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.

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.

Bisphenol A-induced neurobehavioral transformation is associated with augmented monoamine oxidase activity and neurodegeneration in zebrafish brain.

As bisphenol A (BPA) effortlessly crosses the blood-brain barrier, its serious impacts on the neuronal microenvironment towards precocious induction of oxidative stress and neuromorphological alteration can't be ignored. Incidentally, a symmetric study establishing the possible link of transformed neurobehavior with heightened monoamine oxidase (MAO) activity and neuromorphological alteration in zebrafish brain subsequent to BPA-exposure is limiting in the literature. The study was conducted to delineate the role of BPA towards the genesis of aggressive behaviour in zebrafish and its correlation with brain MAO activity. Mirror biting test and open field test were conducted to evaluate the aggressive and explorative behaviour respectively. Biochemical studies were performed to delineate the modulation of the antioxidant defence system. Cresyl violet staining and Hoechst staining in the periventricular grey zone of the zebrafish brain were conducted to evaluate neuronal pyknosis and chromatin condensation. Our study showed that BPA exposure is associated with the genesis of aggressive neurobehavioral response. Moreover, the brain MAO activity, oxidative stress and chromatin condensation were increased with increase in exposure duration. The results of the present study gave conclusive evidence that BPA act as a potent neurotoxicant in transforming the native neurobehavioral response of zebrafish through heightened oxidative stress, MAO activity and altered neuromorphology.

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.

Recent Advances Towards Diagnosis and Therapeutic Fingerprinting for Alzheimer's Disease.

Since the report of "a peculiar severe disease process of the cerebral cortex" by Alois Alzheimer in 1906, it was considered to be a rare condition characterized by loss of cognition, memory impairment, and pathological markers such as senile plaques or neurofibrillary tangles (NFTs). Later on, the report was published in the textbook "Psychiatrie" and the disease was named as Alzheimer's disease (AD) and was known to be the consequences of aging; however, owing to its complex etiology, there is no cure for the progressive neurodegenerative disorder. Our current understanding of the mechanisms involved in the pathogenesis of AD is still at the mechanistic level. The treatment strategies applied currently only alleviate the symptoms and co-morbidities. For instance, the available treatments such as the usage of acetylcholinesterase inhibitors and N-methyl D-aspartate antagonists have minimal impact on the disease progression and target the later aspects of the disease. The recent advancements in the last two decades have made us more clearly understand the pathophysiology of the disease which has led to the development of novel therapeutic strategies. This review gives a brief idea about the various facets of AD pathophysiology and its management through modern investigational therapies to give a new direction for development of targeted therapeutic measures.

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.

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.

Temporal exposure to chronic unpredictable stress induces precocious neurobehavioral deficits by distorting neuromorphology and glutathione biosynthesis in zebrafish brain.

Modelling of chronic stress conditions in experimental animals and its neuropsychiatric outcomes has been well documented in literature. Zebrafish (Danio rerio) by exhibiting significant genetic and epidemiological similarities with human beings, has now emerged as a promising animal model of translational research. In this line, risk assessment following exposure to chronic unpredictable stress (CUS) towards neurobehavioral response and neuromorphology of sensitive brain region in zebrafish is the prime objective of the present study. With the existing knowledge on CUS in affecting diverse neurobehavioral aspects, we were primarily interested in whether this neurobehavioral transformation is an outcome of altered glutathione biosynthesis in zebrafish. We were also concerned about whether the precocious neurobehavioral transformation has been linked to altered neuromorphology in the periventricular grey zone (PGZ) of the zebrafish brain. Our basic findings showed that CUS itself represented as a universal factor in altering native bottom-dwelling and scototaxis behaviour of zebrafish. Our findings also backing the argument that CUS itself represented a collective stress regimen by altering the brain glutathione biosynthesis in zebrafish. Correspondingly, a temporal transformation in CUS instigated augmentation in neuronal pyknosis and chromatin condensation were observed in PGZ of the zebrafish brain. Collectively, these findings designate that CUS induced temporal neurobehavioral transformation is an outcome of augmented oxidative stress and neuromorphological alteration in the zebrafish brain. However, the underlying mechanism of such neuropathological manifestation associated with CUS might provide novel insight towards the development of prophylactic/therapeutic intervention to counter such co-morbid behavioral alteration.

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.

Multicentric evaluation of a novel point of care electrochemical ELISA platform for SARS-CoV-2 specific IgG and IgM antibody assay.

New diagnostics technologies for the efficient detection and quantification of SARS-CoV-2 antibodies are very crucial to manage the COVID-19 pandemic, especially in the context of emerging vaccination paradigms. Herein, we report on a novel point-of-care Electrochemical ELISA platform with disposable screen printed electrodes functionalized with SARS-CoV-2 Spike Glycoprotein S1, to enable fast and accurate quantitative estimation of total antibody concentration (IgG and IgM) in clinical samples. The quantification is performed with a comparison of electrochemical redox current against the current produced by the spiked monoclonal antibodies with known concentration. The assay is validated through multicentric evaluation against 3 different FDA authorized Laboratory standard techniques, using both EDTA whole blood and serum samples. We demonstrate that the proposed assay has excellent sensitivity and specificity, making it a suitable candidate for epidemiological surveys and quantification of antibodies in COVID-19 vaccination programs.

