查看更多>>摘要：Herpes simplex virus type 1 (HSV-1),a neurotropic herpes virus,is able to establish a lifelong latent infection in the human host.Following primary replication in mucosal epithelial cells,the virus can enter sensory neurons innervating peripheral tissues via nerve termini.The viral genome is then transported to the nucleus where it can be maintained without producing infectious progeny,and thus latency is established in the cell.Yin-Yang balance is an essential concept in traditional Chinese medicine (TCM) theory.Yin represents stable and inhibitory factors,and Yang represents the active and aggressive factors.When the organism is exposed to stress,especially psychological stress caused by emotional stimulation,the Yin-Yang balance is disturbed and the virus can re-engage in productive replication,resulting in recurrent diseases.Therefore,a better understanding of the stress-induced susceptibility to HSV-1 primary infection and reactivation is needed and will provide helpful insights into the effective control and treatment of HSV-1.Here we reviewed the recent advances in the studies of HSV-1 susceptibility,latency and reactivation.We included mechanisms involved in primary infection and the regulation of latency and described how stress-induced changes increase the susceptibility to primary and recurrent infections.
Puvanesswaray RamakrishnanWei Mee LohSubash C.B.GopinathSrinivasa Reddy Bonam...
399-413页
查看更多>>摘要：Activated pancreatic stellate cells (PSCs) have been widely accepted as a key precursor of excessive pancreatic fibrosis,which is a crucial hallmark of chronic pancreatitis (CP) and its formidable associated disease,pancreatic cancer (PC).Hence,anti-fibrotic therapy has been identified as a novel therapeutic strategy for treating CP and PC by targeting PSCs.Most of the anti-fibrotic agents have been limited to phase Ⅰ/Ⅱ clinical trials involving vitamin analogs,which are abundant in medicinal plants and have proved to be promising for clinical application.The use of phytomedicines,as new anti-fibrotic agents,has been applied to a variety of complementary and alternative approaches.The aim of this review was to present a focused update on the selective new potential anti-fibrotic agents,including curcumin,resveratrol,rhein,emodin,green tea catechin derivatives,metformin,eruberin A,and ellagic acid,in combating PSC in CP and PC models.It aimed to describe the mechanism(s) of the phytochemicals used,either alone or in combination,and the associated molecular targets.Most of them were tested in PC models with similar mechanism of actions,and curcumin was tested intensively.Future research may explore the issues of bioavailability,drug design,and nano-formulation,in order to achieve successful clinical outcomes with promising activity and tolerability.
查看更多>>摘要：The T cell co-stimulatory molecule OX40 and its cognate ligand OX40L have attracted broad research interest as a therapeutic target in T cell-mediated diseases.Accumulating preclinical evidencehighlights the therapeutic efficacy of both agonist and blockade of the OX40-OX40L interaction.Despite this progress,many questions about the immuno-modulator roles of OX40 on T cell function remain unanswered.In this review we summarize the impact of the OX40-OX40L interaction on T cell subsets,including Thl,Th2,Th9,Th17,Th22,Treg,Tfh,and CD8+ T cells,to gain a comprehensive understanding of anti-OX40 mAb-based therapies.The potential therapeutic application of the OX40 -OX40L interaction in autoimmunity diseases and cancer immunotherapy are further discussed;OX40 -OX40L blockade may ameliorate autoantigen-specific T cell responses and reduce immune activity in autoimmunity diseases.We also explore the rationale of targeting OX40-OX40L interactions in cancer immunotherapy.Ligation of OX40 with targeted agonist anti-OX40 mAbs conveys activating signals to T cells.When combined with other therapeutic treatments,such as anti-PD-1 or anti-CTLA-4 blockade,cytokines,chemotherapy,or radiotherapy,the anti-tumor activity of agonist anti-OX40 treatment will be further enhanced.These data collectively suggest great potential for OX40-mediated therapies.
