G-quadruplexes and associated proteins in aging and Alzheimer's disease.

Aging is a prominent risk factor for many neurodegenerative disorders, such as Alzheimer's disease (AD). Alzheimer's disease is characterized by progressive cognitive decline, memory loss, and neuropsychiatric and behavioral symptoms, accounting for most of the reported dementia cases. This disease is now becoming a major challenge and burden on modern society, especially with the aging population. Over the last few decades, a significant understanding of the pathophysiology of AD has been gained by studying amyloid deposition, hyperphosphorylated tau, synaptic dysfunction, oxidative stress, calcium dysregulation, and neuroinflammation. This review focuses on the role of non-canonical secondary structures of DNA/RNA G-quadruplexes (G4s, G4-DNA, and G4-RNA), G4-binding proteins (G4BPs), and helicases, and their roles in aging and AD. Being critically important for cellular function, G4s are involved in the regulation of DNA and RNA processes, such as replication, transcription, translation, RNA localization, and degradation. Recent studies have also highlighted G4-DNA's roles in inducing DNA double-strand breaks that cause genomic instability and G4-RNA's participation in regulating stress granule formation. This review emphasizes the significance of G4s in aging processes and how their homeostatic imbalance may contribute to the pathophysiology of AD.

COVID-19 Associated Mucormycosis.

Mucormycosis is a life-threatening opportunistic fungal infection seen in immunocompromised states. Rising incidence of mucormycosis among Coronavirus Disease-2019 infected individuals is an increasing concern in India. The disease which was endemic has blown out to become an epidemic. The purpose of this research is to study the epidemiology, management and outcome of Coronavirus Disease-2019 Associated Mucormycosis (CAM) cases. Additionally, the role of diabetes and steroids in the causation of CAM was determined. A hospital-based observational study was conducted at a tertiary care centre involving cases with rhino-orbital mucormycosis with recent history of COVID-19 infection. Out of 205,166(81%) cases had Diabetes Mellitus as a comorbid condition. Among them, 75(36.6%) cases were diagnosed with diabetes during COVID-19 treatment. 161/205(78.5%) cases received corticosteroids during COVID-19 treatment. Corticosteroids were notindicated in 43(26.7%) cases. 177/205(85.4%) cases were alive at the end of 12 weeks. 8 out of 10 deaths were seen in cases having diabetes. As the incidence of mucormycosis is increasing, better awareness among general population about the disease, early diagnosis and multidisciplinary approach is required to improve prognosis.

Post market surveillance registry (PIONEER) of the Yukon Choice PC-Elite Coronary Stent System for percutaneous coronary intervention in Indian acute coronary syndrome population.

AIM: The aim of this study was to assess the safety and efficacy profile of a newer generation biodegradable DES, the Yukon Choice PC Elite with a temperature controlling mechanism, in patients with acute coronary syndrome (ACS). METHODS: This prospective multi-center study (PIONEER Registry) was conducted in an Indian ACS population, therefore providing data in real world clinical practice. Patients with ACS underwent DES implantation in de novo native-vessel coronary lesions with the Yukon Choice PC Elite biodegradable polymer DES and were followed up for a year. RESULTS: A total 999 patients were evaluated. The majority of patients were male (79.2%). A total of 6.7% of the patients had a history of prior myocardial infarction (MI) and 2.7% of patients had a history of previous coronary artery bypass graft. The clinical presentations of the patients included: unstable angina pectoris (UA) (46.4%), ST-segment elevation MI (STEMI) (38.1%), and Non-ST-segment elevation MI (NSTEMI) (15.4%). Implantation of the device was successful in 99.9% of cases. The median stent length and stent size were 21.0 mm (Range: 8.0-40.0 mm) and 2.8 mm (Range 2.0-4.0 mm), respectively. Through to one-year clinical follow-up after percutaneous coronary intervention, all-cause death occurred in 4 of 999 patients (Crude Percentage: 0.4%). Cardiac death, MI, TLR, and stent thrombosis were occurred in 1 (0.1%), 8 (0.8%), 12 (1.2%) and 1 (0.1%) patients, respectively. CONCLUSION: The results of this post marketing surveillance registry suggest favorable safety and efficacy outcomes associated with the Yukon Choice PC Elite biodegradable DES in a real world Indian ACS population.

Transdermal Delivery of Curcumin-Loaded Solid Lipid Nanoparticles as Microneedle Patch: an In Vitro and In Vivo Study.

