The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy.

Several large-scale genome-wide association studies genetically linked IRGM to Crohn's disease and other inflammatory disorders in which the IRGM appears to have a protective function. However, the mechanism by which IRGM accomplishes this anti-inflammatory role remains unclear. Here, we reveal that IRGM/Irgm1 is a negative regulator of the NLRP3 inflammasome activation. We show that IRGM expression, which is increased by PAMPs, DAMPs, and microbes, can suppress the pro-inflammatory responses provoked by the same stimuli. IRGM/Irgm1 negatively regulates IL-1ß maturation by suppressing the activation of the NLRP3 inflammasome. Mechanistically, we show that IRGM interacts with NLRP3 and ASC and hinders inflammasome assembly by blocking their oligomerization. Further, IRGM mediates selective autophagic degradation of NLRP3 and ASC. By suppressing inflammasome activation, IRGM/Irgm1 protects from pyroptosis and gut inflammation in a Crohn's disease experimental mouse model. This study for the first time identifies the mechanism by which IRGM is protective against inflammatory disorders.

Suppression of Chronic Unpredictable Stress-Persuaded Increased Monoamine Oxidase Activity by Taurine Promotes Significant Neuroprotection in Zebrafish Brain.

Neuropsychiatric upshots following chronic exposure to unpredictable adverse stressors have been well documented in the literature. Considering the significant impact of chronic unpredictable stress (CUS), the literature is elusive regarding the neuroprotective efficacy of taurine against CUS-induced oxidative stress and chromatin condensation in the zebrafish brain. In this study, to ameliorate CUS-persuaded neurological outcomes, waterborne treatment of taurine as a prophylactic intervention was undertaken. Further, our approach also focused on the gross neurobehavioral response of zebrafish, oxidative stress indices and neuromorphology of the zebrafish brain following CUS exposure with taurine treatment. Because taurine provides significant neuroprotection against oxidative insult, the cytosolic level of monoamine oxidase (MAO) in the zebrafish brain following CUS exposure is worth investigating. Further, as heightened MAO activity is associated with augmented oxidative and chromatin condensation, the focus of this study was on whether taurine provides neuroprotection by downregulating MAO levels in the brain. Our findings show that CUS-persuaded altered neurobehavioral response was significantly rescued by taurine. Moreover, our findings firmly support the hypothesis that taurine acts as a radical neuroprotector by restoring glutathione biosynthesis in the zebrafish brain subsequent to CUS exposure. Additionally, the rising level of brain MAO following chronic exposure to CUS is ameliorated by taurine treatment. These findings strongly advocate the role of taurine as a natural MAO inhibitor through the neuroprotection it provides against CUS-instigated oxidative stress in zebrafish. However, the fundamental neuroprotective mechanism of such natural compounds needs to be elucidated to determine their neuroprotective efficacy against stress regimens.

Strategies for organ preservation: Current prospective and challenges.

In current therapeutic approaches, transplantation of organs provides the best available treatment for a myriad of end-stage organ failures. However, shortage of organ donors, lacunae in preservation methods, and lack of a suitable match are the major constraints in advocating this life-sustaining therapy. There has been continuous progress in the strategies for organ preservation since its inception. Current strategies for organ preservation are based on the University of Wisconsin (UW) solution using the machine perfusion technique, which allows successful preservation of intra-abdominal organs (kidney and liver) but not intra-thoracic organs (lungs and heart). However, novel concepts with a wide range of adapted preservation technologies that can increase the shelf life of retrieved organs are still under investigation. The therapeutic interventions of in vitro-cultured stem cells could provide novel strategies for replacement of nonfunctional cells of damaged organs with that of functional ones. This review describes existing strategies, highlights recent advances, discusses challenges and innovative approaches for effective organ preservation, and describes application of stem cells to restore the functional activity of damaged organs for future clinical practices.

Di-2-ethylhexyl phthalate-induced neurobehavioural transformation is associated with altered glutathione biosynthesis and neurodegeneration in zebrafish brain.

