PEI, a new transfection method, augments the inhibitory effect of RBM5 on prostate cancer.

PEI is a cationic polymer, serving as a non-viral transfection carrier grounded in nanotechnology that enhances transfection efficiency via the proton sponge effect. RBM5 is an RNA-binding protein that can inhibit tumor development. This study involved the transfection of RBM5 in prostate cancer cells with PEI, Lipo2000, and their combination. Transwell and wound healing assays were used to observe invasion and migration of prostate cancer cells and flow cytometry was used to observe the apoptosis. Detect the expression of invasion and migration-related protein MMP9 through western blotting experiment. An activity detection kit was used to detect the activity of apoptotic protein caspase-3. We found that there was no significant difference in transfection efficiency when PEI and Lipo2000 were used alone but it significantly improved when they are combined. RBM5 reduced invasion, migration, and proliferation of prostate cancer and enhanced apoptosis. MMP9 expression was reduced, and the activity of caspase-3 was increased. PEI transfection could improve the inhibition of RBM5 on tumors more than Lipo2000. The inhibitory effect is more obvious when the two are used together. RBM5 transfected with PEI can amplify its inhibitory effect on prostate cancer, and this effect is more evident when combined with Lipo2000.

Assessment of Quinidine-Induced Torsades de Pointes Risks Using a Whole-Body Physiologically Based Pharmacokinetic Model Linked to Cardiac Ionic Current Inhibition.

The lethality of torsades de pointes (TdP) by drugs is one of main reasons that some drugs were withdrawn from the market. In order to assess drug-induced TdP risks, a model of cardiac ionic current suppression in human ventricular myocytes (ToR-ORd model), combined with the maximum effective free therapeutic plasma concentration or the maximum effective free therapeutic myocyte concentration was often used, with the latter proved to be more relevant and more accurate. We aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model, incorporated with a human cardiomyocyte pharmacodynamic (PD) model, to provide a comprehensive assessment of drug-induced TdP risks in normal and specific scenarios. Quinidine served as an example to validate the PBPK-PD model via predicting plasma quinidine concentrations and quinidine-induced changes in QT interval (ΔQTc). The predicted plasma quinidine concentrations and ΔQTc values following oral administration or intravenous administration of quinidine were comparable to clinic observations. Visual predictive checks showed that most of the observed plasma concentrations and ΔQTc values fell within the 5th and 95th percentiles of simulations. The validated PBPK-PD model was further applied to assess the TdP risks using frequencies of early afterdepolarization and long-QT syndrome occurrence in 4 scenarios, such as therapeutic dose, supra-therapeutic dose, alkalosis, and hyperkalemia in 200 human subjects. In conclusion, the developed PBPK-PD model may be applied to predict the quinidine pharmacokinetics and quinidine-induced TdP risks in healthy subjects, but also simulate quinidine-induced TdP risks under disease conditions, such as hypokalemia and alkalosis.

What is the role of CHCHD2 in adrenal tumourigenesis?

PURPOSE: CHCHD2 is an antiapoptotic mitochondrial protein acting through the BCL2/BAX pathway in various cancers. However, data on the regulatory role of CHCHD2 in adrenal tumourigenesis are scarce. METHODS: We studied the expression of CHCHD2, BCL2, and BAX in human adrenocortical tissues and SW13 cells. mRNA and protein levels were analyzed through qPCR and immunoblotting, respectively, in 16 benign adrenocortical neoplasms (BANs), along with their adjacent normal adrenal tissues (controls), and 10 adrenocortical carcinomas (ACCs). BCL2/BAX mRNA expression was also analyzed in SW13 cells after CHCHD2 silencing. MTS, flow cytometry and scratch assays were performed to assess cell viability, apoptosis, and invasion, respectively. RESULTS: BCL2 and CHCHCD2 mRNA and protein expression was increased in BANs compared to normal adrenal tissues whereas BAX was decreased. BAX and CHCHD2 mRNA and protein levels were significantly downregulated and upregulated, respectively, in ACCs compared with either BANs or controls. Expression of the studied genes was not different among cortisol-secreting and nonfunctional ACAs. No significant association was found between genes' expression and other established prognostic markers of ACCs patients. In vitro analysis showed that CHCHD2 silencing resulted in reduced cell viability and invasion as well as increased SW13 cells apoptosis. CONCLUSIONS: CHCHD2 expression seems to be implicated in adrenal tumourigenesis and its absence resulted to increased apoptosis in vitro. However, the exact mechanism of action and particularly its association with the BAX/BCL2 pathway needs to be further studied and evaluate whether it could be a protentional therapeutic target.

