anthelmintic effect. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Fufang E׳jiao Jiang (FEJ), which has been widely used in clinic to replenish qi (vital energy) and nourish blood, is a famous traditional Chinese medicine formula made up of Colla corii Asini (Donkey-hide gelatin prepared by stewing and concentrating from the hide of Equus asinus Linnaeus.), Radix Codonopsis Pilosulae (the root of Codonopsis pilosula (Franch.) Nannf.), Radix Ginseng Rubra (the steamed and dried root of Panax ginseng C.A. Mey.), Fructus Crataegi (the fruit of Crataegus pinnatifida Bunge) and Radix Rehmanniae Preparata (the steamed and sun dried tuber of Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. & C.A. Mey.). The present study aimed to investigate the hematopoietic effects of FEJ on myelosuppressed mice induced by radiotherapy and chemotherapy systematically and to explore the underlying hematopoietic regulation mechanisms. Methods: The myelosuppressed mouse model was induced by 60Co radiation, cyclophosphamide and chloramphenicol. FEJ was then administered by i.g. at the dosages of 5, 10, or 20mL/kg·d for 10d. The numbers of blood cells from peripheral blood and bone marrow nucleated cells (BMNC) were counted. Body weight and the thymus and spleen indices were also measured. The numbers of hemopoietic progenitor cells and colony-forming unit-fibroblast (CFU-F) were measured in vitro. The ratio of hematopoietic stem cells (HSC) in BMNC, cell cycle and apoptosis of BMNC were determined by flow cytometry. The histology of femoral bone was examined by H&E staining. The levels of transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and interleukin-6 (IL-6) in serum were measured by ELISA. IL-1β, IL-3, IL-6 mRNA levels in spleen were detected by real-time quantitative PCR (RT-qPCR). In addition, bone marrow stromal cells (BMSC) were cultured in vitro followed by treatment with different doses of FEJ (2.5, 5, 10μL/mL) for 48h. Then the levels of cytokines (IL-6, SCF, GM-CSF) in the conditioned media and their mRNA levels in BMSC were determined by ELISA and RT-qPCR, respectively. Results: FEJ could significantly increase the numbers of peripheral blood cells and BMNC, and reverse the loss of body weight and the atrophy of thymus and spleen in a dose-dependent manner. The quantities of hemopoietic progenitor cells and CFU-F in bone marrow were also significantly increased in a dose-dependent manner after FEJ administration. A high-dose FEJ of 20mL/kg·d could significantly increase the ratio of HSC in BMNC, promote bone marrow cells entering the proliferative cycle phase (S+G2/M) and prevent cells from proceeding to the apoptotic phase. FEJ could also improve the femoral bone marrow morphology. Furthermore, FEJ could increase the levels of GM-CSF and IL-3 and reduce the level of TGF-β in serum, and enhance the expressions of IL-1β and IL-3 mRNA in spleen. Lastly, the levels of cytokines (IL-6, SCF, GM-CSF) in the conditioned media and their mRNA levels in BMSC were elevated after treatment with FEJ. Conclusions: FEJ was clearly confirmed to promote the recovery of bone marrow hemopoietic function in a myelosuppressed mouse model, which may be attributed to (i) improving bone marrow hematopoietic microenvironment; (ii) facilitating the cell proliferation and preventing BMNC from apoptosis; (iii) stimulating the expressions of IL-1β, IL-3, IL-6, SCF and GM-CSF and inhibiting the expression of TGF-β. