Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Alcohol consumption exacerbates hepatitis C virus (HCV) pathogenesis and promotes disease progression, although the mechanisms are not quite clear. We have previously observed that acetaldehyde (Ach) continuously produced by the acetaldehyde-generating system (AGS), temporarily enhanced HCV RNA levels, followed by a decrease to normal or lower levels, which corresponded to apoptosis induction. Here, we studied whether Ach-induced apoptosis caused depletion of HCV-infected cells and what role apoptotic bodies (AB) play in HCV-alcohol crosstalk. In liver cells exposed to AGS, we observed the induction of miR-122 and miR-34a. As miR-34a has been associated with apoptotic signaling and miR-122 with HCV replication, these findings may suggest that cells with intensive viral replication undergo apoptosis. Furthermore, when AGS-induced apoptosis was blocked by a pan-caspase inhibitor, the expression of HCV RNA was not changed. AB from HCV-infected cells contained HCV core protein and the assembled HCV particle that infect intact hepatocytes, thereby promoting the spread of infection. In addition, AB are captured by macrophages to switch their cytokine profile to the proinflammatory one. Macrophages exposed to HCV+ AB expressed more IL-1β, IL-18, IL-6, and IL-10 mRNAs compared with those exposed to HCV-AB. The generation of AB from AGS-treated HCV-infected cells even enhanced the induction of aforementioned cytokines. We conclude that HCV and alcohol metabolites trigger the formation of AB containing HCV particles. The consequent spread of HCV to neighboring hepatocytes via infected AB, as well as the induction of liver inflammation by AB-mediated macrophage activation potentially exacerbate the HCV infection course by alcohol and worsen disease progression

Pharmacodynamics of folic acid receptor targeted antiretroviral nanotherapy in HIV-1-infected humanized mice.

Long-acting nanoformulated antiretroviral therapy (nanoART) can sustain plasma drug levels and improve its biodistribution. Cell targeted-nanoART can achieve this and bring drug efficiently to viral reservoirs. However, whether such improvements affect antiretroviral responses remains unknown. To these ends, we tested folic acid (FA)-linked poloxamer407-coated ritonavir-boosted atazanavir (FA-nanoATV/r) nanoparticles for their ability to affect chronic HIV-1 infection in humanized mice. Following three, 100mg/kg FA-nanoATV/r intramuscular injections administered every other week to infected animals, viral RNA was at or below the detection limit, cell-associated HIV-1p24 reduced and CD4+ T cell counts protected. The dosing regimen improved treatment outcomes more than two fold from untargeted nanoATV/r. We posit that these nanoformulations have potential for translation to human use

Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice

Polymer micelles with cross-linked ionic cores are shown here to improve the therapeutic performance of the platinum-containing anticancer compound cisplatin. Biodistribution, antitumor efficacy, and toxicity of cisplatin-loaded core cross-linked micelles of poly(ethylene glycol)-b-poly(methacrylic acid) were evaluated in a mouse ovarian cancer xenograft model. Cisplatin-loaded micelles demonstrated prolonged blood circulation, increased tumor accumulation, and reduced renal exposure. Improved antitumor response relative to free drug was seen in a mouse model. Toxicity studies with cisplatin-loaded micelles indicate a significantly improved safety profile and lack of renal abnormalities typical of free cisplatin treatment. Overall, the study supports the fundamental possibility of improving the potential of platinum therapy using polymer micelle-based drug delivery

Results of Epizootiological Monitoring of Small Mammals Habitant in Crimea Over the Period of 2015–2017

Objective of this work is to analyze the spatial distribution of various species of small mammals, caught between 2015 and 2017, and to identify the dominant species in different landscape areas, as well as their role in functioning of natural foci of zoonotic infections (tularemia, leptospirosis, tick-borne encephalitis, Lyme disease, Crimean hemorrhagic fever, hantavirus infection) in the territory of Crimea. Materials and methods. Small mammals were caught during the period of 2015–2017 and investigated using polymerase chain reaction (PCR), enzyme immunoassay (ELISA) and direct hemagglutination reaction. Results and conclusions. The dominant species of small mammals, containing the causative agents of some or other natural-focal infection are ubiquitous species, i.e. disseminated across the territory of the whole peninsula. In the presence of concomitant favorable conditions, they may contribute to the expansion of the natural foci of these infections. Positive tests for Lyme disease detected not only in small mammals caught in mountain-forest areas, but in steppe zone too may testify to the fact that the border of the natural focus of this infection is expanded. To clarify the boundaries of the natural foci of infections circulating in the territory of Crimea, it is necessary to conduct comprehensive analysis of distribution of small mammals, blood-sucking ectoparasites, and also epidemic manifestations in different natural areas of Crimea

