Proximity driven plastid-nucleus relationships are facilitated by tandem plastid-ER dynamics.

Peri-nuclear clustering (PNC) of chloroplasts has largely been described in senescent and pathogen- or ROS- stressed cells. Stromules, tubular plastid extensions are also observed under similar conditions. Coincident observations of PNC and stromules associate the two phenomena in facilitating retrograde signaling between chloroplasts and the nucleus. However, PNC incidence in non-stressed cells under normal growth and developmental conditions, when stromules are usually not observed, remains unclear. Using transgenic Arabidopsis expressing different organelle-targeted fluorescent proteins we show that PNC is a dynamic subcellular phenomenon that continues in the absence of light and is not dependent on stromule formation. PNC is facilitated by tandem plastid-ER dynamics created through membrane contact sites between the two organelles. While PNC increases upon ER-membrane expansion, some plastids may remain in the peri-nuclear region due to their localization in ER-lined nuclear indentions. Moreover, some PNC plastids may sporadically extend stromules into ER-lined nuclear grooves. Our findings strongly suggest that PNC is not an exclusive response to stress caused by pathogens, high light or exogenous-H2O2 treatment and does not require stromule formation. However, morphological and behavioural alterations in ER and concomitant changes in tandem, plastid-ER dynamics play a major role in facilitating the phenomenon.

From Gut Microbiomes to Infectious Pathogens: Neurological Disease Game Changers.

Gut microbiota and infectious diseases affect neurological disorders, brain development, and function. Compounds generated in the gastrointestinal system by gut microbiota and infectious pathogens may mediate gut-brain interactions, which may circulate throughout the body and spread to numerous organs, including the brain. Studies shown that gut bacteria and disease-causing organisms may pass molecular signals to the brain, affecting neurological function, neurodevelopment, and neurodegenerative diseases. This article discusses microorganism-producing metabolites with neuromodulator activity, signaling routes from microbial flora to the brain, and the potential direct effects of gut bacteria and infectious pathogens on brain cells. The review also considered the neurological aspects of infectious diseases. The infectious diseases affecting neurological functions and the disease modifications have been discussed thoroughly. Recent discoveries and unique insights in this perspective need further validation. Research on the complex molecular interactions between gut bacteria, infectious pathogens, and the CNS provides valuable insights into the pathogenesis of neurodegenerative, behavioral, and psychiatric illnesses. This study may provide insights into advanced drug discovery processes for neurological disorders by considering the influence of microbial communities inside the human body.

Bridging the gap between GLP1-receptor agonists and cardiovascular outcomes: evidence for the role of tirzepatide.

Tirzepatide is a new drug targeting glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP) receptors. This drug has demonstrated great potential in improving the clinical outcomes of patients with type 2 diabetes. It can lead to weight loss, better glycemic control, and reduced cardiometabolic risk factors. GLP1 receptor agonists have been proven effective antidiabetic medications with possible cardiovascular benefits. Even though they have been proven to reduce the risk of major adverse cardiovascular events, their effectiveness in treating heart failure is unknown. Unlike traditional GLP1 receptor agonists, tirzepatide is more selective for the GIP receptor, resulting in a more balanced activation of these receptors. This review article discusses the possible mechanisms tirzepatide may use to improve cardiovascular health. That includes the anti-inflammatory effect, the ability to reduce cell death and promote autophagy, and also its indirect effects through blood pressure, obesity, and glucose/lipid metabolism. Additionally, tirzepatide may benefit atherosclerosis and lower the risk of major adverse cardiac events. Currently, clinical trials are underway to evaluate the safety and efficacy of tirzepatide in patients with heart failure. Overall, tirzepatide's dual agonism of GLP1 and GIP receptors appears to provide encouraging cardiovascular benefits beyond glycemic control, offering a potential new therapeutic option for treating cardiovascular diseases and heart failure.

Evidence that tirzepatide protects against diabetes-related cardiac damages.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. METHODS: A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT. RESULTS: Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40-0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure. CONCLUSION: Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT.

Using ER-Targeted Photoconvertible Fluorescent Proteins in Living Plant Cells.