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Fufang E׳jiao Jiang (FEJ), which has been widely used in clinic to replenish qi (vital energy) and nourish blood, is a famous traditional Chinese medicine formula made up of Colla corii Asini (Donkey-hide gelatin prepared by stewing and concentrating from the hide of Equus asinus Linnaeus.), Radix Codonopsis Pilosulae (the root of Codonopsis pilosula (Franch.) Nannf.), Radix Ginseng Rubra (the steamed and dried root of Panax ginseng C.A. Mey.), Fructus Crataegi (the fruit of Crataegus pinnatifida Bunge) and Radix Rehmanniae Preparata (the steamed and sun dried tuber of Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. & C.A. Mey.). The present study aimed to investigate the hematopoietic effects of FEJ on myelosuppressed mice induced by radiotherapy and chemotherapy systematically and to explore the underlying hematopoietic regulation mechanisms. Methods: The myelosuppressed mouse model was induced by 60Co radiation, cyclophosphamide and chloramphenicol. FEJ was then administered by i.g. at the dosages of 5, 10, or 20mL/kg·d for 10d. The numbers of blood cells from peripheral blood and bone marrow nucleated cells (BMNC) were counted. Body weight and the thymus and spleen indices were also measured. The numbers of hemopoietic progenitor cells and colony-forming unit-fibroblast (CFU-F) were measured in vitro. The ratio of hematopoietic stem cells (HSC) in BMNC, cell cycle and apoptosis of BMNC were determined by flow cytometry. The histology of femoral bone was examined by H&E staining. The levels of transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and interleukin-6 (IL-6) in serum were measured by ELISA. IL-1β, IL-3, IL-6 mRNA levels in spleen were detected by real-time quantitative PCR (RT-qPCR). In addition, bone marrow stromal cells (BMSC) were cultured in vitro followed by treatment with different doses of FEJ (2.5, 5, 10μL/mL) for 48h. Then the levels of cytokines (IL-6, SCF, GM-CSF) in the conditioned media and their mRNA levels in BMSC were determined by ELISA and RT-qPCR, respectively. Results: FEJ could significantly increase the numbers of peripheral blood cells and BMNC, and reverse the loss of body weight and the atrophy of thymus and spleen in a dose-dependent manner. The quantities of hemopoietic progenitor cells and CFU-F in bone marrow were also significantly increased in a dose-dependent manner after FEJ administration. A high-dose FEJ of 20mL/kg·d could significantly increase the ratio of HSC in BMNC, promote bone marrow cells entering the proliferative cycle phase (S+G2/M) and prevent cells from proceeding to the apoptotic phase. FEJ could also improve the femoral bone marrow morphology. Furthermore, FEJ could increase the levels of GM-CSF and IL-3 and reduce the level of TGF-β in serum, and enhance the expressions of IL-1β and IL-3 mRNA in spleen. Lastly, the levels of cytokines (IL-6, SCF, GM-CSF) in the conditioned media and their mRNA levels in BMSC were elevated after treatment with FEJ. Conclusions: FEJ was clearly confirmed to promote the recovery of bone marrow hemopoietic function in a myelosuppressed mouse model, which may be attributed to (i) improving bone marrow hematopoietic microenvironment; (ii) facilitating the cell proliferation and preventing BMNC from apoptosis; (iii) stimulating the expressions of IL-1β, IL-3, IL-6, SCF and GM-CSF and inhibiting the expression of TGF-β. [Copyright &y& Elsevier]