The contamination of life-sustaining environments with synthetic pollutants such as plastic-derived compounds has increased at an alarming rate in recent decades. Among such contaminants, di-2-ethylhexyl phthalate (DEHP) is an extensively used compound in plastics and plastic products to make them flexible. DEHP causes several adverse effects such as reproductive toxicity leading to infertility, miscarriage and litter size reduction, disruption of the thyroid endocrine system, oxidative stress, neurodevelopmental defect and cognitive impairment. An aquatic environment is a fragile site, where the accumulation of DEHP poses a significant threat to living organisms. In this context, the present study focused on whether the neurobehavioural transformation following exposure to DEHP is an outcome of augmented oxidative stress and neuromorphological alteration in the zebrafish brain. Our preliminary findings advocate that DEHP acts as a typical neurotoxicant in inducing neurobehavioural transformation in zebrafish. Furthermore, our study also supports the idea that DEHP itself acts as a potent neurotoxicant by altering the glutathione biosynthetic pathway through the induction of oxidative stress in the zebrafish brain. Similarly, our findings also link the abovementioned neurobehavioural transformation and oxidative stress with augmented neuronal pyknosis and chromatin condensation in the periventricular grey zone of the zebrafish brain following chronic exposure to DEHP. Therefore, the overall conclusion of the present study advocates the potential role of DEHP in inducing neuropathological manifestation in the zebrafish brain. Future research directed towards elucidating the neuroprotective efficacy of natural compounds against DEHP-induced neurotoxicity may provide a new line of intervention.

Autoimmunity gene IRGM suppresses cGAS-STING and RIG-I-MAVS signaling to control interferon response.

Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.

Twelve tips for surgeons to maximise medical student learning in the operating theatre.

Theatre-based learning is an essential component of undergraduate surgical education and offers a wide range of learning opportunities. However, studies have demonstrated that medical students have not always benefited from this holistic learning environment due to many reasons, including intimidation, hierarchies within the surgical environment and fear of making mistakes. The lead surgical educator's approach is an important influence on the experience and learning of their medical students. These twelve tips are aimed at surgical educators with undergraduate teaching responsibilities. This guidance is based upon evidence from literature and established theories of teaching and learning, supplemented by qualitative interviews with surgeons and medical students. The resulting tips were checked and refined by surgical teaching fellows. These learner-centred tips provide guidance on thorough induction, managing mutual expectations and approaches that optimise teaching and learning in the operating theatre. They are designed to support surgical educators in improving their students' engagement and learning experiences in this setting.

Chronic bisphenol A exposure induces temporal neurobehavioral transformation and augmented chromatin condensation in the periventricular gray zone of zebrafish brain.

Bisphenol A (BPA) is an industrial synthetic chemical that is extensively used for manufacturing polycarbonate plastics and epoxy resins. However, there is limited literature on BPA-induced temporal neurobehavioral transformation and oxidative stress-mediated neurodegeneration in the subtle region of the zebrafish brain. Consequently, an investigational setup was prepared to study the temporal response to duration-dependent BPA exposure on neurobehavioral, oxidative stress, and neurodegeneration in zebrafish. Zebrafish were divided into five groups: naïve, control, 7 days (BPA7D), 14 days (BPA14D), and 21 days (BPA21D). Our findings indicated that chronic waterborne exposure to BPA substantially altered the light/dark preference and bottom-dwelling behavior of zebrafish in the BPA14D, and BPA21D groups compared with naïve and control groups. Biochemical studies revealed that there was a significant downregulation in the cellular level of small-molecule antioxidants evidenced by reduced glutathione (GSH) and activity of antioxidant enzymes of glutathione biosynthesis in a duration-dependent manner after exposure to BPA. However, exposure to BPA for 7 days did not induce substantial alteration in biochemical parameters, such as GSH level, protein carbonylation, and superoxide dismutase activity, although the neurobehavioral responses expressively differed from those of the naïve and control groups. Moreover, our histopathological observation also indicated a temporal augmentation in chromatin condensation in the periventricular gray zone (PGZ) of the zebrafish brain after chronic exposure to BPA. The overall outcomes of the present study indicated that the transformed neurobehavioral phenotypes in zebrafish are a consequence of BPA-induced oxidative stress and PGZ neurodegeneration and clearly show a temporal transformation under BPA exposure.

