Association Between Multiple Sclerosis Risk and Human Immunodeficiency Virus Infection: Insights and Challenges

Multiple sclerosis (MS) is a convoluted autoimmune and inflammatory disease of the central nervous system (CNS) in which the protective myelin sheath is eroded and the underlying nerve fibers are damaged. There is no conclusive knowledge on the role played by different etiological factors in its development, and studies have shown that it primarily results due to complex interactions between the genetic, geographic and infectious components. Among the risk factors reported to have a possible role in MS development, retroviruses also appear to influence it. Studies suggest human immunodeficiency virus (HIV) infection to be inversely related to MS risk, but to date, the association between the two remains enigmatic. This protective inverse association has become an area of active research and the most plausible explanations for this may be immune suppression and/or antiretroviral medications. The purpose of writing this chapter is to provide background information on the unfathomable relationship between HIV infection and the risk of developing MS while at the same time providing description of the insights garnered from recent studies. While highlighting the application of ART (antiretroviral therapy) as budding future alternative for MS management, this chapter provides momentum for further studies

Antioxidant and Protective Effect of Ethyl Acetate Extract of Podophyllum Hexandrum Rhizome on Carbon Tetrachloride Induced Rat Liver Injury

The antioxidant and hepatoprotective activities of ethyl acetate extract was carefully investigated by the methods of DPPH radical scavenging activity, Hydroxyl radical scavenging activity, Superoxide radical scavenging activity, Hydrogen peroxide radical scavenging activity and its Reducing power ability. All these in vitro antioxidant activities were concentration dependent which were compared with standard antioxidants such as BHT, α-tocopherol. The hepatoprotective potential of Podophyllum hexandrum extract was also evaluated in male Wistar rats against carbon tetrachloride (CCl4)-induced liver damage. Pre-treated rats were given ethyl acetate extract at 20, 30 and 50 mg/kg dose prior to CCl4 administration (1 ml/kg, 1:1 in olive oil). Rats pre-treated with Podophyllum hexandrum extract remarkably prevented the elevation of serum AST, ALT, LDH and liver lipid peroxides in CCl4-treated rats. Hepatic glutathione levels were significantly increased by the treatment with the extract in all the experimental groups. The extract at the tested doses also restored the levels of liver homogenate enzymes (glutathione peroxidase, glutathione reductase, superoxide dismutase and glutathione-S- transferase) significantly. This study suggests that ethyl acetate extract of P. hexandrum has a liver protective effect against CCl4-induced hepatotoxicity and possess in vitro antioxidant activities

Scavenger receptors in host defense: from functional aspects to mode of action

Scavenger receptors belong to a superfamily of proteins that are structurally heterogeneous and encompass the miscellaneous group of transmembrane proteins and soluble secretory extracellular domain. They are functionally diverse as they are involved in various disorders and biological pathways and their major function in innate immunity and homeostasis. Numerous scavenger receptors have been discovered so far and are apportioned in various classes (A-L). Scavenger receptors are documented as pattern recognition receptors and known to act in coordination with other co-receptors such as Toll-like receptors in generating the immune responses against a repertoire of ligands such as microbial pathogens, non-self, intracellular and modified self-molecules through various diverse mechanisms like adhesion, endocytosis and phagocytosis etc. Unlike, most of the scavenger receptors discussed below have both membrane and soluble forms that participate in scavenging; the role of a potential scavenging receptor Angiotensin- Converting Enzyme-2 has also been discussed whereby only its soluble form might participate in preventing the pathogen entry and replication, unlike its membrane-bound form. This review majorly gives an insight on the functional aspect of scavenger receptors in host defence and describes their mode of action extensively in various immune pathways involved with each receptor type

Targeting HMGB1 in Cellular Milieu and Elucidating its Effect in Mice Model of Endotoxemia

Bacterial endotoxin stimulates macrophages / monocytes to release various cytokines early (e.g., TNF-α, IL-1β, and IFN-γ) and late (HMGB-1) which then mediate sepsis (or endotoxemia). HMGB1 recently discovered as late mediator of sepsis, is now seen as one of main mediator of sepsis lethality and prompting investigations for development of new drugs. Present study was undertaken to screen some novel target for ameliorating HMGB1 release and investigate their effect in mice model of endotoxemia. Here we demonstrate that psychosine increases the HMGB1 in primary peritoneal macrophage cells. The psychosine induced HMGB1 may have some interesting role in pathobiology of Krabbe disease. Aloe-emodin was seen to abrogate HMGB1 release dose dependently in both RAW 264.7 cells and primary peritoneal macrophage cells. The aloe-emodin was observed to attenuate the release of pro-inflammatory cytokines (TNF-α, IL1β) and LPS – induced oxidative stress markers iNOS, HO-1. The aloe-emodin showed protective effect in endotoxemia rescuing mice from endotoxemia lethality. Aloe-emodin also decreased the systemic accumulation of proinflammatory mediators (TNF-α, IL1-β) within hours in endotoxemic mice. Endotoxemia induced multi-organ dysfunction was also ameliorated by aloe-emodin treatment depicted by serum biochemistry (ALT, ALP, BUN and creatinine) and histopathology of lung, liver and kidney. The neutrophil infiltration was also reduced in lung tissues of aloe-emodin treated mice. The inhibition of HMGB1 release by aloe-emodin and rescue of endotoxemic mice makes aloe-emodin a potential candidate for sepsis therapy

