Gadd45A-mediated autophagy regulation and its impact on Alzheimer's disease pathogenesis: Deciphering the molecular Nexus.

BACKGROUND: The growth arrest and DNA damage-inducible 45 (Gadd45) gene has been implicated in various central nervous system (CNS) functions, both normal and pathological, including aging, memory, and neurodegenerative diseases. In this study, we examined whether Gadd45A deletion triggers pathways associated with neurodegenerative diseases including Alzheimer's disease (AD). METHODS: Utilizing transcriptome data from AD-associated hippocampus samples, we identified Gadd45A as a pivotal regulator of autophagy. Comprehensive analyses, including Gene Ontology enrichment and protein-protein interaction network assessments, highlighted Cdkn1A as a significant downstream target of Gadd45A. Experimental validation confirmed Gadd45A's role in modulating Cdkn1A expression and autophagy levels in hippocampal cells. We also examined the effects of autophagy on hippocampal functions and proinflammatory cytokine secretion. Additionally, a murine model was employed to validate the importance of Gadd45A in neuroinflammation and AD pathology. RESULTS: Our study identified 20 autophagy regulatory factors associated with AD, with Gadd45A emerging as a critical regulator. Experimental findings demonstrated that Gadd45A influences hippocampal cell fate by reducing Cdkn1A expression and suppressing autophagic activity. Comparisons between wild-type (WT) and Gadd45A knockout (Gadd45A-/-) mice revealed that Gadd45A-/- mice exhibited significant cognitive impairments, including deficits in working and spatial memory, increased Tau hyperphosphorylation, and elevated levels of kinases involved in Tau phosphorylation in the hippocampus. Additionally, Gadd45A-/- mice showed significant increases in pro-inflammatory cytokines and decreases autophagy markers in the brain. Neurotrophin levels and dendritic spine length were also reduced in Gadd45A-/- mice, likely contributing to the observed cognitive deficits. CONCLUSIONS: These findings support the direct involvement of the Gadd45A gene in AD pathogenesis, and enhancing the expression of Gadd45A may represent a promising therapeutic strategy for the treatment of AD.

Systematic review of sarcopenia in inflammatory bowel disease.

INTRODUCTION: There is growing evidence of increased muscle atrophy in IBD patients, likely resulting in a higher sarcopenia prevalence in IBD. The aims of this systematic review are A1; to estimate sarcopenia prevalence in IBD patients, A2; to investigate its impact on IBD patients, and A3; the effectiveness of nutritional interventions on muscle mass and/or strength in IBD patients. METHODS: On 28 July 2021, three electronic databases were used to identify eligible studies, including peer-reviewed studies (randomised controlled trials [RCTs], non-RCTs, observation studies) in adult (⩾ 18 years) IBD patients. For A1 and A2 only, studies defined low muscle mass and/or strength cut-off points. For A2, studies assessed association between sarcopenia and IBD complication. For A3, studies assessed the nutrition effect among IBD patients. RESULTS: 35 studies were included, 34 for A1, 20 for A2, and three for A3. 42% of adult IBD patients have myopenia, 34% have pre-sarcopenia, and 17% sarcopenia. Myopenic IBD was significantly associated with therapy failure including IBD-related surgery risk in six studies, risk of medical therapy failure in four studies, risk of hospitalisation in one study. A significant association existed with postoperative complications risk in IBD patients in four studies, reduction in BMD in two studies, and increased incidence of non-alcoholic fatty liver disease (NAFLD) in one study. Sarcopenia in IBD was significantly associated with a reduction in BMD in one study. Two studies found a personalised nutrition plan (high protein) in IBD patients significantly improved muscle mass. One study found a significant positive association between muscle mass and dietary intake including high protein intake. CONCLUSION: Over one third of adult IBD patients have myopenia and pre-sarcopenia, and nearly a fifth have sarcopenia. Myopeninc IBD is significantly associated with increased risk of IBD therapy failure, postoperative complications, and low BMD, with possible association with increased NAFLD risk. Nutritional therapy may play a role in reversing low muscle mass though yet unclear if this is through disease activity reversal. Further studies on adult IBD patients focusing on sarcopenia/myopenia are needed with recommended study designs of 1) standardised population-based definitions with recommended standard methods used to measure skeletal muscle mass, 2) prospective studies with IBD patients stratified by Montreal classification, disease activity, disease duration and concomitant medication to observe muscle changes, 3) mechanistic studies on sarcopenia aetiology, specifically focusing on protein handling atrophy and absorption, 4) properly designed RCT to assess nutrition intervention in sarcopenic IBD patients.