CD4+ Effector T cells Accelerate Alzheimer\u27s Disease in Mice

BACKGROUND: Alzheimer\u27s disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. METHODS: In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IA RESULTS: The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. CONCLUSIONS: These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs

Colorectal Cancer in Patient with Functional Gastrointestinal Symptoms

Aim. A clinical observation to highlight the importance of detailed examination in patients with functional gastrointestinal symptoms.Key points. A 28-yo female patient was admitted with complains of left ileal pain, abdominal distention and up to 4-day stool delay. The complaints had long been interpreted as clinical manifestations of irritable bowel syndrome. No significant abnormalities were revealed in outpatient check-up (general and biochemical blood panels, stool test, abdominal ultrasound, oesophagogastroduodenoscopy). Colonoscopy was performed on admission, with diagnosis of rectal adenocarcinoma. The patient had a prompt surgical intervention, repeated courses of polychemotherapy and is currently followed by an oncologist and coloproctologist. No relapse signs have been reported.Conclusion. Patients with the complaints satisfying the Rome Criteria Revision IV for functional gastrointestinal diseases should have a thorough examination as per recommendations of the Russian Gastroenterological Association and Russian Association of Coloproctologists

АКТУАЛЬНЫЕ ПРОБЛЕМЫ ТУБЕРКУЛЕЗА У ПОДРОСТКОВ ИЗ ОЧАГОВ ТУБЕРКУЛЕЗНОЙ ИНФЕКЦИИ

The article characterizes respiratory tuberculosis in adolescents exposed to tuberculous infection. Exposure to tuberculosis in the family or when contacting close relatives makes the biggest contribution into development of the disease unless the patient is isolated from those exposed. Advanced and severe forms of tuberculosis with bacillary excretion are detected, compromising the life quality of adolescents. The main causes of late diagnostics are poor performance of TB services, primary medical units, low level of health education aimed at the increase of motivation to have planned medical examinations in the general population and to take relevant sanitary and hygienic measures in the sites of infection. Adolescents from the sites with bacillary excretion, and, first of all, if multiple or extensive drug resistant tuberculosis is detected, are to be considered a high priority group facing the risk to develop the disease with more frequent monitoring and deeper examination. In primary medical units, should any sings typical of tuberculosis be presented, it is sensible to add skin tests (Mantoux test and test with tuberculous recombinant allergen) to the minimum diagnostic procedures. Organizational, methodical and health education activities in the sites of infection are to be improved.Дана характеристика туберкулеза органов дыхания у подростков из контакта с больным туберкулезом. Набольшее значение для развития заболевания имеет контакт в семье и с близкими родственниками без изоляции контактирующих лиц от больного. Выявляются тяжелые, распространенные процессы с бактериовыделением, которые снижают качество жизни заболевшего подростка. Основные причины поздней диагностики – недостатки в работе противотуберкулезной службы, первичной медико-санитарной помощи (ПМСП), низкий уровень санитарно-просветительной работы по повышению мотивации населения к плановым обследованиям и соблюдению санитарно-гигиенических мероприятий в очаге. Подростки из очагов с бактериовыделением, в первую очередь при обнаружении микобактерий туберкулеза с множественной/широкой лекарственной устойчивостью, должны рассматриваться как приоритетная группа риска развития заболевания с более частым мониторингом, углубленным обследованием. В учреждениях ПМСП при наличии клинических признаков, таких же как при туберкулезе, целесообразно включить в диагностический минимум кожные иммунологические тесты (проба Манту и проба с аллергеном туберкулезным рекомбинантным). Необходимо совершенствование работы организационно-методической и санитарно-просветительной работы в очагах