Photoconvertible fluorescent proteins (pcFPs) enable differential coloring of a single organelle. Several pcFP-based probes have been targeted to the endoplasmic reticulum (ER) and can serve as useful tools to study ER dynamics and interactions with other organelles. Here, we describe the procedure to conduct live-cell imaging experiments using ER-targeted pcFP-based probes. Potential problems that might occur during the experiments, their solutions, and several ways to improve the experiments are discussed.

Tirzepatide prevents neurodegeneration through multiple molecular pathways.

BACKGROUND: Several evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment. In this study, we elucidated the molecular processes underlying the protective effect of Tirzepatide (TIR), a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP-RA)/ GLP-1RA, against learning and memory disorders. METHODS: We investigated the effects of TIR on markers of neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3 and SORBS1) in a neuroblastoma cell line (SHSY5Y) exposed to normal and high glucose concentration. The potential role on DNA methylation of genes involved in neuroprotection and epigenetic modulators of neuronal growth (miRNA 34a), apoptosis (miRNA 212), and differentiation (miRNA 29c) was also investigated. The cell proliferation was detected by measuring Ki-67 through flow cytometry. The data were analysed by SPSS IBM Version 23 or GraphPad Prism 7.0 software and expressed as the means ± SEM. Differences between the mean values were considered significant at a p-value of < 0.05. GraphPad Prism software was used for drawing figures. RESULTS: For the first time, it was highlighted: (a) the role of TIR in the activation of the pAkt/CREB/BDNF pathway and the downstream signaling cascade; (b) TIR efficacy in neuroprotection; (c) TIR counteracting of hyperglycemia and insulin resistance-related effects at the neuronal level. CONCLUSIONS: We demonstrated that TIR can ameliorate high glucose-induced neurodegeneration and overcome neuronal insulin resistance. Thus, this study provides new insight into the potential role of TIR in improving diabetes-related neuropathy.

Impact of COVID-19 pandemic on surgical residency: Residents' perception.

BACKGROUND: World Health Organization declared COVID-19 outbreak a pandemic, and till the month of March 2023, globally, there have been 761,402,282 confirmed cases of COVID-19, including 6887,000 deaths. In India, almost 44,707,525 cases been recorded till date. Here, almost 30,000,000 cases been recorded after the second wave. The working force fighting this pandemic is majority formed by resident doctors all over the country and globally. MATERIALS AND METHODS: This study was conducted among 110 residents pursuing postgraduation in surgery and allied departments in various training institutions in Tamil Nadu for a duration of 6 months (after the second wave). A pretested and validated questionnaire was formulated to assess the effect of COVID-19 pandemic on surgical trainee's residency program from their perspective. The questionnaire contained basic social-demographic details and general information like the details of surgical specialty they are admitted to, the overall details of changes in their surgical residency experience in the times of COVID pandemic and the changes faced by them in their day-to-day clinical, diagnostic, and surgical learning. The questionnaire also investigated the redeployment status of the surgical trainees to COVID treatment units and their perspective on the changes in their clinical research and surgical skills training. RESULTS: The study participants, 66%, were aged between 25 and 30 years, followed by 30 and 35 years (25.5%). Almost 80% of the participants belong to the final year of postgraduation; 67.3% of surgical trainees strongly perceives and all 100% of them accept the fact that their surgical residency has been affected by the ongoing pandemic. Fifty percent of the trainees were redeployed to COVID duties for 8 h a day shift and rest attended a minimum of 4 h of COVID duties. More than 75% of the residents had COVID duties of 5-10 h/day and more than 90% of these redeployed trainees involved in COVID duties have expressed that they had been suffering from extra stress and more than 60% were suffering from stress grade between 5 and 10 suggestive of high-stress level. Fifty-nine percent of the postgraduates in the current study mentioned that they require extra-surgical or skill-based training after their postgraduation period. CONCLUSION: The influence of COVID-19 on surgical trainees in various institutions of India has been immense due to overburdening of health systems by the large population of the country. Second wave of COVID, especially, has drastically changed the postgraduate surgical trainees' lives. Detrimental effects are not restricted to operative and clinical experience but also the mental health and well-being of them. The observations of the present study make recommendations for the future provision of training through skill-based surgical simulations so that the lost days of their trainings can be compensated and they become the confident surgeons of the future.