Curcumin is well known for its neuroprotective effect, and also able to alleviate Parkinsonian features. Clinical application of curcumin is limited due to its low bioavailability. Hence, we hypothesized that the microneedles (MN) containing drug-loaded solid lipid nanoparticles (SLNs) may be able to improve its bioavailability and efficacy. The SLNs were prepared with microemulsion technique using glyceryl monostearate as a lipid and tween 80 as a stabilizer. The particle size, polydispersity index, zeta potential, and entrapment efficiency of prepared SLNs were determined. The optimized formulation was incorporated into microneedle arrays using micromolding technique and fabricated microneedle patch were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, optical microscopy, ex vivo permeation studies, histology studies, and fluorescent microscopy. The fabricated microneedle patch was also evaluated for neuroprotective activity and skin irritation potential. Fourier transform infrared spectroscopy studies of SLNs and microneedles confirmed the chemical compatibility of excipients with curcumin. The developed microneedles were also found to be non-irritant with decreased degree of bradykinesia, high motor coordination, and balance ability. The study provided a theoretical basis for the use of novel microneedle containing curcumin-loaded solid lipid nanoparticles as a useful tool for the treatment of Parkinson's disease.

Critical aspects of neurodevelopment.

Organisms have the unique ability to adapt to their environment by making use of external inputs. In the process, the brain is shaped by experiences that go hand-in-hand with optimisation of neural circuits. As such, there exists a time window for the development of different brain regions, each unique for a particular sensory modality, wherein the propensity of forming strong, irreversible connections are high, referred to as a critical period of development. Over the years, this domain of neurodevelopmental research has garnered considerable attention from many scientists, primarily because of the intensive activity-dependent nature of development. This review discusses the cellular, molecular, and neurophysiological bases of critical periods of different sensory modalities, and the disorders associated in cases the regulators of development are dysfunctional. Eventually, the neurobiological bases of the behavioural abnormalities related to developmental pathologies are discussed. A more in-depth insight into the development of the brain during the critical period of plasticity will eventually aid in developing potential therapeutics for several neurodevelopmental disorders that are categorised under critical period disorders.

Disparate effects of antibiotics on hypertension.

Gut microbiota are associated with a variety of complex polygenic diseases. The usage of broad-spectrum antibiotics by patients affected by such diseases is an important environmental factor to consider, because antibiotics, which are widely prescribed to curb pathological bacterial infections, also indiscriminately eliminate gut commensal microbiota. However, the extent to which antibiotics reshape gut microbiota and per se contribute to these complex diseases is understudied. Because genetics play an important role in predisposing individuals to these modern diseases, we hypothesize that the extent to which antibiotics influence complex diseases depends on the host genome and metagenome. The current study tests this hypothesis in the context of hypertension, which is a serious risk factor for cardiovascular diseases. A 3 × 2 factorial design was used to test the blood pressure (BP) and microbiotal effects of three different antibiotics, neomycin, minocycline, and vancomycin, on two well-known, preclinical, genetic models of hypertension, the Dahl salt-sensitive (S) rat and the spontaneously hypertensive rat (SHR), both of which develop hypertension, but for different genetic reasons. Regardless of the class, oral administration of antibiotics increased systolic blood pressure of the S rat, while minocycline and vancomycin, but not neomycin, lowered systolic blood pressure in the SHR. These disparate BP effects were accompanied by significant alterations in gut microbiota. Our study highlights the need to consider an individualized approach for the usage of antibiotics among hypertensives, as their BP could be affected differentially based on their individual genetic and microbiotal communities.

An essential role of Ffar2 (Gpr43) in dietary fibre-mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis.

Composition of the gut microbiota has profound effects on intestinal carcinogenesis. Diet and host genetics play critical roles in shaping the composition of gut microbiota. Whether diet and host genes interact with each other to bring specific changes in gut microbiota that affect intestinal carcinogenesis is unknown. Ability of dietary fibre to specifically increase beneficial gut microbiota at the expense of pathogenic bacteria in vivo via unknown mechanism is an important process that suppresses intestinal inflammation and carcinogenesis. Free fatty acid receptor 2 (FFAR2 or GPR43) is a receptor for short-chain fatty acids (acetate, propionate and butyrate), metabolites of dietary fibre fermentation by gut microbiota. Here, we show FFAR2 is down modulated in human colon cancers than matched adjacent healthy tissue. Consistent with this, Ffar2(-/-) mice are hypersusceptible to development of intestinal carcinogenesis. Dietary fibre suppressed colon carcinogenesis in an Ffar2-dependent manner. Ffar2 played an essential role in dietary fibre-mediated promotion of beneficial gut microbiota, Bifidobacterium species (spp) and suppression of Helicobacter hepaticus and Prevotellaceae. Moreover, numbers of Bifidobacterium is reduced, whereas those of Prevotellaceae are increased in human colon cancers than matched adjacent normal tissue. Administration of Bifidobacterium mitigated intestinal inflammation and carcinogenesis in Ffar2(-/-) mice. Taken together, these findings suggest that interplay between dietary fibre and Ffar2 play a key role in promoting healthy composition of gut microbiota that stimulates intestinal health.

