Putting PLX5622 into perspective:microglia in central nervous system viral infection

Elucidating the exact contribution of microglia to central nervous system(CNS)pathology has historically been extremely challenging.These resident parenchymal myeloid cells are considered to have critical roles as frontline responders during pathogen invasion and CNS perturbation.Thus,understanding the precise temporal kinetics of microglial function is central to the evolution of novel therapeutics for disease intervention and/or resolution(Spiteri et al.,2022a).The development of PLX5622,a colony-stimulating factor 1 receptor(CSF-1R)inhibitor typically formulated into a rodent chow for simple oral administration has facilitated exploration of microglial functions in disease(Spangenberg et al.,2019).

Long COVID: A Molecular, Cellular and Histopathology Overview

Long COVID has been studied as different sequelae that some individuals can develop after the acute phase of the disease. Persistent symptoms such as dry cough, fatigue, and dyspnea can remain after six months of COVID-19 cure. Others such as lung fibrosis, kidney injury, and thrombotic risk also are observed. Here, a deep review of each human organ and system infected by the virus was performed aiming to show how molecules expression and cell signaling can induce the organism cure or injuries and, subsequently sequelae. The review also suggests the importance of public health surveillance for these cases including a more comprehensive analysis of molecular biology tools that can clarify and assist in the prognosis, treatment, and preventive methods for potentially more serious disorders in post-COVID-19 patients.

Helicobacter pylori in dental plaque and stomach of patients from Northern Brazil

AIM: To establish whether virulence factor genes vacA and cagA are present in Helicobacter pylori (H. pylori) retrieved from gastric mucosa and dental plaque in pa-tients with dyspepsia. METHODS: Cumulative dental plaque specimens and gastric biopsies were submitted to histological exami-nation, rapid urease test and polymerase chain reac-tion (PCR) assays to detect the presence of cagA and vacA polymorphisms.RESULTS: Detection of H. pylori from dental plaque and gastric biopsy samples was greater by PCR com-pared to histological examination and the rapid ure-ase test. DNA from H. pylori was detected in 96% of gastric mucosa samples and in 72% of dental plaque samples. Sixty-three (89%) of 71 dental plaque sam-ples that were H. pylori-positive also exhibited identical vacA and cagA genotypes in gastric mucosa. The most common genotype was vacAs1bm1 and cagA positive, either in dental plaque or gastric mucosa. These viru-lent H. pylori isolates were involved in the severity of clinical outcome.CONCLUSION: These pathogenic strains were found simultaneously in dental plaque and gastric mucosa, which suggests that gastric infection is correlated with the presence of H. pylori in the mouth.

Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells

In the last years,several studies have been focused on elucidate the role of tumor microenvironment(TME)in cancer development and progression.Within TME,cells from adaptive and innate immune system are one of the main abundant components.The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth.This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer,such as hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA).Liver is well-known to be an important immunological organ with unique microenvironment.Here,in normal conditions,the rich immune-infiltrating cells cooperate with non-parenchymal cells,such as liver sinusoidal endothelial cells and Kupffer cells,favoring self-tolerance against gut antigens.The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells,in order to understand how this cross-talk promotes tumor growth.Deeper attention is,in fact,focused on immune-based therapy for these tumors,as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment.In this review,we will examine the key pathways underlying TME cell-cell communications,with deeper focus on the role of natural killer cells in primary liver tumors,such as HCC and iCCA,as new opportunities for immune-based therapeutic strategies.

Qualitative and Quantitative Studies of Polygene Proteins Expression in Esophageal Precancerous Lesions and Esophageal Carcinoma

