Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.

This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.

Understanding and Managing Metabolic Deficiencies Post Bariatric and Esophagectomy Surgeries: A Narrative Review of the Literature.

Gastrectomy and esophagectomy are the most performed surgeries in the treatment of both esophageal and gastric cancers. The type of esophagectomy depends on the type of malignancy, site of the tumor, criteria of resection, and field of resection. The three standard approaches to esophagectomy are the transhiatal approach, the left thoracoabdominal approach, and a three-stage procedure. The transhiatal approach involves abdominal and cervical incisions, while the left thoracoabdominal approach is a one-stage procedure that utilizes a single incision exposing the dissection field. The Ivor Lewis and McKeown esophagectomies are two-stage and three-stage surgeries that include laparotomy with right thoracotomy. Malabsorption often emerges as a significant postoperative complication following esophagectomy and gastrectomy surgeries. Malnutrition linked with these cancers has detrimental effects, including heightened rates of postoperative complications, elevated infection risks, delayed wound healing, reduced tolerance to treatment, diminished quality of life, and heightened mortality rates. Our narrative review summarizes and sheds light on solutions to treat malabsorption disorders and malnutrition after gastric bypass surgery. These solutions include methods such as adjustments, supplements, and treatment. Although more research is needed to confirm their effectiveness, these methods indicate potential for lowering the impact on patients' diets. By considering the beneficial implications of these effects and considering solutions, we aim to improve the management of these adverse effects, ultimately improving the overall health and postoperative outcomes of patients.

Grafting-from Synthesis of Plant-Polynorbornene Biohybrid Materials.

Plants, essential for food, oxygen, and economic stability, are under threat from human activities, biotic threats, and climate change, requiring rapid technological advancements for protection. Biohybrid systems, merging synthetic macromolecules with biological components, have provided improvement to biological systems in the past, namely, in the biomedical arena, motivating an opportunity to enhance plant well-being. Nevertheless, strategies for plant biohybrid systems remain limited. In this study, we present a method using grafting-from ring-opening metathesis polymerization (ROMP) under physiological conditions to integrate norbornene-derived polymers into live plants by spray coating. The approach involves creating biological macroinitiators on leaf surfaces, which enable subsequent polymerization of norbornene-derived monomers. Characterization techniques, including FTIR spectroscopy, SEM EDS imaging, ICP-MS, nanoindentation, and XPS, confirmed the presence and characterized the properties of the polymeric layers on leaves. The demonstrated modifiability and biocompatibility could offer the potential to maintain plant health in various applications, including the development of thermal barriers, biosensors, and crop protection layers.

The ecto-enzyme CD38 modulates CD4 T cell immunometabolic responses and participates in HIV pathogenesis.

Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4 T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after TCR-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular NAD and NMN concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the OCR/ECAR ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ectoCD38 catalytic activity in memory CD4 T cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous pro-inflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morpho-functionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4 T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.

Erk1/2 signaling mediates the HGF-induced protection against ethanol and acetaldehyde-induced toxicity in the pancreatic RINm5F cell line.

Alcohol-induced pancreas damage remains as one of the main risk factors for pancreatitis development. This disorder is poorly understood, particularly the effect of acetaldehyde, the primary alcohol metabolite, in the endocrine pancreas. Hepatocyte growth factor (HGF) is a protective protein in many tissues, displaying antioxidant, antiapoptotic, and proliferative responses. In the present work, we were focused on characterizing the response induced by HGF and its protective mechanism in the RINm5F pancreatic cell line treated with ethanol and acetaldehyde. RINm5F cells were treated with ethanol or acetaldehyde for 12 h in the presence or not of HGF (50 ng/ml). Cells under HGF treatment decreased the content of reactive oxygen species and lipid peroxidation induced by both toxics, improving cell viability. This effect was correlated to an improvement in insulin expression impaired by ethanol and acetaldehyde. Using a specific inhibitor of Erk1/2 abrogated the effects elicited by the growth factor. In conclusion, the work provides mechanistic evidence of the HGF-induced-protective response to the alcohol-induced damage in the main cellular component of the endocrine pancreas.

Púrpura de Schönlein Henoch en paciente adulto

RESUMEN La púrpura de Schönlein-Henoch es una vasculitis por fragmentación de leucocitos inmunomediada que afecta a pequeños vasos sanguíneos. Los cuatro componentes clínicos esenciales son púrpuras, dolor abdominal, artralgia y afectación renal. El caso trata de una mujer de 50 años que ingresa por dolor abdominal y hematoquecia de 72 horas de evolución, posterior a laparotomía exploratoria. Al examen físico presenta lesiones purpúricas en tronco y extremidades inferiores de 2 meses de aparición. En paraclínicos se observa hemograma con plaquetas normales, proteínas en orina 500 mg/dL, proteinuria 2,4 g/24 hs. Ante sospecha de vasculitis con plausible inclusión cutáneo-renal, se pide anticuerpos antinucleares, ANCA y se realiza biopsia cutánea evidenciándose una vasculitis neutrofílica necrotizante de pequeños vasos. En la biopsia renal se observa en inmunofluorescencia directa depósito de IgA, C3 positivo. En relación clínica de la proteinuria y compromiso cutáneo junto con la confirmación de biopsia renal se concluye en diagnóstico de púrpura de Schönlein Henoch. El interés de este caso radica en la inconsistencia de esta patología en los adultos, a pesar de que bien podría ser de una gravedad más notable dado que existe un mayor peligro de falla renal persistente.

