Regulation of murine arthritis by systemic,spinal, and intra-articular adrenoceptors

BackgroundThe regulation of the immune system by the sympathetic nervous system is allowing the design of novel treatments for inflammatory disorders such as arthritis. In this study, we have analyzed the effects of α- and β-adrenoceptor agonists injected subcutaneously, intrathecally, or intra-articularly in zymosan-induced arthritis.MethodsMurine arthritis was induced by intra-articular (knee joint) injection of zymosan. α1 (phenylephrine), α2 (clonidine), β1 (dobutamine), or β2 (salbutamol)-adrenoceptor agonists were injected subcutaneously (sc), intrathecally (it), or intra-articularly (ia) to activate peripheral, spinal, or intra-articular adrenoceptors and to study their effects on articular edema formation and neutrophil migration into the synovial cavity.ResultsTreatments with phenylephrine did not affect the edema formation, but it increased neutrophil migration when injected subcutaneously (155.3%) or intra-articularly (187.7%). Treatments with clonidine inhibited neutrophil migration (59.9% sc, 68.7% it, 42.8% ia) regardless of the route of administration, but it inhibited edema formation only when injected intrathecally (66.7%) or intra-articularly (36%) but not subcutaneously. Treatments with dobutamine inhibited both edema (42.0% sc, 69.5% it, 61.6% ia) and neutrophil migration (28.4% sc, 70.3% it, 82.4% ia) in a concentration dependent manner. Likewise, all the treatments with salbutamol also inhibited edema formation (89.9% sc, 62.4% it, 69.8% ia) and neutrophil migration (76.6% sc, 39.1% it, 71.7% ia).ConclusionWhereas the β-adrenoceptor agonists induced anti-inflammatory effects regardless of their route of administration, α1- and α2-adrenoceptor agonists induced either pro- and anti-inflammatory effects, respectively.     

Emblica officinalis improves glycemic status and oxidative stress in STZ induced type 2 diabetic model rats

Objective:To evaluate the antidiabetic and antioxidant potential of Emblica officinalis(E.officinalis)fruit on normal and type 2 diabetic rats.Methods:Type 2 diabetes was induced into the male Long-Evans rats.The rats were divided into nine groups including control groups receiving water,type 2 diabetic controls,type 2 diabetic rats treated with glibenclamide(T2GT)and type 2diabetic rats treated with aqueous extract of fruit pulp of E.officinalis.They were fed orally for8 weeks with a single feeding.Blood was collected by cutting the tail tip on 0 and 28 days and by decapitation on 56 day.Packed red blood cells and serum were used for evaluating different biochemical parameters.Results:Four weeks administration of aqueous extract of E.officinalis improved oral glucose tolerance in type 2 rats and after 8 weeks it caused significant(P0.007)reduction in fasting serum glucose level compared to 0 day.Triglycerides decreased by 14%but there was no significant change in serum ALT,creatinine,cholesterol and insulin level in any group.Furthermore,reduced erythrocyte malondialdehyde level showed no significant change(P0.07)but reduced glutathione content was found to be increased significantly(P0.05).Conclusions:The aqueous extract of E.officinalis has a promising antidiabetic and antioxidant properties and may be considered for further clinical studies in drug development.     

Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection

The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 12 (NLRP12) plays a protective role in intestinal inflammation and carcinogenesis, but the physiological function of this NLR during microbial infection is largely unexplored. Salmonella enterica serovar Typhimurium (S. typhimurium) is a leading cause of food poisoning worldwide. Here, we show that NLRP12-deficient mice were highly resistant to S. typhimurium infection. Salmonella-infected macrophages induced NLRP12-dependent inhibition of NF-κB and ERK activation by suppressing phosphorylation of IκBα and ERK. NLRP12-mediated down-regulation of proinflammatory and antimicrobial molecules prevented efficient clearance of bacterial burden, highlighting a role for NLRP12 as a negative regulator of innate immune signaling during salmonellosis. These results underscore a signaling pathway defined by NLRP12-mediated dampening of host immune defenses that could be exploited by S. typhimurium to persist and survive in the host.The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family consists of a large number of intracellular pathogen recognition receptors that function as sensors of microbial-derived and danger-associated molecules in the cytoplasm of host cells. A subset of NLR proteins, including NLRP1, NLRP3, and NLRC4, activate caspase-1 via the formation of a cytosolic multiprotein complex termed the inflammasome (1). These inflammasome-forming NLRs mediate processing of the proinflammatory cytokines pro–IL-1β and pro–IL-18, which are then secreted by the cell. The non–inflammasome-forming members of the NLR family contribute to regulation of other key inflammatory pathways. For example, NOD1 and NOD2 activate NF-κB and MAPK pathways (2–5), whereas NLRP6, NLRC3, NLRC5, and NLRX1 have been demonstrated to regulate inflammation negatively (6–9).NLRP12 (NALP12, MONARCH-1, or PYPAF7) is a poorly characterized member of the NLR family. It has a tripartite domain structure, which consists of an N-terminal PYRIN domain, a central nucleotide binding site domain, and a C-terminal domain composed of at least 12 leucine-rich repeat motifs (10). In humans, NLRP12 is expressed in peripheral blood leukocytes, including granulocytes, eosinophils, monocytes, and dendritic cells (DCs) (10, 11). Similarly, mouse NLRP12 is highly expressed in bone marrow neutrophils and granulocytes, macrophages, and DCs (12, 13). Genetic studies in humans have shown that mutations in the NLRP12 gene are associated with periodic fever syndromes and atopic dermatitis (14–16). More recent studies have demonstrated that NLRP12 has both inflammasome-dependent and inflammasome-independent roles in health and disease. Our laboratory and others have previously reported that NLRP12 mediates protection against colon inflammation and tumorigenesis in vivo by negatively regulating inflammatory responses (12, 17).Recent studies have revealed a potential role for NLRP12 during infectious diseases. Vladimer et al. (18) reported that Nlrp12^−/− mice are hypersusceptible to Yersinia pestis infection, whereby NLRP12 is required to drive caspase-1 activation and IL-1β and IL-18 release. Another study found that WT and Nlrp12^−/− mice exhibit similar host innate responses in lung infections induced by Mycobacterium tuberculosis or Klebsiella pneumoniae (13). However, in vitro studies reported that a synthetic analog cord factor, trehalose-6,6-dimycolate (TDP), from M. tuberculosis and LPS from K. pneumoniae induced substantially elevated levels of TNF-α and IL-6 in Nlrp12^−/− bone marrow-derived DCs compared with their WT counterpart, although levels of secreted IL-1β were not changed (13). These results suggest that unlike the case in Yersinia infection, NLRP12 does not contribute to inflammasome-mediated protection against M. tuberculosis and K. pneumoniae infections. Overall, the physiological and functional relevance of NLRP12 in the host defense against infectious diseases is not fully understood.Salmonella enterica serovar Typhimurium (S. typhimurium) is a Gram-negative intracellular pathogen, and one of the most prevalent etiological agents of gastroenteritis worldwide. Salmonella infection accounts for 93.8 million cases of gastroenteritis annually in the world and is a leading cause of death among bacterial foodborne pathogens in the United States (19, 20). Previous studies have found that members of the Toll-like receptor (TLR) family, especially TLR4, are critical for the recognition and clearance of S. typhimurium (21, 22). One consequence of Salmonella-induced TLR activation is the production of inflammatory cytokines and antimicrobial compounds, including pro–IL-1β, pro–IL-18, IFN-γ, TNF-α, and reactive oxygen species, which are critical mediators for the control of bacterial growth in host tissues (23). In addition to TLR-mediated host responses, certain members of the NLR family, including NLRC4 and NLRP3, initiate inflammasome formation to drive processing and release of IL-1β and IL-18 following Salmonella infection (24, 25). Although the precise signals that trigger NLRP3 activation during Salmonella infection are unknown, NLRC4 is activated by NAIPs, a subset of receptors within the NLR family that detect Salmonella flagellin (mouse NAIP5 and NAIP6) or certain rod (mouse NAIP2) or needle (human NAIP and mouse NAIP1) proteins associated with the Salmonella type III secretion system (26–30). Nevertheless, the functional relevance of NLRP12 in response to Salmonella infection is unknown.Here, we show that NLRP12 negatively regulates antibacterial host defense during Salmonella infection independent of inflammasomes. NLRP12 inhibited TLR-induced NF-κB activation by dampening phosphorylation of IκBα and ERK, consequently enhancing intracellular bacterial survival. Together, our work unveiled an NLRP12-dependent innate immune pathway that may be strategically exploited by S. typhimurium to persist and survive in the host.     