查看更多>>摘要：Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis.Here we demonstrated that post-ischemic treatment with ciclopirox olamine (CPX),a potent antifungal clinical drug,alleviated brain infarction,neurological deficits and brain edema in a classic rat model of ischemic stroke.Single dose post-ischemic administration of CPX provided a long-lasting neuroprotective effect,which can be further enhanced by multiple doses administration of CPX.CPX also effectively reversed ischemia-induced neuronal loss,glial activation as well as blood-brain barrier (BBB) damage.Employing quantitative phosphoproteomic analysis,130 phosphosites in 122 proteins were identified to be significantly regulated by CPX treatment in oxygen glucose deprivation (OGD)-exposed SH-SY5Y cells,which revealed that phosphokinases and cell cycle-related phosphoproteins were largely influenced.Subsequently,we demonstrated that CPX markedly enhanced the AKT (protein kinase B,PKB/AKT) and GSK3β (glycogen synthase kinase 3β) phosphorylation in OGD-exposed SH-SY5Y cells,and regulated the cell cycle progression and nitric oxide (NO) release in lipopolysaccharide (LPS)-induced BV-2 cells,which may contribute to its ameliorative effects against ischemia-associated neuronal death and microglial inflammation.Our study suggests that CPX could be a promising compound to reduce multiple ischemic injuries;however,further studies will be needed to clarify the molecular mechanisms involved.
查看更多>>摘要：Ulcerative colitis (UC) manifests as an etiologically complicated and relapsing gastrointestinal disease.The enteric nervous system (ENS) plays a pivotal role in rectifying and orchestrating the inflammatory responses in gut tract.Berberine,an isoquinoline alkaloid,is known as its antiinflammatory and therapeutic effects in experimental colitis.However,little research focused on its regulatory function on ENS.Therefore,we set out to explore the pathological role of neurogenic inflammation in UC and the modulating effects of berberine on neuro-immune interactions.Functional defects of enteric glial cells (EGCs),with decreased glial fibrillary acidic protein (GFAP) and increased substance P expression,were observed in DSS-induced murine UC.Administration of berberine can obviously ameliorate the disease severity and restore the mucosal barrier homeostasis of UC,closely accompanying by maintaining the residence of EGCs and attenuating inflammatory infiltrations and immune cells overactivation.In vitro,berberine showed direct protective effects on monoculture of EGCs,bone marrowderived dendritic cells (BMDCs),T cells,and intestinal epithelial cells (IECs) in the simulated inflammatory conditions.Furthermore,berberine could modulate gut EGCs-IECs-immune cell interactions in the co-culture systems.In summary,our study indicated the EGCs-IECs-immune cell interactions might function as a crucial paradigm in mucosal inflammation and provided an infusive mechanism of berberine in regulating enteric neurogenic inflammation.
查看更多>>摘要：Bone diseases such as osteoporosis and periodontitis are induced by excessive osteoclastic activity,which is closely associated with inflammation.Benzydamine (BA) has been used as a cytokine-suppressive or non-steroidal anti-inflammatory drug that inhibits the production of proinflammatory cytokines or prostaglandins.However,its role in osteoclast differentiation and function remains unknown.Here,we explored the role of BA in regulating osteoclast differentiation and elucidated the underlying mechanism.BA inhibited osteoclast differentiation and strongly suppressed interleukin-1β (IL-1β) production.BA inhibited osteoclast formation and bone resorption when added to bone marrowderived macrophages and differentiated osteoclasts,and the inhibitory effect was reversed by IL-1β treatment.The reporter assay and the inhibitor study of IL-1β transcription suggested that BA inhibited nuclear factor-κB and activator protein-1 by regulating IκB kinase,extracellular signal regulated kinase and P38,resulting in the down-regulation of IL-1β expression.BA also promoted osteoblast differentiation.Furthermore,BA protected lipopolysaccharide-and ovariectomy-induced bone loss in mice,suggesting therapeutic potential against inflammation-induced bone diseases and postmenopausal osteoporosis.