Harnessing the beneficial properties of adipogenic microbes for improving human health.

Obesity is associated with numerous metabolic comorbidities. Weight loss is an effective measure for alleviating many of these metabolic abnormalities. However, considering the limited success of most medical weight-management approaches in producing a sustained weight loss, approaches that improve obesity-related metabolic abnormalities independent of weight loss would be extremely attractive and of practical benefit. Metabolically healthy obesity supports the notion that a better metabolic profile is possible despite obesity. Moreover, adequate expansion of adipose tissue appears to confer protection from obesity-induced metabolic comorbidities. To this end, the 10th Stock conference examined new approaches to improve metabolic comorbidities independent of weight loss. In particular, human adenovirus 36 (Ad36) and specific gut microbes were examined for their potential to influence lipid and glucose homeostasis in animals and humans. While these microbes possess some undesirable properties, research has identified attributes of adenovirus Ad36 and gut microbes that may be selectively harnessed to improve metabolic profile without the obligatory weight loss. Furthermore, identifying the host signalling pathways that these microbes recruit to improve the metabolic profile may offer new templates and targets, which may facilitate the development of novel treatment strategies for obesity-related metabolic conditions.

Heterozygosity for TGF ß1 -509C/T Polymorphism is associated with risk for breast cancer in South Indian population.

Transformation growth factor ß1 is a multipotent cytokine that mediates the development, differentiation, and neoplasm of the mammary gland. TGF ß1 is known to exert both tumor suppressive and progressive effect at different stages of carcinogenesis. Several studies have shown the association of TGF ß1 expression with breast cancer markers like estrogen receptor (ER), progesterone receptor (PR), and Her2/neu. TGF ß1 expression is known to be influenced by -509C/T promoter polymorphism. Hence, the present study is aimed to evaluate the possible role of TGF ß1 -509C/T promoter polymorphism in breast cancer and its association with ER, PR, and Her2 status based on case-control study in South Indian population from Andhra Pradesh. Our study revealed a significant increase of CT genotype in breast cancer patients compared to controls (CT vs. CC: χ (2) = 6.054, P = 0.014, OR 2.005, 95 % CI 1.182-3.403). However, there was no correlation between TGF ß1 -509C/T polymorphism and other factors like age at onset, ER, PR, Her2 status, etc. Further, CT genotype was found to be associated with increased risk in advanced stages of breast cancer (CC vs. CT: OR 2.315, 95 % CI 1.143-4.688) and a border line significance with postmenopausal women (CT vs. CC: χ (2) = 3.128, P = 0.07, OR 2.095, 95 % CI 0.991-4.428).

Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges.

Bacterial flagellin is a dominant innate immune activator of the intestine. Therefore, we examined the role of the intracellular flagellin receptor, NLRC4, in protecting the gut and/or driving inflammation. In accordance with NLRC4 acting through transcription-independent pathways, loss of NLRC4 did not reduce the rapid robust changes in intestinal gene expression induced by flagellin administration. Loss of NLRC4 did not alter basal intestinal homeostasis nor predispose mice to development of colitis upon administration of an anti-interleukin (IL)-10R monoclonal antibody. However, epithelial injury induced by dextran sulfate sodium in mice lacking NLRC4 resulted in a more severe disease, indicating a role for NLRC4 in protecting the gut. Moreover, loss of NLRC4 resulted in increased mortality in response to flagellate, but not aflagellate Salmonella infection. Thus, despite not being involved in rapid intestinal gene remodeling upon detection of flagellin, NLRC4-mediated inflammasome activation results in production of IL-1ß and IL-18, two cytokines that protect mice from mucosal and systemic challenges.

Biotransformation of α-Pinene to Terpineol by Resting Cell Suspension of Absidia corulea.