Carbon tetrachloride induced kidney and lung tissue damages and antioxidant activities of the aqueous rhizome extract of Podophyllum hexandrum

BACKGROUND: The present study was conducted to evaluate the in vitro and in vivo antioxidant properties of aqueous extract of Podophyllum hexandrum. The antioxidant potential of the plant extract under in vitro situations was evaluated by using two separate methods, inhibition of superoxide radical and hydrogen peroxide radical. Carbon tetrachloride (CCl(4)) is a well known toxicant and exposure to this chemical is known to induce oxidative stress and causes tissue damage by the formation of free radicals. METHODS: 36 albino rats were divided into six groups of 6 animals each, all animals were allowed food and water ad libitum. Group I (control) was given olive oil, while the rest groups were injected intraperitoneally with a single dose of CCl(4 )(1 ml/kg) as a 50% (v/v) solution in olive oil. Group II received CCl(4 )only. Group III animals received vitamin E at a concentration of 50 mg/kg body weight and animals of groups IV, V and VI were given extract of Podophyllum hexandrum at concentration dose of 20, 30 and 50 mg/kg body weight. Antioxidant status in both kidney and lung tissues were estimated by determining the activities of antioxidative enzymes, glutathione reductase (GR), glutathione peroxidase (GPX), glutathione-S-transferase (GST) and superoxide dismutase (SOD); as well as by determining the levels of reduced glutathione (GSH) and thiobarbituric acid reactive substances (TBARS). In addition, superoxide and hydrogen peroxide radical scavenging activity of the extract was also determined. RESULTS: Results showed that the extract possessed strong superoxide and hydrogen peroxide radical scavenging activity comparable to that of known antioxidant butylated hydroxy toluene (BHT). Our results also showed that CCl(4 )caused a marked increase in TBARS levels whereas GSH, SOD, GR, GPX and GST levels were decreased in kidney and lung tissue homogenates of CCl(4 )treated rats. Aqueous extract of Podophyllum hexandrum successfully prevented the alterations of these effects in the experimental animals. CONCLUSION: Our study demonstrated that the aqueous extract of Podophyllum hexandrum could protect the kidney and lung tissue against CCl(4 )induced oxidative stress probably by increasing antioxidant defense activities

AICAR inhibits adipocyte differentiation in 3T3L1 and restores metabolic alterations in diet-induced obesity mice model

BACKGROUND: Obesity is one of the principal causative factors involved in the development of metabolic syndrome. AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolism. The role of AMP-activated protein kinase in adipocyte differentiation is not completely understood, therefore, we examined the effect of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), a pharmacological activator of AMP-activated protein kinase (AMPK) on adipocyte differentiation in 3T3L1 cells and in a mouse Diet induced obesity (DIO) model. METHODS: To examine the effect of AICAR on adipocyte differentiation in 3T3L1 cells and in a mouse Diet induced obesity (DIO) model, 3T3L1 cells were differentiatied in the presence or absence of different concentration of AICAR and neutral lipid content and expression of various adipocyte-specific transcription factors were examined. In vivo study, treated and untreated mice with AICAR (0.1–0.5 mg/g body weight) were fed high-fat diet (60% kcal% fat) to induce DIO and several parameters were studied. RESULTS: AICAR blocked adipogenic conversion in 3T3L1 cells along with significant decrease in the neutral lipid content by downregulating several adipocyte-specific transcription factors including peroxisome proliferators-activated receptor γ (PPARγ), C/EBPα and ADD1/SREBP1, which are critical for adipogenesis in vitro. Moreover, intraperitoneal administration of AICAR (0.5 mg g/body weight) to mice fed with high-fat diet (60% kcal% fat) to induce DIO, significantly blocked the body weight gain and total content of epididymal fat in these mice over a period of 6 weeks. AICAR treatment also restored normal adipokine levels and resulted in significant improvement in glucose tolerance and insulin sensitivity. The reduction in adipose tissue content in AICAR treated DIO mice was due to reduction in lipid accumulation in the pre-existing adipocytes. However, no change was observed in the expression of PPARγ, C/EBPα and ADD1/SREBP1 transcription factors in vivo though PGC1α expression was significantly induced. CONCLUSION: This study suggests that AICAR inhibits adipocyte differentiation via downregulation of expression of adipogenic factors in vitro and reduces adipose tissue content in DIO mice by activating expression of PGC1α without inhibiting adipocyte-specific transcription factors in DIO mice