Increased ventricular ectopy precedes Torsades de Pointes in patients with prolonged QT.

OBJECTIVE: Torsades de Pointes (TdP) is a potentially lethal ventricular tachydysrhythmia. Prolonged heartrate corrected QT interval (QTc) predicts TdP; however, with poor specificity. We performed this study to identify other predictors of TdP among patients with prolonged QTc. METHODS: We performed a retrospective case control study with 2:1 matching at an urban academic hospital. We searched our hospital electrocardiogram (ECG) database for tracings with heartrate ≤ 60, QTc ≥ 500, and QRS < 120, followed by a natural language search for electronic records with "Torsades," "polymorphic VT," or similar to identify TdP cases from 2005 to 19. We identified controls from a similar ECG database search matching for QTc, heartrate, age, and sex. We compared cardiologic and historical factors, medications, laboratory values, and ECG measurements including ectopy using univariate statistics. For those cases with saved telemetry strips that included preceding beats or TdP onset, we compared ectopy and TdP onset characteristics between the ECG and telemetry strips using mixed linear modeling. RESULTS: Seventy-five cases including 50 with telemetry strips and 150 controls were included. Historical, pharmacologic, laboratory, and cardiologic testing results were similar between cases and controls. The proportion of telemetry tracings with premature ventricular contractions (PVC's) preceding TdP was 0.78 compared to 0.16 for case ECG's (difference 0.62(95%CI 0.44-0.75)) and 0.10 for control ECGs (difference 0.68(95%CI 0.56-0.80)). Average telemetry heartrate was 72 and QTc 549 immediately preceding TdP, similar to the ECG values. CONCLUSIONS: Clinical factors don't differentiate patients with long QTc who develop TdP, however, an increase in PVC's in patients with prolonged QTc may usefully predict imminent TdP.

C-L Case Conference: Torsades de Pointes in a Patient With Lifelong Medical Trauma, COVID-19, Remdesivir, Citalopram, Quetiapine, and Hemodialysis.

We present a case of Torsades de Pointes (TdP) in a patient with COVID-19 infection and multiple TdP risk factors including QT-interval prolongation, hemodialysis, bradycardia, and treatment with remdesivir, citalopram, and quetiapine. The case was complicated by post-resuscitation anxiety superimposed on a history of medical trauma since childhood. Top experts in the field of consultation-liaison psychiatry, trauma informed care, and cardiac electrophysiology provide perspectives on this case with a review of the literature. Key teaching topics include identification of TdP risk factors in patients with a complex illness; the necessity for prompt electrophysiology consultation in clinical scenarios with high risk for TdP; and the approach to patients with medical trauma using a trauma-informed lens. We highlight the contributions of COVID-19, the pharmacokinetics of QT-interval-prolonging psychotropic medications, the risks of hemodialysis, and the role of remdesivir-induced bradycardia in this first reported case of TdP in a patient treated with remdesivir.

PBRM1 presents a potential prognostic marker and therapeutic target in duodenal papillary carcinoma.

BACKGROUND: Due to its rarity, duodenal papillary carcinoma (DPC) is seldom studied as a unique disease and no specific molecular features or treatment guidelines are provided. METHODS: Whole-exome sequencing was performed to gain new insights into the DPC mutation landscape and to identify potential signalling pathways and therapeutic targets. Mechanistically, immunohistochemistry (IHC), immunofluorescence, RNA-seq, ATAC-seq and in vitro cell function experiments were performed to confirm the underlying mechanisms. RESULTS: We described the mutational landscape of DPC for the first time as a group of rare tumours with a high frequency of dysregulation in the chromatin remodelling pathway, particularly PBRM1-inactivating mutations that are significantly higher than duodenal adenocarcinomas and ampullary adenocarcinoma (27% vs. 0% vs. 7%, p < .01). In vitro cell experiments showed that downregulation of PBRM1 expression could significantly promote the cancer progression and epithelial-to-mesenchymal transition via the PBRM1-c-JUN-VIM axis. The IHC data indicated that PBRM1 deficiency (p = .047) and c-JUN expression (p < .001) were significantly associated with poor prognosis. Meanwhile, the downregulation of PBRM1 expression in HUTU-80 cells was sensitive to radiation, which may be due to the suppression of c-JUN by irradiation. CONCLUSIONS: Our findings define a novel molecular subgroup of PBRM1-inactivating mutations in DPC. PBRM1 play an important role in DPC progression and may serve as a potential therapeutic target and prognostic indicator.