The Regulatory Role of Reticulons in Neurodegeneration: Insights Underpinning Therapeutic Potential for Neurodegenerative Diseases.

In the last few decades, cytoplasmic organellar dysfunction, such as that of the endoplasmic reticulum (ER), has created a new area of research interest towards the development of serious health maladies including neurodegenerative diseases. In this context, the extensively dispersed family of ER-localized proteins, i.e. reticulons (RTNs), is gaining interest because of its regulative control over neural regeneration. As most neurodegenerative diseases are pathologically manifested with the accretion of misfolded proteins with subsequent induction of ER stress, the regulatory role of RTNs in neural dysfunction cannot be ignored. With the limited information available in the literature, delineation of the functional connection between rising consequences of neurodegenerative diseases and RTNs need to be elucidated. In this review, we provide a broad overview on the recently revealed regulatory roles of reticulons in the pathophysiology of several health maladies, with special emphasis on neurodegeneration. Additionally, we have also recapitulated the decisive role of RTN4 in neurite regeneration and highlighted how neurodegeneration and proteinopathies are mechanistically linked with each other through specific RTN paralogues. With the recent findings advocating zebrafish Rtn4b (a mammalian Nogo-A homologue) downregulation following central nervous system (CNS) lesion, RTNs provides new insight into the CNS regeneration. However, there are controversies with respect to the role of Rtn4b in zebrafish CNS regeneration. Given these controversies, the connection between the unique regenerative capabilities of zebrafish CNS by distinct compensatory mechanisms and Rtn4b signalling pathway could shed light on the development of new therapeutic strategies against serious neurodegenerative diseases.

Unravelling the potential of gut microbiota in sustaining brain health and their current prospective towards development of neurotherapeutics.

Increasing incidences of neurological disorders, such as Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are being reported, but an insight into their pathology remains elusive. Findings have suggested that gut microbiota play a major role in regulating brain functions through the gut-brain axis. A unique bidirectional communication between gut microbiota and maintenance of brain health could play a pivotal role in regulating incidences of neurodegenerative diseases. Contrarily, the present life style with changing food habits and disturbed circadian rhythm may contribute to gut homeostatic imbalance and dysbiosis leading to progression of several neurological disorders. Therefore, dysbiosis, as a primary factor behind intestinal disorders, may also augment inflammation, intestinal and blood-brain barrier permeability through microbiota-gut-brain axis. This review primarily focuses on the gut-brain axis functions, specific gut microbial population, metabolites produced by gut microbiota, their role in regulating various metabolic processes and role of gut microbiota towards development of neurodegenerative diseases. However, several studies have reported a decrease in abundance of a specific gut microbial population and a corresponding increase in other microbial family, with few findings revealing some contradictions. Reports also showed that colonization of gut microbiota isolated from patients suffering from neurodegenerative disease leads to the development of enhance pathological outcomes in animal models. Hence, a systematic understanding of the dominant role of specific gut microbiome towards development of different neurodegenerative diseases could possibly provide novel insight into the use of probiotics and microbial transplantation as a substitute approach for treating/preventing such health maladies.

Bisphenol A exposure induces neurobehavioral deficits and neurodegeneration through induction of oxidative stress and activated caspase-3 expression in zebrafish brain.