Indirect effects of cigarette butt waste on the dengue vector Aedes aegypti (Diptera: Culicidae)

Despite major insecticide-based vector control programs, dengue continues to be a major threat to public health in urban areas. The reasons for this failure include the emergence of insecticide resistance and the narrowing of the spectrum of efficient products. Cigarette butts (CBs), the most commonly discarded piece of waste, also represent a major health hazard to human and animal life. CBs are impregnated with thousands of chemical compounds, many of which are highly toxic and none of which has history of resistance in mosquitoes. This study was performed to examine whether exposure to CB alters various biological parameters of parents and their progeny. We examined whether the mosquito changes its ovipositional behaviors, egg hatching, reproductive capacity, longevity and fecundity in response to CB exposure at three different concentrations. Females tended to prefer microcosms containing CBs for egg deposition than those with water only. There were equivalent rates of eclosion success among larvae from eggs that matured in CB and water environments. We also observed decreased life span among adults that survived CB exposure. Extracts of CB waste have detrimental effects on the fecundity and longevity of its offspring, while being attractive to its gravid females. These results altogether indicate that CB waste indirectly affect key adult life traits of Aedes aegypti and could conceivably be developed as a novel dengue vector control strategy, referring to previously documented direct toxicity on the larval stage. But this will require further research on CB waste effects on non-target organisms including humans.     

An Evaluation of the Performance of Direct Agglutination Test on Filter Paper Blood Sample for the Diagnosis of Visceral Leishmaniasis

The attack phase of the visceral leishmaniasis (VL) elimination program in Bangladesh aims to decrease the burden of VL incidence from close to 20 cases to less than one case per 10,000 at sub-district level. The consolidation phase will aim to confirm no increase in VL in endemic areas through active surveillance. During this phase, a reliable diagnostic tool for mass screening is required. Here, we report the diagnostic sensitivity and specificity of a filter paper-based agglutination test (FP-DAT) for diagnosis of VL in patients admitted to an upazila health complex in Mymensingh, a VL-endemic region of Bangladesh. The sensitivity of both the conventional direct agglutination test (DAT) and FP-DAT were 100% and 96%, respectively. The specificity of both assays was 100%. However, when the performances of the two assays were compared using McNamar''s test, neither the sensitivity nor the specificity of the FP-DAT differed significantly from conventional DAT.     

The protective effect of aqueous extracts of roselle (Hibiscus sabdariffa L. UKMR-2) against red blood cell membrane oxidative stress in rats with streptozotocin-induced diabetes

OBJECTIVES:

The aim of this study was to investigate the protective effects of aqueous extracts of roselle (Hibiscus sabdariffa L. UKMR-2) against red blood cell (RBC) membrane oxidative stress in rats with streptozotocin-induced diabetes.

METHODS:

Forty male Sprague-Dawley rats weighing 230-250 g were randomly divided into four groups (n = 10 rats each): control group (N), roselle-treated control group, diabetic group, and roselle-treated diabetic group. Roselle was administered by force-feeding with aqueous extracts of roselle (100 mg/kg body weight) for 28 days.

RESULTS:

The results demonstrated that the malondialdehyde levels of the red blood cell membranes in the diabetic group were significantly higher than the levels in the roselle-treated control and roselle-treated diabetic groups. The protein carbonyl level was significantly higher in the roselle-treated diabetic group than in the roselle-treated control group but lower than that in the diabetic group. A significant increase in the red blood cell membrane superoxide dismutase enzyme was found in roselle-treated diabetic rats compared with roselle-treated control rats and diabetic rats. The total protein level of the red blood cell membrane, osmotic fragility, and red blood cell morphology were maintained.

CONCLUSION:

The present study demonstrates that aqueous extracts of roselle possess a protective effect against red blood cell membrane oxidative stress in rats with streptozotocin-induced diabetes. These data suggest that roselle can be used as a natural antioxidative supplement in the prevention of oxidative damage in diabetic patients.