Structural, functional analysis and association of MSH6 rs1800932, rs1042821 polymorphisms with clinical outcome in North Indian lung cancer patients treated with platinum-based doublet chemotherapy.

BACKGROUND: In this study, we have done structural and functional analysis of rs1800932 rs1042821 polymorphisms and tried to estimate any association of these polymorphisms with clinical outcomes in north Indian lung cancer patients. METHODS: Genotyping of 500 lung cancer patients was completed utilizing PCR-RFLP (Polymerase chain reaction- Restriction fragment length polymorphism). MedCalc statistical software was used to calculate adjusted and unadjusted odds ratios. Various computational tools like SIFT PROVEAN are used for functional analysis. Structural analysis was completed via MODELLER and CHIMERA. RESULTS: In our study, patients suffering from small cell lung cancer (SCLC) and harboring heterozygous genotype (AG) for MSH6 (rs1800932) polymorphism have reported a significant increase in median survival time (MST) (20.6 vs. 7.6 months, p = 0.03). Furthermore, for MSH6 rs1042821 polymorphism, patients undergoing docetaxel and carbo/cisplatin combination chemotherapeutic regimen and carrying heterogeneous genotype (CT) reported a significant increase in MST (16.6 vs.8.36 months, p = 0.03) and a corresponding decrease in hazard ratio 0.42 (95% CI= 0.18-1.03). Structural and Functional analysis of rs1042821 polymorphism revealed that it is present in the non-coding region of MSH6 protein and is significantly associated with increased overall survival. CONCLUSIONS: These results suggest that MSH6 rs1800932 rs1042821 polymorphisms are involved in increasing the overall survival of lung cancer patients, further confirmed by computational analysis.

Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology.

BACKGROUND: Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat. METHODS: In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next-generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance. RESULTS: Other biologically inspired functional interrogations of EPS cultures using gene knockdown or chemical probes demonstrated only limited to modest efficacy in vitro. However, our molecular studies uncovered distinguishing features (including retained dysfunctional SMARCB1 expression and elevated GLI3, FYN and CXCL12 expression) of distal, paediatric/young adult-associated EPS versus proximal, adult-associated EPS. CONCLUSIONS: Overall results highlight the complexity of the disease and a limited chemical space for therapeutic advancement. However, subtle differences between the two EPS subtypes highlight the biological disparities between younger and older EPS patients and emphasise the need to approach the two subtypes as molecularly and clinically distinct diseases.

PARP inhibitor olaparib enhances the efficacy of radiotherapy on XRCC2-deficient colorectal cancer cells.

The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Loss of XRCC2 compromises DNA damage repairs, and induced DNA damage burdens may increase the reliance on PARP-dependent DNA repairs of cancer cells to render cell susceptibility to PARP inhibitor therapy. Here we tested the hypothesis that XRCC2 loss sensitizes colorectal cancer (CRC) to PARP inhibitor in combination with radiotherapy (RT). We show that high levels of XRCC2 or PARP1 in LARC patients were significantly associated with poor overall survival (OS). Co-expression analyses found that low levels of PARP1 and XRCC2 were associated with better OS. Our in vitro experiments indicated that olaparib+IR led to reduced clonogenic survival, more DNA damage, and longer durations of cell cycle arrest and senescence in XRCC2-deficient cells relative to wild-type cells. Furthermore, our mouse xenograft experiments indicated that RT + olaparib had greater anti-tumor effects and led to long-term remission in mice with XRCC2-deficient tumors. These findings suggest that XRCC2-deficient CRC acquires high sensitivity to PARP inhibition after IR treatment and supports the clinical development for the use of olaparib as a radiosensitizer for treatment of XRCC2-deficient CRC.

A Case Study of Clinical Response to Rucaparib in a Patient with Metastatic Castration-Resistant Prostate Cancer and a RAD51B Alteration.

PARP inhibitors, such as rucaparib, have been well characterized in metastatic castration-resistant prostate cancer (mCRPC) associated with BRCA alterations, and the clinical activity of these agents has also been evaluated in patients with mCRPC associated with alterations in other non-BRCA DNA damage repair (DDR) genes, including RAD51B. There is likely a differential sensitivity to PARP inhibition based on the specific DDR gene altered, but research in this area is limited because of the low frequency of alterations in these genes. Here, we describe a mCRPC patient with a truncating rearrangement of RAD51B who had a radiographic and PSA response when treated with the PARP inhibitor rucaparib within the TRITON2 trial. We investigated the patients' response parameters, circulating tumor DNA (ctDNA) fraction and tumor genomics longitudinally, using next-generation sequencing (NGS) of tissue and plasma. ctDNA fraction correlates with radiographic and PSA response and is lower during times of response. NGS did not reveal any potential genomic mechanism of acquired drug resistance. This case shows evidence for rucaparib activity in a rare patient with mCRPC and a RAD51B truncation.