Microbial biotransformation of monoterpenes results in the formation of many valuable compounds. Many microorganisms can be used to carry out extremely specific conversions using substrates of low commercial value. Absidia corulea MTCC 1335 was examined for its ability to transform α-Pinene enantiomers. The substrates (-)-α-Pinene and (+)-α-Pinene converted to α-terpineol and isoterpineol, were detected in gas chromatographic analysis. The Biotransformation kinetics of the oxidized products were analysed using GC-MS. With both the substrates the products formed were similar and not much difference in the rate of transformation was observed, suggesting no enantioselectivity of organism towards the substrate.

TLR5 activation induces secretory interleukin-1 receptor antagonist (sIL-1Ra) and reduces inflammasome-associated tissue damage.

Toll-like receptor-5 (TLR5)-mediated detection of flagellin induces nuclear factor (NF)-κB-mediated transcription of host defense gene expression, whereas recognition of intracellular flagellin by interleukin (IL)-1-converting enzyme protease-activation factor (IPAF) results in maturation/secretion of the inflammasome cytokine IL-1ß. The potent effects of IL-1ß are counter-regulated by secretory IL-1 receptor antagonist (sIL-1Ra). We studied the roles of flagellin receptors in regulating the expression of IL-1ß and sIL-1Ra and their subsequent roles in inflammation. Flagellin induced sIL-1Ra in intestinal epithelia and macrophages in a dose- and time-dependent manner, whereas IL-1ß was only induced in macrophages. In vivo, flagellin-induced sIL-1Ra, but not IL-1ß, was absolutely dependent upon TLR5 expressed on non-hemopioetic cells. Thus, loss of TLR5 increased the IL-1ß/sIL-1Ra ratio on flagellin treatment, which correlated with increased inflammatory pathology in response to this product. Furthermore, the flagellin/TLR5 interaction was important for the induction of sIL-1Ra and limiting inflammatory pathology on Salmonella infection. Finally, reduced sIL-1Ra levels in TLR5KO mice correlated with spontaneous colitis. Taken together, we demonstrate that intestinal epithelia, despite not expressing IL-1ß, secrete sIL-1Ra in a TLR5-dependent manner suggesting that loss of TLR5 may promote inflammation by increasing IL-1ß activity. Thus, optimizing the balance between inflammasome cytokines and their endogenous inhibitors might prove a useful strategy to treat inflammatory disorders.

Evaluation of Testicular Toxicity Following Short-term Exposure to Cypermethrin in Albino Mice.

The present study was undertaken to assess the testicular toxicity following short-term exposure to cypermethrin (α-CP) in albino mice. Cypermethrin was dissolved in arachis oil and administered to two groups of mice (n = 12/group) orally at the dose rate of 250 mg/kg body weight, once a day for 28 days. Fifty percent of the animals in both the groups were sacrificed on day 14 and the remaining on day 28. Plasma samples were subjected to radioimmunoassay to determine testosterone levels. The testes were collected to determine the cholesterol levels and the activity of transaminases (AST and ALT) or epididymal alkaline phosphatase (ALP). Histological study of testicular tissue was also undertaken to examine the α-CP-induced ultrastructural changes using transmission electron microscopy (TEM). α-CP significantly (P<0.05) increased the activities of testicular AST (1.36±0.12 vs. 1.19±0.10), ALT(1.78±0.11 vs. 1.36±0.09), and significantly (P<0.05) decreased the testosterone levels (0.86±0.24 vs. 1.72±0.18). Testicular cholesterol levels were elevated in treated animals as compared to control (1.81±0.16 vs. 1.42±0.08). Epididymal alkaline phosphatase (ALP) activity was also decreased significantly (P<0.05) in treated animals (1.10±0.20 vs. 1.64±0.1). Histological studies on day 28 revealed rupture of spermatogonic cell membrane, shrinkage in the nucleus, stages of apoptosis, condensation of chromatin, and decreased cytoplasmic organelles. The study suggested that short-term exposure to α-CP in albino mice induced toxicopathological lesions in testicular tissue leading to decreased plasma testosterone levels.

Confinement-driven weakening of the rotator phase transitions in an alkane through a possible tricritical point.

We report calorimetric and X-ray measurements in the R1, R2, and R5 rotator phases of a long chain alkane (n-tetracosane) in bulk and confined to porous matrices (PTFE and Anopore) of two different length scales. Probing the order within and normal to the layers, in the Anopore case having a mesoscopic length scale (200 nm), drastic weakening of the R2-R1 and R1-R5 transitions is seen. The effect on the latter is to such an extent that it results in the first observation of a confinement-driven second order transition in these systems. A significant reduction of the temperature range of the R1 phase is also seen in the Anopore case, a feature argued to cause the change in the order of the transition. Comparisons are also made on the recent prediction of such a point in a Landau model. These findings, while paving a new means of realizing a tricritical point, will lead to better understanding of finite size effects in alkanes.