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.

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.

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.

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.

Referral patterns for catheter-directed thrombolysis for iliofemoral deep venous thrombosis.

OBJECTIVES: Post thrombotic syndrome (PTS) is a serious complication of deep venous thromboses (DVTs). PTS occurs more frequently and severely following iliofemoral DVT compared to distal DVTs. Catheter directed thrombolysis (CDT) of iliofemoral DVTs may reduce PTS incidence and severity.We aimed to determine the rate of iliofemoral DVT within our institution, their subsequent management, and compliance with NICE guidelines. METHODS: Retrospective review of all DVTs diagnosed over a 3-year period was conducted. Cases of iliofemoral DVT were identified using ICD-10 codes from patient notes, and radiology reports of Duplex scans. Further details were retrieved, such as patient demographics and referrals to vascular services. NICE guidance was applied to determine if patients would have been suitable for CDT. A survey was sent to clinicians within medicine to identify awareness of CDT and local guidelines for iliofemoral DVT management. RESULTS: 225 patients with lower limb DVTs were identified. Of these, 96 were radiographically confirmed as iliofemoral DVTs. The median age was 77. 67.7% of iliofemoral DVTs affected the left leg. Right leg DVTs made up 30.2% and 2.1% were bilateral DVTs. Of the 96 iliofemoral DVTs, 21 were deemed eligible for CDT. Only 3 patients (14.3%) were referred to vascular services, and 3 received thrombolysis.From our survey, 95.5% of respondents suggested anticoagulation alone as management for iliofemoral DVT. Only one respondent recommended referral to vascular services. There was a knowledge deficiency regarding venous anatomy, including superficial versus deep veins. CONCLUSIONS: CDT and other mechanochemical procedures have been shown to improve outcomes of patients post-iliofemoral DVT, however a lack of awareness regarding CDT as a management option results in under-referral to vascular services. We suggest closer relations between vascular services and their "tributary" DVT clinics, development of guidelines and robust care pathways in the management of iliofemoral DVT.

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.

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.

RNA-Binding RING E3-Ligase DZIP3/hRUL138 Stabilizes Cyclin D1 to Drive Cell-Cycle and Cancer Progression.

DZIP3/hRUL138 is a poorly characterized RNA-binding RING E3-ubiquitin ligase with functions in embryonic development. Here we demonstrate that DZIP3 is a crucial driver of cancer cell growth, migration, and invasion. In mice and zebrafish cancer models, DZIP3 promoted tumor growth and metastasis. In line with these results, DZIP3 was frequently overexpressed in several cancer types. Depletion of DZIP3 from cells resulted in reduced expression of Cyclin D1 and a subsequent G1 arrest and defect in cell growth. Mechanistically, DZIP3 utilized its two different domains to interact and stabilize Cyclin D1 both at mRNA and protein levels. Using an RNA-binding lysine-rich region, DZIP3 interacted with the AU-rich region in 3' untranslated region of Cyclin D1 mRNA and stabilized it. Using a RING E3-ligase domain, DZIP3 interacted and increased K63-linked ubiquitination of Cyclin D1 protein to stabilize it. Remarkably, DZIP3 interacted with, ubiquitinated, and stabilized Cyclin D1 predominantly in the G1 phase of the cell cycle, where it is needed for cell-cycle progression. In agreement with this, a strong positive correlation of mRNA expression between DZIP3 and Cyclin D1 in different cancer types was observed. Additionally, DZIP3 regulated several cell cycle proteins by modulating the Cyclin D1-E2F axes. Taken together, this study demonstrates for the first time that DZIP3 uses a unique two-pronged mechanism in its stabilization of Cyclin D1 to drive cell-cycle and cancer progression. SIGNIFICANCE: These findings show that DZIP3 is a novel driver of cell-cycle and cancer progression via its control of Cyclin D1 mRNA and protein stability in a cell-cycle phase-dependent manner. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/2/315/F1.large.jpg.

Quercetin abrogates bisphenol A induced altered neurobehavioral response and oxidative stress in zebrafish by modulating brain antioxidant defence system.

Bisphenol A (BPA), a well-recognized anthropogenic xenoestrogen, has been identified as a causative agent responsible for inducing carcinogenicity, cognitive impairment, neurotoxicity, oxidative stress, etc. However, BPA-induced neurotoxicity and its possible amelioration through natural compound intervention remain elusive. The current study was performed to elucidate the neurotoxic potential of BPA in zebrafish (Danio rerio) by waterborne exposure and its possible amelioration by quercetin co-supplementation. Protective effect of quercetin against BPA-induced altered neurobehavioral response, oxidative stress and neuromorphological changes were evaluated in zebrafish brain. The present findings reveal that BPA-induced altered neurobehavioral response was ameliorated by quercetin. Biochemical studies advocate the potential therapeutic efficacy of quercetin against BPA-induced oxidative stress in zebrafish brain. Quercetin also shows neuroprotection against BPA-induced augmented neuronal pyknosis in periventricular grey zone (PGZ) of zebrafish brain. These basic findings indicate that quercetin may act as an effective intervention against BPA-induced neurotoxicity in zebrafish through down-regulation of oxidative stress.

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.