Pharmacometric and Electrocardiographic Evaluation of Chloroquine and Azithromycin in Healthy Volunteers.

Chloroquine and azithromycin were developed in combination for the preventive treatment of malaria in pregnancy, and more recently were proposed as coronavirus disease 2019 (COVID-19) treatment options. Billions of doses of chloroquine have been administered worldwide over the past 70 years but concerns regarding cardiotoxicity, notably the risk of torsades de pointes (TdP), remain. This investigation aimed to characterize the pharmacokinetics and electrocardiographic effects of chloroquine and azithromycin observed in a large previously conducted healthy volunteer study. Healthy adult volunteers (n = 119) were randomized into 5 arms: placebo, chloroquine alone (600 mg base), or chloroquine with either 500 mg, 1,000 mg, or 1,500 mg of azithromycin all given daily for 3 days. Chloroquine and azithromycin levels, measured using liquid-chromatography tandem mass spectrometry, and electrocardiograph intervals were recorded at frequent intervals. Time-matched changes in the PR, QRS, and heart rate-corrected JT, and QT intervals were calculated and the relationship with plasma concentrations was evaluated using linear and nonlinear mixed-effects modeling. Chloroquine and azithromycin pharmacokinetics were described satisfactorily by two- and three-compartment distribution models, respectively. No drug-drug interaction between chloroquine and azithromycin was observed. Chloroquine resulted in concentration-dependent prolongation of the PR, QRS, JTc and QTc intervals with a minimal additional effect of azithromycin. QRS widening contributed ~ 28% of the observed QT prolongation. Chloroquine causes significant concentration-dependent delays in both ventricular depolarization and repolarization. Co-administration of azithromycin did not significantly increase these effects. The arrhythmogenic risk of TdP associated with chloroquine may have been substantially overestimated in studies which did not separate electrocardiograph QRS and JT prolongation.

Discovery and characterization of potent And-1 inhibitors for cancer treatment.

Acidic nucleoplasmic DNA-binding protein 1 (And-1), an important factor for deoxyribonucleic acid (DNA) replication and repair, is overexpressed in many types of cancer but not in normal tissues. Although multiple independent studies have elucidated And-1 as a promising target gene for cancer therapy, an And-1 inhibitor has yet to be identified. Using an And-1 luciferase reporter assay to screen the Library of Pharmacologically Active Compounds (LOPAC) in a high throughput screening (HTS) platform, and then further screen the compound analog collection, we identified two potent And-1 inhibitors, bazedoxifene acetate (BZA) and an uncharacterized compound [(E)-5-(3,4-dichlorostyryl)benzo[c][1,2]oxaborol-1(3H)-ol] (CH3), which specifically inhibit And-1 by promoting its degradation. Specifically, through direct interaction with And-1 WD40 domain, CH3 interrupts the polymerization of And-1. Depolymerization of And-1 promotes its interaction with E3 ligase Cullin 4B (CUL4B), resulting in its ubiquitination and subsequent degradation. Furthermore, CH3 suppresses the growth of a broad range of cancers. Moreover, And-1 inhibitors re-sensitize platinum-resistant ovarian cancer cells to platinum drugs in vitro and in vivo. Since BZA is an FDA approved drug, we expect a clinical trial of BZA-mediated cancer therapy in the near future. Taken together, our findings suggest that targeting And-1 by its inhibitors is a potential broad-spectrum anti-cancer chemotherapy regimen.

Predictive value of KRAS mutation and excision repair cross-complementing 1 (ERCC1) protein overexpression in patients with colorectal cancer administered FOLFOX regimen.