Objective： To examine the expressions of MDM2, P53 and P27 proteins in chronic esophagitis, para-cancer mucosa and esophageal carcinoma. Methods： Immunohistochemistry was used to detect the expressions of MDM2, P53 and P27 proteins in forty-seven patients suffering from chronic esophagitis and eighty-five cases of esophageal carcinoma and corresponding para-cancer mucosa. Flow cytometry（（FCM） was applied to detect the quantities of these proteins expressed in fresh tissues of 48 cases of esophageal cancer and their para-cancer tissues and 24 cases of relative normal mucosa at the surface of cutting edge. Results： Immunohistochemistry results showed that the expressions of the three studied proteins were very similar in the epithelia of chronic esophagitis and para-cancer mucosa （P〉0.05）. Both the qualitative and quantitative studies displayed that the P53 protein had no expression and its accumulations would appear only in the early stages of esophagus canceration while the MDM2 and P27 proteins had different degrees of expressions in cases of normal esophageal mucosa. MDM2 protein markedly increased in the advanced stages of esophageal canceration. A quantitative study showed that the expression of P27 protein had a linearity of decreasing tendency （F=9.132, P=0.002） in the course of esophageal canceration. Conclusion： Chronic esophagitis may be a precancerous lesion. Owing to the changes of the P53 and P27 proteins, we can also conclude that these occur in the early stages of esophagus oncogenesis, however the changes of MDM2 expression may occur in the advanced stage of esophageal canceration.

食管原发性恶性纤维组织细胞瘤：3例报告及文献复习(英文)

We reported three cases of polypoid tumor of the esophagus, among them one case of sarcomatous tumor partly covered with superficial squamous cell carcinoma. The sarcoma was consisted of anaplastic spindle and pleomorphic tumor cells, which was similar to malignant fibrous histiocytoma (MFH) of the soft tissue. Diagnosis of the surgery resected speci-men was confirmed by histological, immunohistochemical and electron microscopic methods. Both diagnostic and differential diagnostic problems of primary MFH of the esophagus and world medical literatures were discussed.

Glial derived neurotrophic factor: a sufficient essential molecular regulator of mammalian blood-nerve barrier tight junction formation

Peripheral nerves coordinate signal transduction from the periphery to the central nervous system for processing and transmission back as required for normal mammalian function.Peripheral nerves and nerve roots are structurally divided into three compartments:the outermost epineurium,inner perineurium that surrounds nerve fascicles and the innermost endoneurium(Mizisin and Weerasuriya,2011).

用多聚酶链反应和免疫组织化学方法评估HHV-8/KSHV在卡波济肉瘤发生中的作用

The human γ-herpes virus- 8 (HHV-8) was first described in AIDS- related Kaposi’ s sarcoma (KS) tumour samples. In this study, we report comparative studies on paraffin-embedded biopsies of AIDS-related KS (AKS) and endemic KS (EKS)with regard to HHV-8 content as evaluated using polymerase chain reaction (PCR) and immunohistochemistry. DNA was extracted either using Chelex-100 or using Qia- gene kit and was evaluated with the help of a semiquantitative PCR assay. The PCR detection of HHV- 8 was more sensitive to the Chelex method than to Qia- gene. The threshold for PCR test sensitivity with the help of serial dilution of DNA was at the level of five plasmid ORF-26 regions, and DNA from 25 body cavity-based lymphoma- 1 cells. The results expressed as virus load/actin unit showed progressively higher HHV-8 levels in late (nodular) cases, compared to those in early (patch/plaque)stages. Evaluation of HHV- 8 DNA levels in tumour tissues, thus, indicates a correlation between virus load and KS stage. Double immunostaining of spindle cells(SC)inKSbiopsiesfor CD34 and HHV-8/latency- associated nuclear antigen (LANA)showed an increase in double- positive SC in the lesions of nodular AKS and EKS cases, compared to that in plaque and- patch stages. However, 10- 15% of CD34+ /LANA SC cells were observed during the development from patch to nodular casesofAKSand EKS.Our results indicate that PCR analysis is a simple and sensitive diagnostic method for HHV-8 evaluation in KS tissues, processed for conventional histopathology.