The Effectiveness of Add-on Treatment with Nutraceutical

Aim: evaluation of the effectiveness of the nutraceutical “Standard Zdorovia: Gastro” (“SZ Gastro”) in the treatment of patients with irritable bowel syndrome (IBS).Materials and methods. 52 patients (62 % women) diagnosed with IBS and IBS in combination with functional dyspepsia (FD) were included in the study and divided into two groups. Both groups received basic therapy according to the guidelines. The experimental group received as add-on the nutraceutical “SZ Gastro” (containing a standardized amount of menthol, gingerol and D-limonene); patients in the control group — placebo. The duration of the study was 30 days. The severity of somatic symptoms was assessed with the 7×7 questionnaire. Emotional state was assessed with the Four Dimensional Distress, Depression, Anxiety, and Somatization Questionnaire (4DSQ).Results. Patients of the experimental and control groups did not differ from each other either in terms of demographics, basic treatment, or in the severity of symptoms at the beginning of the study.The effectiveness of the treatment in the patients, who received add-on “SZ Gastro” was significantly higher than in the patients of the control group: in the control group the percentage of improvement of somatic symptoms was 22.35 %, in the experimental group it amounted to 49.18 % (χ2 = 15.9; p = 0.0001). The percentage of patients with significant decrease of emotional disturbances was also higher in the experimental group: distress (χ2 = 18.7; p = 0.0000), anxiety (χ2 = 6.9; p = 0.0097) and somatization (χ2 = 14.99; p = 0.0001). No significant side effects were registered in any of the groups.Conclusions. Add-on of nutraceutical “SZ Gastro” to basic treatment is safe and significantly increases effectiveness of the therapy in the patients with IBS and IBS in combination with PD

HIV-1-Infected and Immune-Activated Macrophages Induce Astrocytic Differentiation of Human Cortical Neural Progenitor Cells via the STAT3 Pathway

Diminished adult neurogenesis is considered a potential mechanism in the pathogenesis of HIV-1-associated dementia (HAD). In HAD, HIV-1-infected and immune-activated brain mononuclear phagocytes (MP; perivascular macrophages and microglia) drive central nervous system (CNS) inflammation and may alter normal neurogenesis. We previously demonstrated HIV-1-infected and lipopolysaccharide (LPS) activated monocyte-derived macrophages (MDM) inhibit human neural progenitor cell (NPC) neurogenesis, while enhancing astrogliogenesis through the secretion of the inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), in vitro and in vivo. Here we further test the hypothesis that HIV-1-infected/activated MDM promote NPC astrogliogenesis via activation of the transcription factor signal transducer and activator of transcription 3 (STAT3), a critical factor for astrogliogenesis. Our results show that LPS-activated MDM-conditioned medium (LPS-MCM) and HIV-infected/LPS-activated MDM-conditioned medium (LPS+HIV-MCM) induced Janus kinase 1 (Jak1) and STAT3 activation. Induction of the Jak-STAT3 activation correlated with increased glia fibrillary acidic protein (GFAP) expression, demonstrating an induction of astrogliogenesis. Moreover, STAT3-targeting siRNA (siSTAT3) decreased MCM-induced STAT3 activation and NPC astrogliogenesis. Furthermore, inflammatory cytokines (including IL-6, IL-1β and TNF-α) produced by LPS-activated and/or HIV-1-infected MDM may contribute to MCM-induced STAT3 activation and astrocytic differentiation. These observations were confirmed in severe combined immunodeficient (SCID) mice with HIV-1 encephalitis (HIVE). In HIVE mice, siRNA control (without target sequence, sicon) pre-transfected NPCs injected with HIV-1-infected MDM showed more astrocytic differentiation and less neuronal differentiation of NPCs as compared to NPC injection alone. siSTAT3 abrogated HIV-1-infected MDM-induced astrogliogenesis of injected NPCs. Collectively, these observations demonstrate that HIV-1-infected/activated MDM induces NPC astrogliogenesis through the STAT3 pathway. This study generates important data elucidating the role of brain inflammation in neurogenesis and may provide insight into new therapeutic strategies for HAD