查看更多>>摘要：ProBiotic-4 is a probiotic preparation composed of Bifidobacterium lactis,Lactobacillus casei,Bifidobacterium bifidum,and Lactobacillus acidophilus.This study aims to investigate the effects of ProBiotic-4 on the microbiota-gut-brain axis and cognitive deficits,and to explore the underlying molecular mechanism using senescence-accelerated mouse prone 8 (SAMP8) mice.ProBiotic-4 was orally administered to 9-month-old SAMP8 mice for 12 weeks.We observed that ProBiotic-4 significantly improved the memory deficits,cerebral neuronal and synaptic injuries,glial activation,and microbiota composition in the feces and brains of aged SAMP8 mice.ProBiotic-4 substantially attenuated aging-related disruption of the intestinal barrier and blood-brain barrier,decreased interleukin-6 and tumor necrosis factor-α at both mRNA and protein levels,reduced plasma and cerebral lipopolysaccharide (LPS) concentration,toll-like receptor 4 (TLR4) expression,and nuclear factor-κB (NF-κB) nuclear translocation in the brain.In addition,not only did ProBiotic-4 significantly decreased the levels of γ-H2AX,8-hydroxydesoxyguanosine,and retinoic-acid-inducible gene-Ⅰ (RIG-Ⅰ),it also abrogated RIG-Ⅰ multimerization in the brain.These findings suggest that targeting gut microbiota with probiotics may have a therapeutic potential for the deficits of the microbiota-gut-brain axis and cognitive function in aging,and that its mechanism is associated with inhibition of both TLR4-and RIG-Ⅰ-mediated NF-κB signaling pathway and inflammatory responses.
查看更多>>摘要：Angiogenesis is an essential process in tumor growth,invasion and metastasis.VEGF receptor 2 (VEGFR2) inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment.However,most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration.Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view.Here we report the discovery and characterization of a novel VEGFR2 inhibitor (CHMFL-VEGFR2-002),which exhibited high selectivity among structurally closed kinases including PDGFRs,FGFRs,CSF1R,etc.CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay (IC50 =66 nmol/L) and VEGFR2 autophosphorylation in cells (EC50s ～ 100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI50 =150 nmol/L).In addition,CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy in vitro and exhibited good in vivo PK (pharmacokinetics) profile with bioavailability over 49％ and antiangiogenesis efficacy in both zebrafish and mouse models without apparent toxicity.These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.
查看更多>>摘要：Ricin is a highly toxic type 2 ribosome-inactivating protein (RIP) which is extracted from the seeds of castor beans.Ricin is considered a potential bioterror agent and no effective antidote for ricin exists so far.In this study,by structural modification of a retrograde transport blocker Retro-2cycl,a series of novel compounds were obtained.The primary screen revealed that compound 27 has an improved anti-ricin activity compare to positive control.In vitro pre-exposure evaluation in Madin-Darby Canine Kidney (MDCK) cells demonstrated that 27 is a powerful anti-ricin compound with an ECs0 of 41.05 nmol/L against one LC (lethal concentration,5.56 ng/mL) of ricin.Further studies surprisingly indicated that 27 confers post-exposure activity against ricin intoxication.An in vivo study showed that 1 h post-exposure administration of 27 can improve the survival rate as well as delay the death of ricin-intoxicated mice.A drug combination of 27 with monoclonal antibody mAb4C13 rescued mice from one LD (lethal dose) ricin challenge and the survival rate of tested animals is 100％.These results represent,for the first time,indication that small molecule retrograde transport blocker confers both in vitro and in vivo post-exposure protection against ricin and therefore provides a promising candidate for the development of anti-ricin medicines.
查看更多>>摘要：A series of 2-(((5-akly/aryl-lH-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3H)-ones were synthesized and their anti-HIV-1 activities were evaluated.Most of these compounds were highly active against wild-type (WT) HIV-1 strain (IIIB) with ECso values in the range of 0.0038-0.4759 μmol/L.Among those compounds,Ⅰ-11 had an EC50 value of 3.8 nmol/L and SI (selectivity index) of up to 25,468 indicating excellent activity against WT HIV-1.In vitro anti-HIV-1 activity and resistance profile studies suggested that compounds Ⅰ-11 and Ⅰ-12 displayed potential anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 4.3 to 63.6 nmol/L and 18.9-219.3 nmol/L,respectively).On the other hand,it was observed that those two compounds were less effective with EC50 values of 2.77 and 4.87 μmol/L for HIV-1A17 (K103N + Y181C).The activity against reverse transcriptase (RT) was also evaluated for those compounds.Both Ⅰ-11 and Ⅰ-12 obtained sub-micromolar IC5o values showing their potential in RT inhibition.The pharmacokinetics examination in rats indicated that compound Ⅰ-11 has acceptable pharmacokinetic properties and bioavailability.Preliminary structure-activity relationships and molecular modeling studies were also discussed.
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