Bisphenol A (BPA) is noted for its adversative effects by inducing oxidative stress, carcinogenicity, neurotoxicity, inflammation, etc. However, the likely act of BPA in inducing neurodegenerative phenotypes remains elusive in the available literature. Hence, the present study was conducted to decipher the neurodegenerative potential of BPA in inducing Parkinson's disease like phenotypes in zebrafish. Zebrafish were subjected to chronic waterborne exposure to BPA for 56 days. Locomotor activities and neurobehavioral response were assessed by the NTDT (novel tank diving test), OFT (open field test), and LDPT (light-dark preference test). The oxidative stress markers and histopathological observation for pyknosis and chromatin condensation were carried out. Immunohistochemistry for activated caspase-3 and targeted proteins expression study was performed. The basic findings reveal that chronic BPA exposure significantly induces locomotor dysfunction through a significant decline in mean velocity and total distance traveled. As a measure of pyknosis and chromatin condensation, pyknotic and Hoechst positive neurons in telencephalon and diencephalon significantly increased by BPA exposure. A higher concentration of BPA adversely affects the neurobehavioral response, antioxidant status, and neuromorphology in zebrafish. Parkinson-relevant targeted protein expression viz. alpha-synuclein and LRRK2, were significantly upregulated, whereas tyrosine hydroxylase, NeuN, and Nurr1 were significantly downregulated in the zebrafish brain. As an indicator of cell death by apoptosis, the expression of activated caspase-3 was significantly increased in the BPA-exposed zebrafish brain. These basic results of the current study indicate that chronic waterborne exposure to BPA induces neuropathological manifestation leading to the development of motor dysfunction and Parkinsonism-like neurodegenerative phenotypes in zebrafish.

Suppression of bisphenol A-induced oxidative stress by taurine promotes neuroprotection and restores altered neurobehavioral response in zebrafish (Danio rerio).

Bisphenol A (BPA) has been documented as a mediator for a number of health effects, including inflammation, oxidative stress, carcinogenicity, and mood dysfunction. The literature on the role of BPA in inducing altered neurobehavioral response and brain morphology and plausible neuroprotective role of taurine against BPA induced oxidative stress mediated neurotoxicity is limited. Therefore, the present experimental paradigm was set for 21 days to expound the neuroprotective efficacy of taurine against BPA-induced neurotoxicity in zebrafish (Danio rerio) following waterborne exposure. Neurobehavioral studies were conducted by light-dark preference test (LDPT) and novel tank diving test (NTDT). To validate that the neuroprotective efficacy of taurine against BPA-induced neurotoxicity is associated with the modulation of the antioxidant defense system, we have conducted biochemical studies in zebrafish brain. Changes in brain morphology leading to neurobehavioral variations following co-supplementation of BPA and taurine were evaluated by Hoechst staining and cresyl violet staining (CVS) in periventricular gray zone (PGZ) of zebrafish brain. Our findings show that taurine co-supplementation significantly improved the BPA-induced altered scototaxis and explorative behavior of zebrafish. Further, BPA-induced augmented oxidative stress was considerably ameliorated by taurine co-supplementation. Subsequently, our observation also points toward the neuroprotective role of taurine against BPA-induced neuronal pyknosis and chromatin condensation in PGZ of zebrafish brain. In a nutshell, the findings of the current study show the neuroprotective efficacy of taurine against BPA-induced oxidative stress-mediated neurotoxicity. Elucidation of the underlying signaling mechanism of taurine-mediated neuroprotection would provide novel strategies for the prevention/treatment of BPA-persuaded serious neurological consequences.

Microcirculatory changes in venous leg ulcers using intermittent electrostimulation of common peroneal nerve.