Scavenger receptor B1 facilitates the endocytosis of \u3ci\u3eEscherichia coli\u3c/i\u3e via TLR4 signaling in mammary gland infection

SCARB1 belongs to class B of Scavenger receptors (SRs) that are known to be involved in binding and endocytosis of various pathogens. SRs have emerging role in regulating innate immunity and host–pathogen interactions by acting in co-ordination with Toll-like receptors.Query Little is known about the function of SCARB1 in milk-derived mammary epithelial cells (MECs). This study reports the role of SCARB1 in infection and its potential association in TLR4 signaling on bacterial challenge in Goat mammary epithelial cells (GMECs). The novelty in the establishment of MEC culture lies in the method that aims to enhance the viability of the cells with intact characteristics upto a higher passage number. We represent MEC culture to be used as a potential infection model for deeper understanding of animal physiology especially around the mammary gland. On E.coli challenge the expression of SCARB1 was signifcant in induced GMECs at 6 h. Endoribonuclease-esiRNA based silencing of SCARB1 affects the expression of TLR4 and its pathways i.e. MyD88 and TRIF pathways on infection. Knockdown also affected the endocytosis of E.coli in GMECs demonstrating that E.coli uses SCARB1 function to gain entry in cells. Furthermore, we predict 3 unique protein structures of uncharacterized SCARB1 (Capra hircus) protein. Overall, we highlight SCARB1 as a main participant in host defence and its function in antibacterial advances to check mammary gland infections

Amelioration of Oxidative Stress in Mouse Model of Diabetic Retinopathy by Arnebia benthamii

Diabetes mellitus is a chronic, multisystem heterogeneous metabolic disorder characterized by hyperglycemia which attacks both microvessels and macrovessels throughout the body resulting in the development of the specific microvascular and macrovascular complications.Diabetic retinopathy (DR), a disease of the retina, is the most common and specific microvascular complication of diabetes which remains a major cause of visual impairment worldwide among the people in working age and is a leading cause of visual loss in older patients.DR is a duration-dependent disease and both the prevalence and the incidence of retinopathy increase with increasing duration of diabetes. Diabetic retinopathy is a complex disease and the precise mechanism remains unknown. The multiple metabolic pathways have been implicated in this disease but inflammation and oxidative stress have emerged as the key players in the development of this disease. Due to this multifactorial nature the treatment of this complex disease is difficult and limited treatment options are available. The surgical procedures-laser photocoagulation and vitrectomy are currently the primary treatment options available for diabetic retinopathy. However, the use of antioxidants and antiinflammatory agents as treatment options for this disease has shown promising results in several animal studies and clinical trials. In this study, we evaluated the effect of aqueous extract of the plant Arnebia benthamii on the oxidative stress and inflammatory processes in mouse model of diabetic retinopathy. Arnebia benthamii is a traditional medicinal herb of Ayurvedic, Unani and other indigenous systems of medicine and has been known to possess antibacterial, antifungal, anti-inflammatory and wound-healing properties and also antioxidant properties. In our study and under the conditions used, we found that the aqueous extract of Arnebia benthamii instead of ameliorating the inflammation and oxidative stress associated with the disease rather further induced the pro-inflammatory and oxidative stress markers. Further study is therefore required to find if any of the individual components of the extract may be having anti-inflammatory and/or antioxidative property and or even pro-inflammatory role

Novel mutations identified in EIF2B5 gene in Kashmiri patients as susceptibility factor for multiple sclerosis

115-120White matter disease refers to a set of diseases that affect the white matter of the brain and all of which have different consequences on brain function. Most of the studies have shown that it results from the defects during protein synthesis, with the gene defects in EIF2B1–5, encoding the five subunits of eukaryotic translation initiation factor 2B (eIF2B) α, β, γ, δ and ε, respectively. eIF2B plays a crucial role in protein translation and its regulation under different conditions. The previous studies have shown that mutations in five subunits of eIF2B cause white matter disease of the brain and thus EIF2B is the main culprit in development of white matter disease. In this study, the mutational screening of EIF2B5 gene encoding eIF2Bε was performed for the first time in 12 Kashmiri patients, each having a unique white matter disease condition. We found two novel missense mutations in EIF2B5: c.580A>G, p.Thr194Ala and c.611C>T, p.Ala204Val among the patients with demyelinating disease (multiple sclerosis), but no mutation was found in other patients. In conclusion our study suggests involvement of the EIF2B5 gene in MS development, thus suggesting p.Thr194Ala to be a susceptibility factor for the development of multiple sclerosis. </span