BACKGROUND: Recent studies have reported that KRAS mutational status is correlated with ERCC1 expression level. The purpose of this study was to determine the clinical significance of the KRAS mutation and ERCC1 overexpression status as predictive factors for resistance against oxaliplatin-based treatment. METHODS: We retrospectively analyzed clinicopathologic features, KRAS mutation status, and ERCC1 overexpression status in 386 patients with colorectal cancer (CRC) who underwent curative-intent surgery. Of these patients, 84 were administered the FOLFOX regimen as a first-line or adjuvant treatment. Disease-free survival and overall survival in groups separated by KRAS and ERCC1 statuses were analyzed. RESULTS: Wild-type KRAS and ERCC1 overexpression were observed in 25.5% of all patients. Among the 84 patients who were treated with the FOLFOX regimen, 73 patients were evaluated for KRAS and ERCC1 status. There were no significant differences in disease-free survival or overall survival in groups separated by KRAS mutation and ERCC1 expression status. Subgroup analysis of patients with wild-type KRAS showed that overall survival in the ERCC1 overexpression group was lower than that of patients in the ERCC1 underexpression group (p = 0.029); however, no significant difference was found in the mutant KRAS patient group (p = 0.671). CONCLUSIONS: Our results suggest that CRC with wild-type KRAS and ERCC1 overexpression might be associated with oxaliplatin resistance. When considering oxaliplatin-based chemotherapy, the status of both KRAS mutation and ERCC1 overexpression should be evaluated.

ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin's lymphoma and testicular cancer cells.

It is of clinical importance to identify biomarkers predicting the efficacy of DNA damaging drugs (genotoxins) so that nonresponders are not unduly exposed to the deleterious effects of otherwise inefficient drugs. Here, we initially focused on the bleomycin genotoxin because of the limited information about the genes implicated in the sensitivity or resistance to this compound. Using a whole-genome CRISPR/Cas9 gene knockout approach, we identified ASH2L, a core component of the H3K4 methyl transferase complex, as a protein required for bleomycin sensitivity in L1236 Hodgkin lymphoma. Knocking down ASH2L in these cells and in the NT2D1 testicular cancer cell line rendered them resistant to bleomycin, etoposide, and cisplatin but did not affect their sensitivity toward ATM or ATR inhibitors. ASH2L knockdown decreased cell proliferation and facilitated DNA repair via homologous recombination and nonhomologous end-joining mechanisms. Data from the Tumor Cancer Genome Atlas indicate that patients with testicular cancer carrying alterations in the ASH2L gene are more likely to relapse than patients with unaltered ASH2L genes. The cell models we have used are derived from cancers currently treated either partially (Hodgkin's lymphoma), or entirely (testicular cancer) with genotoxins. For such cancers, ASH2L levels could be used as a biomarker to predict the response to genotoxins. In situations where tumors are expressing low levels of ASH2L, which may allow them to resist genotoxic treatment, the use of ATR or ATM inhibitors may be more efficacious as our data indicate that ASH2L knockdown does not affect sensitivity to these inhibitors.

The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway.

Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2-/-) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2-/- mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2-/- mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing ß cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.

Targeting DNA binding proteins for cancer therapy.

Dysregulation or mutation of DNA binding proteins such as transcription factors (TFs) is associated with the onset and progression of various types of disease, including cancer. Alteration of TF activity occurs in numerous cancer tissues due to gene amplification, deletion, and point mutations, and epigenetic modification. Although cancer-associated TFs are promising targets for cancer therapy, development of drugs targeting these TFs has historically been difficult due to the lack of high-throughput screening methods. Recent advances in technology for identification and selective inhibition of DNA binding proteins enable cancer researchers to develop novel therapeutics targeting cancer-associated TFs. In the present review, we summarize known cancer-associated TFs according to cancer type and introduce recently developed high-throughput approaches to identify selective inhibitors of cancer-associated TFs.

Protective effects of Nesfatin-1 peptide on cerebral ischemia reperfusion injury via inhibition of neuronal cell death and enhancement of antioxidant defenses.

Nesfatin-1 is a novel peptide with anorexigenic and anti-hyperglycemic properties. According to previous studies, this multi-functional peptide protects dopaminergic cells against neurotoxicity via anti-apoptotic effects. In addition, Nesfatin-1 protects myocardial tissue after myocardial infarction via anti-inflammatory and anti-apoptotic mechanisms. In this study, we investigated the neuroprotective effects of nesfatin-1 against cerebral ischemia reperfusion injury in the CA1 area of hippocampus in rats. 56 male Wistar rats (240-270 g) were randomly selected and allocated into four groups: (1) sham, (2) nesfatin-1, (3) ischemia/reperfusion, (4) ischemia/reperfusion+nesfatin-1. Cerebral ischemia induced by the occlusion of the common carotid arteries for 20 min was followed by reperfusion. Saline as a vehicle and nesfatin-1 (20 µg/kg) were injected intraperitoneally (IP) at the start of cerebral reperfusion. Apoptotic and necrotic cell death was detected by TUNEL and Nissl staining. Malondialdehyde (MDA) and antioxidant enzymes (GSH and SOD) levels were measured by the ELISA method. The results showed that cerebral ischemia increased the apoptotic and necrotic cell death in the CA1 area of hippocampus, while, treatment with nesfatin-1significantly reduced apoptotic and necrotic cell death. Moreover, the MDA levels of the hippocampus in ischemic rats were higher, whereas in nesfatin-1-treated rats the MDA levels were decreased. Furthermore, the SOD and GSH levels in the ischemic rats were decreased, whilst in ischemic rats treated with nesfatin-1, the SOD and GSH levels were increased. This study for the first time found that nesfatin-1 treatment improves CA1 hippocampus injuries after cerebral ischemia through preventing neuronal cell death and enhancement of antioxidant defenses.