Intestinal epithelia activate anti-viral signaling via intracellular sensing of rotavirus structural components.

Rotavirus (RV), a leading cause of severe diarrhea, primarily infects intestinal epithelial cells (IECs) causing self-limiting illness. To better understand innate immunity to RV, we sought to define the extent to which IEC activation of anti-viral responses required viral replication or could be recapitulated by inactivated RV or its components. Using model human intestinal epithelia, we observed that RV-induced activation of signaling events and gene expression typically associated with viral infection was largely mimicked by administration of ultraviolet (UV)-inactivated RV. Use of anti-interferon (IFN) neutralizing antibodies revealed that such replication-independent anti-viral gene expression required type I IFN signaling. In contrast, RV-induction of nuclear factor-κB-mediated interleukin-8 expression was dependent on viral replication. The anti-viral gene expression induced by UV-RV was not significantly recapitulated by RV RNA or RV virus-like particles although the latter could enter IEC. Together, these results suggest that RV proteins mediate viral entry into epithelial cells leading to intracellular detection of RV RNA that generates an anti-viral response.

Flagellin: key target of mucosal innate immunity.

The mucosal immune system is charged with defending the host's vast interfaces with the outside world from the enormous and diverse group of microbes that colonizes these surfaces. A key means by which the mucosal immune system protects the host from such diverse microbes is using germ-line-encoded receptors that target structurally conserved motifs that mediate important bacterial functions. This review focuses on one embodiment of this notion, namely, the mucosal innate immune targeting of flagellin, the primary structural component of flagella, which afford bacteria the ability of directed locomotion. Specifically, we discuss the mechanisms by which flagellin is recognized by the innate immune system, their role in host defense, chronic inflammatory disease, and potential approaches to pharmacologically manipulate these pathways to benefit the host. Discussion will focus on the intestinal tract but will also incorporate key findings in other mucosal surfaces.

Blockade of adenosine A2B receptors ameliorates murine colitis.

BACKGROUND AND PURPOSE: The adenosine 2B (A2B) receptor is the predominant adenosine receptor expressed in the colon. Acting through the A2B receptor, adenosine mediates chloride secretion, as well as fibronectin and interleukin (IL)-6 synthesis and secretion in intestinal epithelial cells. A2B receptor mRNA and protein expression are increased during human and murine colitis. However, the effect of the A2B receptor in the activation of the intestinal inflammatory response is not known. In this study, we examined the effect of A2B receptor antagonism on murine colitis. EXPERIMENTAL APPROACH: Dextran sodium sulphate (DSS)-treated mice and piroxicam-treated IL-10-/- mice were used as animal models of colitis. The A2B receptor-selective antagonist, ATL-801, was given in the diet. KEY RESULTS: Mice fed ATL-801 along with DSS showed a significantly lower extent and severity of colitis than mice treated with DSS alone, as shown by reduced clinical symptoms, histological scores, IL-6 levels and proliferation indices. The administration of ATL-801 prevented weight loss, suppressed the inflammatory infiltrate into colonic mucosa and decreased epithelial hyperplasia in piroxicam-treated IL-10-/- mice. IL-6 and keratinocyte-derived chemokine (KC) concentrations in the supernatants of colonic organ cultures from colitic mice were significantly reduced by ATL-801 administration. CONCLUSIONS AND IMPLICATIONS: Taken together, these data demonstrate that the intestinal epithelial A2B receptor is an important mediator of pro-inflammatory responses in the intestine and that A2B receptor blockade may be an effective therapeutic strategy to treat inflammatory bowel disease.

Osteosarcoma of the jaw bones.

Osteosarcoma of the jaw bone is comparatively rare and accounts for about 6.5% of all osteosarcomas. We treated eight cases of osteosarcoma of the jaw bone involving the mandible and maxilla in equal proportions between 1986-1992. The median age was 31 years and male: female ratio was 5:3. Swelling and bony expansion were the most common presentations. Radiologically six patients had lytic lesions, and histopathologically they were osteoblastic (n = 4), chondroblastic (n = 3) and fibroblastic (n = 1). Three patients, two with mandibular and one with maxillary osteosarcoma underwent radical surgery and six courses of cisplatinum-based chemotherapy. All were alive and disease free 24, 30, and 54 months after treatment. Histologically all three were chondroblastic. Five patients had incomplete or palliative treatment. All patients died of progressive or locally recurrent disease within 2 years.