OBJECTIVE: Activation of the venous muscle pumps of the leg by intermittent transdermal neuromuscular stimulation of the common peroneal nerve has been previously shown to augment venous and arterial flow in patients with leg ulcers. This study aims to establish if microcirculation in the wound bed and periwound area are augmented by the activation of a neuromuscular electrostimulation device (NMES) (Geko, Firstkind Ltd., UK). METHOD: In this self-controlled, observational study, laser speckle contrast imaging was used to map and quantify microcirculatory flow in the wound bed and periwound area of patients with venous leg ulcers (VLU). Values of flow and pulsatility in these locations were compared with the NMES device, both active and inactive. RESULTS: A total of 16 patients took part in the study. Microvascular flux increased by 27% (p=0.014) in the wound bed, and by 34% (p=0.004) in the periwound area, when the NMES device was activated. Pulsatility increased by 170% (p<0.001) in the wound bed and 173% (p<0.001) in the periwound area when the device was activated. CONCLUSION: Intermittent electrostimulation of the common peroneal nerve substantially increased both microcirculatory flux and pulsatility in the wound bed and in the periwound area of the VLUs of patients in this study. This provides a plausible mechanistic explanation for its reported efficacy in healing VLUs.

Neuromuscular stimulation of the common peroneal nerve increases arterial and venous velocity in patients with venous leg ulcers.

Activation of the venous muscle pumps by neuromuscular stimulation of the common peroneal nerve has been previously shown to increase venous and arterial flow in the legs of healthy subjects. The aim of this study is to determine whether a similar effect is observed in patients with chronic venous leg ulcers. 1 Hz intermittent electrostimulation of the common peroneal nerve was applied to 14 patients with ulcers between 1 and 10 cm in diameter, eliciting a small, painless, regular, muscular twitch of the leg. Flow was measured using Duplex ultrasound in the popliteal vein and the popliteal artery. Peak arterial velocity increased from 57 to 78 cm/s (P = .001) in sitting position, and from 79 to 98 cm/s in recumbent position (P = .001). Peak venous velocity increased from 10 to 33 cm/s (P = .001) sitting, and from 14 to 47 cm/s (P = .001) recumbent. Significant increases were observed in both venous and arterial blood flow in the lower limb. This suggestsed that activation of the venous muscle pump and improvement of arterial flow assisted oxygen delivery at the wound site. Moreover this may be a worthwhile intervention to assist in the healing of venous leg ulcers, and may provide a mechanistic explanation for the increased healing rates previously reported with neuromuscular stimulation of the common peroneal nerve.

Microcirculatory changes and thrombotic complications in COVID-19.

Despite its many devastating effects, the COVID-19 pandemic has had a positive impact in the ways in which society, scientific institutions, governing bodies, businesses, educational organisations, and communication have functioned unchallenged over the years. Rapid advancement in science enabled identification and characterisation of the virus and in developing vaccines to combat the disease. The mysterious ways in which the virus attacks the vital organs that lead on to multiorgan failure and thrombosis of the arterial and venous system have also been revealed. The ability to study the microcirculatory changes at the bedside and predict prognosis is a way forward. All the evidence suggests that the outcome of COVID-19 infection is related to the severity of the disease seen in the intensive care unit setting. This article discusses microcirculatory changes and immune coagulopathy caused by COVID-19.

Prevalence of Pain and Its Characteristics in Hospitalized Patients in an Indian Teaching Hospital.

BACKGROUND: Pain has a great impact on the physical and mental condition of hospitalized patients, reduces quality of life, and increases economic burden. AIMS: The study aimed to determine pain prevalence, its characteristics, analgesic treatment, and associated factors for severity and chronicity of pain in hospitalized patients. METHODS: A cross-sectional study was carried out including 847 eligible adult in-patients, aged ≥18 years, admitted to the All India Institute of Medical Sciences, Bhubaneswar, India, from June to August 2018. Pain severity was evaluated by visual analog scale (VAS) at the time of interview and after 1 week/completion of pain treatment. RESULTS: The prevalence of pain during the 24 hours preceding the interview was 70.6%. The duration of pain was ≥4 weeks in 162 (27.1%) patients and severe (VAS ≥ 7) in 144 (24.1%) patients. The mean VAS score was 6.27 ± 1.97 at the time of interview and 3.31 ± 1.89 after 1 week/completion of pain treatment (p < .001). Use of opioid analgesics (adjusted odds ratio [aOR]: 3.18; confidence interval [CI]: 2.23-4.55) was significantly related to pain severity, whereas patients ≥60 years (aOR: 1.64; CI: 0.99-2.70), patients in a nonsurgical ward (aOR: 1.78; CI: 1.21-2.60), and patients using opioid analgesics (aOR: 2.63; CI: 1.73-3.98) had prolonged pain, defined as ≥4 weeks. CONCLUSION: Pain prevalence and intensity in this Indian hospital were high and pain treatment was adequate in many cases. Timely assessment and appropriate management of pain in hospitalized patients is needed to prevent further pain and its complications in these patients.

