Argonaute protein as a linker to command center of physiological processes

MicroRNAs （miRNAs） post-transcriptionally regulate gene expression by binding to target mRNAs with perfect or imperfect complementarity, recruiting an Argonaute （AGO） protein complex that usually results in degradation or translational repression of the target mRNA. AGO proteins function as the Slicer enzyme in miRNA and small interfering RNA （siRNA） pathways involved in human physiological and pathophysiological processes, such as antiviral responses and disease formation. Although the past decade has witnessed rapid advancement in studies of AGO protein functions, to further elucidate the molecular mechanism of AGO proteins in cellular function and biochemical process is really a challenging area for researchers. In order to understand the molecular causes underlying the pathological processes, we mainly focus on five fundamental problems of AGO proteins, including evolution, functional domain, subcellular location, post-translational modification and protein-protein interactions. Our discussion highlight their roles in early diagnosis, disease prevention, drug target identification, drug response, etc.

Sodium alginate and naloxone loaded macrophage-derived nanovesicles for the treatment of spinal cord injury

Spinal cord injury(SCI)causes Ca^(2+) overload,which can lead to inflammation and neuronal apoptosis.In this study,we prepared a nanovesicle derived from macrophage membrane(MVs),which encapsulated sodium alginate(SA)and naloxone(NAL)to inhibit inflammation and protect neurons by reducing the free Ca^(2+) concentration at the SCI site.Based on the transmission electron microscopy(TEM)image,the encapsulated sample(NAL–SA–MVs)had a particle size of approximately 134±11 nm and exhibited a sustained release effect.The encapsulation rate of NAL and SA was 82.07%±3.27%and 72.13%±2.61%in NAL–SA–MVs,respectively.Targeting tests showed that the NAL–SA–MVs could accumulate in large quantities and enhance the concentration of SA and NAL at the lesion sites.In vivo and in vitro studies indicated that the NAL–SA–MVs could decrease the concentration of free Ca^(2+),which should further alleviate the inflammatory response and neuronal apoptosis.Anti-inflammation results demonstrated that the NAL–SA–MVs could reduce the pro-inflammation factors(iNOS,TNF-α,IL-1β,IL-6)and increase the expression of antiinflammation factors(IL-10)at the cell and animal level.Concurrently,fluorescence,flow cytometry and western blot characterization showed that the apoptotic condition of the neurons was significantly inhibited.In addition,the motor function of C57 mice were significantly improved after NAL–SA–MVs treatment.In conclusion,it is suggested that the NAL–SA–MVs has tremendous potential in the treatment of SCI.

Wenjing Zhitong recipe exhibits potential anti-primary dysmenorrhea properties by inhibiting COX2 and PKC signaling pathway in rats induced by estradiol benzoate and oxytocin

Objective:To explore the effect and mechanism of action of the Wenjing Zhitong recipe(WZR)in primary dysmenorrhea(PD)treatment.Methods:Uterine contractions were induced by estradiol benzoate and oxytocin in a PD model and WZR was administrated.The rate of change in uterine contractility and the writhing test were used to evaluate the effects of WZR.The serum levels of prostaglandin F_(2a)(PGF_(2a))and prostaglandin E_2(PGE_2),and the activity of cyclooxygenase-2(COX2)were detected by enzyme-linked immunosorbent assay(ELISA).The changes in phosphor-phospholipase C(pPLC/PLC),phosphor-protein kinase C(pPKC/PKC),and connexin 43(CX43)expression were detected using immunohistochemistry and western blot.Results:WZR significantly reduced the rate of change in uterine contractility and writhing times in the PD model.WZR treatment inhibited the enzymatic activity of COX2 and reduced the levels of PGF_(2a),PGF_(2a)/PGE2and COX2 in the PD model.WZR also significantly reduced the expression of pPLC/PLC,pPKC/PKC and CX43.Targeting the inhibition of COX2 activity,caffeic acid and 1-acetyl-β-carboline were validated as the active ingredients in WZR responsible for reducing uterine contractions.Conclusion:WZR attenuated PD by inhibiting COX2 activity,downregulating PGF_(2a)/PGE_2 expression,and inhibiting the PKC signaling pathway.

Dynamic observation of the progression of chronic gastritis to gastric cancer in a diseasee-TCM pattern rat model

Objective:To dynamically observe the progression of chronic gastritis to gastric cancer(GC)in diseasetraditional Chinese medicine(TCM)pattern rats to provide data for understanding the disease progression and effective approaches for drug screening and mechanism exploration.Methods:Wistar rats were randomly divided into control(n=96,half female and half male)and model(n=336,half female and half male)groups.Model rats received free access to N-methyl-N0-nitro-Nnitrosoguanidine(120 mg/mL),sodium deoxycholate(20 mmol/L),and alcohol(45%),and were subjected to intermittent fasting.Mortality rate,body weight,water consumption,food intake,gastric pathology,blood content analysis,and liver and kidney function of model rats were dynamically monitored over 30 weeks.In the 30th week,pattern characteristics were assessed.Gastric pathology and pattern characteristics were observed for an additional 8 weeks to evaluate stability.Results:The overall mortality of the model group was 34.82%(33.10%for females and 36.55%for males)at 30 weeks post-intervention.Inflammatory cell infiltration,glandular atrophy,atypical hyperplasia,and GC manifested successively in the gastric mucosa of rats.In model rats,N-methyl-N0-nitro-N-nitrosoguanidine intake was lower in males than in females,whereas pathological changes in the gastric mucosa occurred earlier in females than in males.Notably,gastric mucosal lesions were more severe in males than in females.Our modeling methods maintained stable gastric mucosal lesions for at least 8 weeks after final intervention.The pattern characteristics observed in model rats at the 30th and 38th week were consistent with those of spleen deficiency,blood stasis,and yin deficiency pattern.Blood content and indexes of liver and kidney function in the model group were normal.Conclusion:Our findings provide evidence for the pathological stages underscoring the progression of chronic gastritis to GC in disease-TCM pattern rats,which may facilitate development of relevant pharmacotherapies.