Intestinal parasitic nematodes infect approximately two billion people worldwide. In the absence of vaccines for human intestinal nematodes, control of infections currently relies mainly on chemotherapy, but resistance is an increasing problem. Thus, there is an urgent need for the discovery and development of new anthelmintic drugs, especially ones with novel mechanisms of action. Medicinal plants hold great promise as a source of effective treatments, including anthelmintic therapy. They have been used traditionally for centuries and are mostly safe (if not, their toxicity is well-known). However, in most medicinal plants the compounds active against nematodes have not been identified thus far. The free-living nematode C. elegans was demonstrated to be an excellent model system for the discovery of new anthelmintics and for characterizing their mechanism of action or resistance. The compounds discussed in this review are of botanical origin and were published since 2002. Most of them need further studies of their toxicity, mechanisms and structure-activity relationship to assess more fully their potential as drugs. [ABSTRACT FROM AUTHOR]

Warburgia ugandensis Sprague subspecies ugandensis is a plant widely distributed in Eastern, Central and Southern Africa. In humans, it is used to treat respiratory infections, tooth aches, malaria, skin infections, venereal diseases, diarrhea, fevers and aches. This study aims to identify the bioactive compounds against clinically important biofilm-forming strains of Candida and staphylococci that are responsible for tissue and implanted device-related infections. Using a bioassay-guided fractionation approach, hexane -, ethanol -, acetone - and water extracts from the leaves of W. ugandensis , their subsequent fractions and isolated compounds were tested against both developing and preformed 24 h-biofilms of Candida albicans SC5314, Candida glabrata BG2, Candida glabrata ATCC 2001, Staphylococcus epidermidis 1457 and Staphylococcus aureus USA 300 using microtiter susceptibility tests. Planktonic cells were also tested in parallel for comparison purposes. Confocal scanning laser microscopy was also used to visualize effects of isolated compounds on biofilm formation. Warburganal, polygodial and alpha-linolenic acid (ALA) were the major bioactive compounds isolated from the acetone extract of W. ugandensis. For both warburganal and polygodial, the biofilm inhibitory concentration that inhibits 50% of C. albicans developing biofilms (BIC 50) was 4.5 ± 1 and 10.8 ± 5 μg/mL respectively. Against S. aureus developing biofilms, this value was 37.9 ± 8 μg/mL and 25 μg/mL with warburganal and ALA respectively. Eradication of preformed 24 h biofilms was also observed. Interestingly, synergy between the sesquiterpenoids and azoles against developing C. albicans biofilms resulted in an approximately ten-fold decrease of the effective concentration required to completely inhibit growth of the biofilms by individual compounds. The hydroxyl group in position C-9 in warburganal was identified as essential for activity against staphylococcal biofilms. We also identified additional promising bioactive sesquiterpenoids; drimenol and drimendiol from the structure-activity relationship (SAR) studies. ALA and four sesquiterpenoids: polygodial, warburganal, drimenol and drimendiol, have shown biofilm-inhibitory activity that has not been reported before and is worth following up. These compounds are potential drug candidates to manage biofilm-based infections, possibly in combination with azoles. Image 1 [ABSTRACT FROM AUTHOR]

Polygala tenuifolia is used in a variety of Chinese medicine prescriptions for the classic dementia treatment, and polysaccharide is an important active component in the herb. This study investigated the in vivo anti-Alzheimer's disease (AD) activity of the polysaccharide PTPS from Polygala tenuifolia using the senescence-accelerated mouse/prone8 (SAMP8) model and explored its molecular mechanism to lay the foundation for the development of polysaccharide-based anti-AD drugs. The Morris water maze test (MWM)was used to detect changes in the spatial cognitive ability of mice, and Nissl staining was applied to observe the state of neurons in the classic hippocampus. The levels of acetylcholine (ACh) and acetylcholinesterase (AChE) were measured by ELISA. Immunofluorescence was used to reflect β-amyloid (Aβ) levels in brain tissue. Apoptosis was evaluated by TdT-mediated dUTP Nick-End Labeling (TUNEL) method. The status of dendritic branches and spines was observed by Golgi staining. Meanwhile, the expression levels of recombinant human insulin-degrading enzyme (IDE), brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB), extracellular regulated protein kinases (ERK), and cAMP-response element binding protein (CREB) proteins were determined by Western blotting. PTPS improves spatial cognitive deficits in AD mice, reduces cellular damage in the CA3 region of the hippocampus, maintains the balance of the cholinergic system, and exerts an anti-AD effect in vivo. The molecular mechanism of its action may be related to the reduction of Aβ deposition as well as the activation of ERK pathway-related proteins with enhanced synaptic plasticity. PTPS is able to exert anti-AD activity in vivo by mitigating Aβ damage and targeting the ERK pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

• CD317 protects cancer cells from immunocytolysis by maintaining membrane integrity in response to perforin. • CD317 mediates membrane protection through RICH2/cytoskeleton-dependent manner. • Knockdown of CD317 or RICH2, or disruption of cytoskeleton strikingly increases the tumor sensitivity to immunocytolysis. Immune evasion is a common hallmark of cancers. Immunotherapies that aim at restoring or increasing the immune response against cancers have revolutionized outcomes for patients, but the mechanisms of resistance remain poorly defined. Here, we report that CD317, a surface molecule with a unique topology that is double anchored into the membrane, protects tumor cells from immunocytolysis. CD317 knockdown in tumor cells renders more severe death in response to NK or chimeric antigen receptor-modified NK cells challenge. Such effects of CD317 silencing might be the results of increasing sensitivity of tumor cells to immune killing rather than strengthening immune response, since neither effector-target cell contact nor the activation of effector cells was affected, and the enhanced cytolysis was also not counteracted by the addition of recombinant CD317 proteins. Mechanistically, CD317 might endow tumor cells with more flexibility to modulate cytoskeleton through its association with RICH2, thereby protects membrane integrity against perforin and consequently promotes survival in response to immunocytolysis. These results reveal a new mechanism of immunocytolysis resistance and suggest CD317 as an attractive target which can be exploited for improving the efficacy of cancer immunotherapies. [ABSTRACT FROM AUTHOR]