Fabrication, assessment, and optimization of alendronate sodium nanoemulsion-based injectable in-situ gel formulation for management of osteoporosis.

Low bone mass, degeneration of bone tissue, and disruption of bone microarchitecture are all symptoms of the disease osteoporosis, which can decrease bone strength and increase the risk of fractures. The main objective of the current study was to use a phospholipid-based phase separation in-situ gel (PPSG) in combination with an alendronate sodium nanoemulsion (ALS-NE) to help prevent bone resorption in rats. The effect of factors such as concentrations of the ALS aqueous solution, surfactant Plurol Oleique CC 497, and Maisine CC oil on nanoemulsion characteristics such as stability index and globular size was investigated using an l-optimal coordinate exchange statistical design. Injectable PPSG with the best nanoemulsion formulation was tested for viscosity, gel strength, water absorption, and in-vitro ALS release. ALS retention in the rats' muscles was measured after 30 days. The droplet size and stability index of the optimal nanoemulsion were 90 ± 2.0 nm and 85 ± 1.9%, respectively. When mixed with water, the optimal ALS-NE-loaded PPSG became viscous and achieved 36 seconds of gel strength, which was adequate for an injectable in-situ formulation. In comparison with the ALS solution-loaded in-situ gel, the newly created optimal ALS-NE-loaded PPSG produced the sustained and regulated release of ALS; hence, a higher percentage of ALS remained in rats' muscles after 30 days. PPSG that has been loaded with an ALS-NE may therefore be a more auspicious, productive, and effective platform for osteoporosis treatment than conventional oral forms.

The long-term effects of exposure to ionising radiation on gene expression in mice.

Despite great advancement in our understanding of the biological response to ionising radiation in mammals, a number of pertinent questions remain unanswered. For instance, the mechanisms underlying the long-term effects of acute radiation in vivo still eludes us. Here we report that acute exposure to X-rays in male mice significantly affects their transcriptome. Using microarrays and miRNA-sequencing, we profiled the gene expression pattern in the brain, the kidney, the liver and the sperm of irradiated and control from CBA/Ca and BALB/c in the timeline of 4 h, 24 h, 1 week and 10 weeks post-exposure. Acute exposure to 1 Gy of X-rays resulted in profound tissue- and strain-specific changes in gene expression pattern. There was profound change in the gene expression in the kidney of BALB/c irradiated mice over the period of 10 weeks after irradiation, whereas in the CBA/Ca strain the significant transcriptomic changes manifest over a shorter period of time up to 1 week post exposure. In the brain of irradiated CBA/Ca, significant changes in transcriptome were seen up to 10 weeks post-irradiation, while only short-term changes up to 4 h post-exposure was detected in the brain of irradiation BALB/c. Similarly, alteration in gene expression pattern was observed in the liver of irradiated BALB/c up to 10 weeks post-radiation, whereas only immediate but significant changes were observed in the CBA/Ca at 4 h post-irradiation. Furthermore, the analysis of miRNA in irradiated and control male mice also revealed highly tissue- and strain-specific changes in expression level, with no overlap between the differentially regulated miRNA genes across the three somatic tissues and the two inbred strains. We also analysed the pattern of miRNA expression in sperm of irradiated males, sacrificed at 24 h, 1 week and 10 weeks after irradiation. Only one miRNA (mmu-miR-217-5p) was significantly down-regulated in the CBA/Ca males. The results of our study may provide a plausible explanation for the delayed in vivo effects of irradiation.