Nesfatin-1 Improve Spatial Memory Impairment Following Transient Global Cerebral Ischemia/Reperfusion via Inhibiting Microglial and Caspase-3 Activation.

Nesfatin-1, a recently discovered peptide, is involved in important functions such as food intake regulation and energy homeostasis. Previous studies have demonstrated that it has protective effects following myocardial injury and also protects dopaminergic cells against neurotoxicity with the anti-inflammatory and anti-apoptotic mechanisms. In this study, we aimed to assay the neuroprotective effects of Nesfatin-1 after brain ischemia/reperfusion. Twenty-eight male Wistar rats were randomly selected and allocated in the form of four groups (sham, Nesfatin-1, ischemia, ischemia+Nesfatin-1). Ischemia was created by obstruction couple common carotid arteries in 20-min period. Saline as a vehicle and Nesfatin-1 (20 µg/kg, intraperitoneally) were injected at the time of reperfusion. Spatial memory performances were evaluated by the Morris water maze. The level of protein expression was determined by immunohistochemical and immunofluorescence staining. Nesfatin-1 significantly reduced caspase-3 (P < 0.01) and microglial activation (P < 0.01) and improved spatial memory impairments (P < 0.05) induced by brain ischemia. Nesfatin-1 has significant neuroprotective effects and can be introduced as a therapeutic agent against cerebral ischemia-induced injuries.

AIBP reduces atherosclerosis by promoting reverse cholesterol transport and ameliorating inflammation in apoE-/- mice.

BACKGROUND AND AIMS: ApoA-1 binding protein (AIBP) is a secreted protein that interacts with apoA-I and accelerates cholesterol efflux from cells. We have recently reported that AIBP promotes apoA-1 binding to ABCA1 in the macrophage cell membrane, partially through 115-123 amino acids. However, the effects of AIBP on the development of atherosclerosis in vivo remain unknown. METHODS: ApoE-/- mice with established atherosclerotic plaques were infected with rAAV-AIBP or rAAV-AIBP(Δ115-123), respectively. RESULTS: AIBP-treated mice showed reduction of atherosclerotic lesion formation, increase in circulating HDL levels and enhancement of reverse cholesterol transport to the plasma, liver, and feces. AIBP increased ABCA1 protein levels in aorta and peritoneal macrophages. Furthermore, AIBP could diminish atherosclerotic plaque macrophage content and the expression of chemotaxis-related factors. In addition, AIBP prevented macrophage inflammation by inactivating NF-κB and promoted the expression of M2 markers like Mrc-1 and Arg-1. However, lack of 115-123 amino acids of AIBP(Δ115-123) had no such preventive effects on the progression of atherosclerosis. CONCLUSIONS: Our observations demonstrate that AIBP inhibits atherosclerosis progression and suggest that it may be an effective target for prevention of atherosclerosis.

TSG101: Tumor Susceptibility Gene 101 (tsg101) Product-Role in Therapy Against HIV/AIDS.

HIV infection presents a major community health hazard, partially because the HIV virus is capable of evading antiretroviral therapies. Most anti-HIV drugs were intended to target virus-encoded mechanisms; however, some host-encoded molecules comparatively execute a vital role in the life cycle of virus. Thus, these might be considered as target sites for antiviral agents. TSG101 is important among these antiviral therapies because, as a cytoplasmic molecule, it facilitates viral budding and release. In this review, HIV-infected cells have TSG101 on their surface and thus can be used in antibody-based therapies. The development of a monoclonal antibody CB8-2 lessens the assembly of viruses from infected cells. This mechanism represents the potential use of TSG101-directed antibodies to fight against AIDS.