Potential of breastmilk in stem cell research.

Breastmilk is a dynamic, multi-faceted, and complex fluid containing a plethora of biochemical and cellular components that execute developmental effects or differentiation program, providing nourishment and immunity to newborns. Recently, it was reported that breastmilk contains a heterogeneous population of naïve cells, including pluripotent stem cells, multipotent stem cells, immune cells, and non-immune cells. The stem cells derived from breastmilk possess immune privilege and non-tumorigenic properties. Thus, breastmilk may represent an ideal source of stem cells collected by non-perceive procedure than other available sources. Thus, this "maternally originating natural regenerative medicine" may have innumerable applications in clinical biology, cosmetics, and pharmacokinetics. This review describes the efficient integrated cellular system of mammary glands, the impressive stem cell hierarchy of breastmilk, and their possible implications in translational research and therapeutics.

Simple, Green, and High-Yield Production of Boron-Based Nanostructures with Diverse Morphologies by Dissolution and Recrystallization of Layered Magnesium Diboride Crystals in Water.

Layered metal diborides that contain metal atoms sandwiched between boron honeycomb planes offer a rich opportunity to access graphenic forms of boron. We recently demonstrated that magnesium diboride (MgB2 ) could be exfoliated by ultrasonication in water to yield boron-based nanosheets. However, knowledge of the fate of metal boride crystals in aqueous phases is still in its incipient stages. This work presents our preliminary findings on the discovery that MgB2 crystals can undergo dissolution in water under ambient conditions to result in precursors (prenucleation clusters) that, upon aging, undergo nonclassical crystallization preferentially growing in lateral directions by two-dimensional (2D) oriented attachment. We show that this recrystallization can be utilized as an avenue to obtain a high yield (≈92 %) of boron-based nanostructures, including nanodots, nanograins, nanoflakes, and nanosheets. These nanostructures comprise boron honeycomb planes chemically modified with hydride and oxy functional groups, which results in an overall negative charge on their surfaces. This ability of MgB2 crystals to yield prenucleation clusters that can self-seed to form nanostructures comprising chemically modified boron honeycomb planes presents a new facet to the physicochemical interaction of MgB2 with water. These findings also open newer avenues to obtain boron-based nanostructures with tunable morphologies by varying the chemical milieu during recrystallization.

Holistic feedback approach with video and peer discussion under teacher supervision.

BACKGROUND: High quality feedback is vital to learning in medical education but many students and teachers have expressed dissatisfaction on current feedback practices. Lack of teachers' insight into students' feedback requirements may be a key, which might be addressed by giving control to the students with student led feedback practices. The conceptual framework was built on three dimensions of learning theory by Illeris and Vygotsky's zone of proximal development and scaffolding. We introduced a feedback session with self-reflection and peer feedback in the form of open discussion on video-recorded student performances under teacher's guidance. The aims of this qualitative study were to explore students' perception on this holistic feedback approach and to investigate ways of maximising effective feedback and learning. METHODS: Semi-structured interviews were used to gather data which were evaluated using a thematic analytical approach. The participants were third year medical students of Imperial College London on clinical placements at Hillingdon Hospital. RESULTS: Video based self-reflection helped some students to identify mistakes in communication and technical skills of which they were unaware prior to the session. Those who were new to video feedback found their expected self-image different to that of their actual image on video, leading to some distress. However many also identified that mistakes were not unique to themselves through peer videos and learnt from both model performances and from each other's mistakes. Balancing honest feedback with empathy was a challenge for many during peer discussion. The teacher played a vital role in making the session a success by providing guidance and a supportive environment. CONCLUSIONS: This study has demonstrated many potential benefits of this holistic feedback approach with video based self-reflection and peer discussion with students engaging at a deeper cognitive level than the standard descriptive feedback.