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008μM and 9.453 μM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19. Author summary: Currently, a novel coronavirus called SARS-COV-2 is spreading across many parts of the world. Unfortunately, there is still a lack of effective drugs against the virus. Additionally, it usually takes much longer time to develop a new drug using traditional methods. Thus, it is now better to rely on some alternative methods to develop drugs that can treat such a disease effectively. In this paper, we have proposed a deep learning and molecular dynamics simulation based hybrid drug screening procedure for identifying potential drug candidates targeting RdRp from 1906 market available drugs. Our screening have successfully identified a FDA-approved drug called Pralatrexate that strongly inhibits the replication of 2019-nCoV in vitro with EC50 values of 0.008μM. This work demonstrated the feasibility of accurate virtual drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19. [ABSTRACT FROM AUTHOR]

Background. Infections by microbes (viruses, bacteria, and fungi) and parasites can cause serious diseases in both humans and animals. Heavy use of antimicrobials has created selective pressure and caused resistance to currently available antibiotics, hence the need for finding new and better antibiotics. Natural products, especially from plants, are known for their medicinal properties, including antimicrobial and anthelmintic activities. Geoclimatic variation, together with diversity in ethnomedicinal traditions, has made the Himalayas of Nepal an invaluable repository of traditional medicinal plants. We studied antiviral, antibacterial, antifungal, and anthelmintic activities of medicinal plants, selected based upon ethnobotanical evidence. Methods. Ethanolic and methanolic extracts were tested (1) on a panel of microbes: two Gram-positive bacteria (Staphylococcus aureus and Listeria innocua), four Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, and Shigella sonnei), and one fungal species: Candida albicans; (2) against three different viruses: yellow fever, chikungunya, and enterovirus; and (3) on the nematode Caenorhabditis elegans. Also, cytotoxicity was assessed on human hepatoma (Huh), rhabdosarcoma (RD), and Vero (VC) cell lines. Results. Of 18 plants studied, Ampelocissus tomentosa and Aleuritopteris anceps inhibited S. aureus (MIC 35 μg/mL and 649 μg/mL, respectively) and Pseudomonas aeruginosa (MIC 15 μg/mL and 38 μg/mL, respectively). Rhododendron arboreum and Adhatoda vasica inhibited S. enterica (MIC 285 μg/mL and 326 μg/mL, respectively). Kalanchoe pinnata, Ampelocissus tomentosa, and Paris polyphylla were active against chikungunya virus, and Clerodendrum serratum was active against yellow fever virus (EC50 15.9 μg/mL); Terminalia chebula was active against enterovirus (EC50 10.6 μg/mL). Ampelocissus tomentosa, Boenninghausenia albiflora, Dichrocephala integrifolia, and Kalanchoe pinnata significantly reduced C. elegans motility, comparable to levamisole. Conclusions. In countries like Nepal, with a high burden of infectious and parasitic diseases, and a current health system unable to combat the burden of diseases, evaluation of local plants as a treatment or potential source of drugs can help expand treatment options. Screening plants against a broad range of pathogens (bacteria, viruses, fungi, and parasites) will support bioprospecting in Nepal, which may eventually lead to new drug development. [ABSTRACT FROM AUTHOR]

Thymic immunosuppressive pentapeptide (TIPP) is a novel pentapeptide originally obtained from calf thymic immunosuppressive extract. In this study we aimed to investigate the anti-inflammatory effect and mechanisms of TIPP in vivo with an ovalbumin-induced mouse allergic asthma model. We investigated the effects of TIPP on the infiltration of inflammation cells, immune cell subtypes, Th2 cytokines in BALF and IgE in serum, mRNA levels of IL-4, IL-10, TNF-α and eotaxin-1, expression of MCP-1, VCAM-1 and COX-2, and activation of MAP kinases and NF-κB. Our results showed that TIPP significantly inhibited the increase in Th2 cytokines and OVA-specific IgE production, mRNA levels of IL-4, TNF-α and eotaxin-1 and the expression of MCP-1, VCAM-1 and COX-2 in lung tissues, as well effectively resisting the balance changes of cells in BALF. In addition, it was found that the administration of TIPP attenuated the activation of MAP kinases and NF-κB in the lung tissues of the allergic mice. Our data suggest that TIPP effectively suppresses the allergic and inflammatory responses in allergic mice via blocking MAP kinases/NF-κB signalling pathway. The investigation indicated that TIPP may become an anti-allergic and anti-inflammatory drug. [ABSTRACT FROM AUTHOR]