Apoptosis and Proinflammatory Cytokine Responses of Primary Mouse Microglia and Astrocytes Induced by Human H1N1 and Avian H5N1 Influenza Viruses

Patients with an influenza virus infection can be complicated by acute encephalopathy and encephalitis. To investigate the immune reactions involved in the neurocomplication, mouse microglia and astrocytes were isolated, infected with human H1N1 and avian H5N1 influenza viruses, and examined for their immune responses. We observed homogeneously distributed viral receptors, sialic acid （SA）-a2,3-Galactose （Gal） and SA-a2,6-Gal, on microglia and astrocytes. Both viruses were replicative and productive in microglia and astrocytes. Virus-induced apoptosis and cytopathy in infected cells were observed at 24 h post-infection （p.i.）. Expression of IL-1β, IL-6 and TNF-a mRNA examined at 6 h and 24 h p.i. was up-regulated, and their expression levels were considerably higher in H5N1 infection. The amounts of secreted proinflammatory IL-1β, IL-6 and TNF-a at 6 h and 24 h p.i. were also induced, with greater induction by H5N1 infection. This study is the first demonstration that both human H1N1 and avian H5N1 influenza viruses can infect mouse microglia and astrocytes and induce apoptosis, cytopathy, and proinflammatory cytokine production in them in vitro. Our results suggest that the direct cellular damage and the consequences of immunopathological injury in the CNS contribute to the influenza viral pathogenesis. Cellular ＆ Molecular Immunology.

Effects of NS1 variants of H5N1 influenza virus on interferon induction, TNFa response and p53 activity

Non-structural protein 1(NS1)is an important virulence factor of the highly pathogenic H5N1 avian influenza virus.A five-amino-acid(5 aa)deletion at position 80–84 and an aspartic acid to glutamic acid substitution at position 92(D92E)are two major NS1 mutations that are highly correlated with enhanced virulence.To investigate the effect of these mutations in H5N1 virulence,three H5N1-NS1 variants were constructed:NS51(lacking 5 aa at position 80–84),NS51(I)(carrying a 5-aa insertion at position 80–84)and NS51(IM)(carrying both the 5-aa insertion and the D92E mutation).We examined the effects of these mutations on interferon(IFN)induction,tumor-necrosis factor(TNF)a response,p53 activity and apoptosis.We found that the D92E mutation eliminated NS1’s repressive effect on IFN induction,while the 5-aa deletion resulted in enhanced resistance to TNFa responses.We also observed that all three variants exhibited a similar suppressive effect on p53 transcriptional activity,although none of them significantly influenced apoptosis of host cells.Our findings shed new light on the role of NS1 in the pathogenicity of H5N1 virus.

An overview of the marine natural products in clinical trials and on the market

The first marine natural products that served as leads or scaffolds for medicines were discovered in the middle of last century:the arabinosyl glycosides from the marine sponge Tectitethya crypta.Synthesis and modifications of the natural molecules generated antiviral and antileukemic drugs developed in the 1970’s and in the following decades,including the first effective treatment against HIV infection.With the improvement of techniques for the elucidation of chemical structure of the molecules,as well as chemical synthesis,especially from the 1990’s,there was an increase in the number of bioactive natural products characterized from marine organisms.New chemical structures with high specificity towards molecular targets in cells allowed the development of new drugs with indication for the treatment of several illnesses,from cancer to new antibiotics,and even neurological disorders.Currently there are at least 13 molecules derived from marine natural products on advanced clinical trials,and nine were approved to be used as medicines.Considering that in the past eight years,more than 1000 new compounds from marine organisms were described,per year,the expectation is that many more drugs will be derived from marine natural products in a near future.

Heterologous interactions between NS1 proteins from different influenza A virus subtypes/strains

Non-structural protein 1(NS1) of the influenza virus plays a crucial role in modulating the host immune response and facilitating virus replication.The formation of a homodimer or an oligomer is necessary for NS1 to exert its function efficiently.In the present study,the NS1 protein from the A/Shantou/602/06(H3N2) virus(herein abbreviated as NS32) was found to interact with NS1 from A/Shantou/169/06(H1N1),A/Chicken/Guangdong/1/05(H5N1) and A/Quail/Hong Kong/G1/97(H9N2)(abbreviated as NS11,NS51 and NS92,respectively) viruses,although NS32 shares 17.4% 20.9% sequence diversity with NS11,NS51 and NS92.This indicates that the heterologous interactions between NS1 proteins from different influenza A virus subtypes/strains may be a common event during co-infection.