Neonatal Benzo[a]pyrene Exposure Induces Oxidative Stress and DNA Damage Causing Neurobehavioural Changes during the Early Adolescence Period in Rats.

Humans are exposed to polycyclic aromatic hydrocarbons (PAHs) by ingestion of contaminated food and water. Prenatal exposure to benzo[a]pyrene (B[a]P) like PAHs through the placental barrier and neonatal exposure by breast milk and the environment may affect early brain development. In the present study, single intracisternal administration of B[a]P (0.2 and 2.0 µg/kg body weight) to male Wistar rat pups at postnatal day 5 (PND5) was carried out to study its specific effect on neonatal brain development and its consequences at PND30. B[a]P administration showed a significant increase in exploratory and anxiolytic-like behaviour with elevated hippocampal lipid peroxidation and protein oxidation at PND30. Further, DNA damage was estimated in vitro (Neuro2a and C6 cell lines) by the comet assay, and oxidative DNA damage of hippocampal sections was measured in vivo following exposure to B[a]P. DNA strand breaks (single and double) significantly increased due to B[a]P at PND30 in hippocampal neurons and increased the nuclear tail moment in Neuro2a cells. Hippocampal 8-oxo-2'-deoxyguanosine production was significantly elevated showing expression of more TUNEL-positive cells in both doses of B[a]P. Histological studies also revealed a significant reduction in mean area and perimeter of hippocampal neurons in rats treated with B[a]P 2.0 µg/kg, when compared to naïve and control rats. B[a]P significantly increased anxiolytic-like behaviour and oxidative DNA damage in the hippocampus causing apoptosis that may lead to neurodegeneration in adolescence. The findings of the present study address the potential role of B[a]P in inducing oxidative stress-mediated neurodegeneration in the hippocampus through oxidative DNA damage in the early adolescence period of rats.

Insulin receptor A and Sirtuin 1 synergistically improve learning and spatial memory following chronic salidroside treatment during hypoxia.

Hypoxia has been reported to cause hippocampal neurodegeneration resulting in learning and memory deficits. In the present study, we investigated the potential of salidroside, a glucoside derivative of tyrosol, in ameliorating hypoxia-induced neurodegeneration and memory impairment. Morris water maze test showed improvement in learning and spatial memory of salidroside-treated hypoxic rats correlating with increased dendritic intersections and arborization. Salidroside administration increased phosphorylation of insulin receptor subunit A (IRA) at Y972, Y1162/63, and Y1146 sites and subsequent activation of AMP-activated protein kinase (AMPK) α subunit isoforms pAMPKα1 and pAMPKα2 resulting in mitochondrial biogenesis. Contrarily, silencing of IRA in salidroside-supplemented hypoxic hippocampal cells could not improve cell viability or alter pAMPKα1 and pAMPKα2 expression. Rats administered with salidroside showed elevated expression of phosphorylated cAMP response element-binding protein in the hippocampus. Salidroside administration also resulted in increased sirtuin 1 (SIRT1) activity through a cytochrome P4502E1 (CYP2E1)-regulated mechanism that was independent of pIRA. Taken together, these findings suggest a synergistic role of pIRA and SIRT1 in salidroside-mediated neuroprotection, mitochondrial biogenesis, and cognitive improvement during hypoxia. We propose a novel mechanism for salidroside-mediated neuroprotection in hypoxia.