ABSTRACT Schönlein-Henoch purpura is an immune-mediated leukocyte fragmentation vasculitis that affects small blood vessels. The four essential clinical components are purpura, abdominal pain, arthralgia, and renal involvement. This case concerns a 50-year-old woman who is admitted due to abdominal pain and hematochezia of 72 hours of evolution, after an exploratory laparotomy. On physical examination, she presents purpuric lesions on the trunk and lower extremities of 2 months of appearance. In paraclinical tests, a blood count with normal platelets, urine protein 500 mg/dL, and proteinuria 2.4 g/24 hours are observed. Suspecting vasculitis with plausible cutaneous-renal inclusion, antinuclear antibodies and ANCA are requested, and a skin biopsy is performed, showing necrotizing neutrophilic vasculitis of small vessels. In the renal biopsy, IgA deposit, C3 positive is observed in the direct immunofluorescence. In the clinical relationship of proteinuria and skin involvement together with the confirmation of renal biopsy, the diagnosis of Schönlein-Henoch purpura is concluded. The interest of this case lies in the inconsistency of this pathology in adults, despite the fact that it could be more serious given that there is a greater risk of persistent renal failure.

Obesity in male volcano mice Neotomodon alstoni affects the daily rhythm of metabolism and thermoregulation.

The mouse N. alstoni spontaneously develops the condition of obesity in captivity when fed regular chow. We aim to study the differences in metabolic performance and thermoregulation between adult lean and obese male mice. The experimental approach included indirect calorimetry using metabolic cages for VO2 intake and VCO2 production. In contrast, the body temperature was measured and analyzed using intraperitoneal data loggers. It was correlated with the relative presence of UCP1 protein and its gene expression from interscapular adipose tissue (iBAT). We also explored in this tissue the relative presence of Tyrosine Hydroxylase (TH) protein, the rate-limiting enzyme for catecholamine biosynthesis present in iBAT. Results indicate that obese mice show a daily rhythm persists in estimated parameters but with differences in amplitude and profile. Obese mice presented lower body temperature, and a low caloric expenditure, together with lower VO2 intake and VCO2 than lean mice. Also, obese mice present a reduced thermoregulatory response after a cold pulse. Results are correlated with a low relative presence of TH and UCP1 protein. However, qPCR analysis of Ucp1 presents an increase in gene expression in iBAT. Histology showed a reduced amount of brown adipocytes in BAT. The aforementioned indicates that the daily rhythm in aerobic metabolism, thermoregulation, and body temperature control have reduced amplitude in obese mice Neotomodon alstoni.

Exceptional T CD4+ Recovery Post-antiretroviral Is Linked to a Lower HIV Reservoir with a Specific Immune Differentiation Pattern.

We present a cohort of individuals who reached CD4+ T cell counts of greater than 1,000 cells/mm3 (Hypers) after starting antiretroviral treatment (ART) and compared them with those who reached between 350 and 999 CD4+ T cells/mm3 (Concordants). Demographic data, immune recovery kinetics, T CD4+ subset phenotypes, and integrated HIV DNA were analyzed. Data from individuals living with HIV on their first ART regimen and after 48 months of follow-up were obtained. Immune phenotype by Flow Cytometry analysis on whole blood was performed, cytokines were measured, and integrated HIV-1 DNA was measured by polymerase chain reaction. From a total of 424 individuals, 26 Hypers (6.1%), 314 Concordants (74.1%), and 84 (19.8%) discordants were identified. Hypers had a higher proportion of CD4+-naive (Nv) T cells (37.6 vs. 24.8, p < .05), and a low proportion of CD4+ effector memory T cells (27.9 vs. 39.4, p < .05), with similar results found in CD8+ T cells. Hypers demonstrated a higher percentage of CD4+CD45RA+CD31neg cells with a lower response to interleukin-2 stimulation and a lower integrated HIV-1 DNA/CD4 ratio (1.2 vs. 2.89, p < .05). In Hypers, T cell recovery occurs very early after initiation of ART. Following this initial recovery state, their CD4+ T cell level homeostasis seems to be driven by nonthymic-central-Nv cells. This exceptional recovery is associated with a lower HIV reservoir, which may be related to an increase in noninfected CD4+ T cells. These patients could then be eligible candidates for cure trials.

Obese Neotomodon alstoni mice exhibit sexual dimorphism in the daily profile of circulating melatonin and clock proteins PER1 and BMAL1 in the hypothalamus and peripheral oscillators.

Obesity is a global health threat and a risk factor for several metabolic conditions. Though circadian dysfunction has been considered among the multiple causes of obesity, little work has been done to explore the relationship between obesity, circadian dysfunction, and sexual dimorphism. The Neotomodon alstoni mouse is a suitable model for such research. This study employed N. alstoni mice in a chronobiological analysis to determine whether there is circadian desynchronization of relative PER1 and BMAL1 protein levels in the hypothalamus, liver, visceral white adipose tissue, kidney, and heart. It also compared differences between sexes and lean and obese N. alstoni adult mice, by recording behavior and daily circulating serum melatonin as markers of circadian output. We found that obese mice display reduced locomotor activity. Additionally, Cosinor analyses of the relative expression of PER1 and BMAL1 show differences between lean and obese mice in a sex-linked manner. The PER1 24 h rhythm was absent in all tissues of obese males and significant in the tissues of obese females. The BMAL1 24 h rhythm also was significant in most of the tissues tested in lean males, whereas it was significant and shifted the acrophase (peak time of rhythm) in most of the tissues in obese females. Both lean male and female mice showed a rhythmic 24 h pattern of circulating serum melatonin. This daily profile was not only absent in obese mice of both sexes but showed sexual dimorphism. Obese male mice showed lower circulating levels of melatonin compared to lean male mice, but they were higher in obese females compared to lean females. Our results suggest that obesity in N. alstoni is associated with an internal circadian desynchronization in a sex-dependent manner. Overall, this study reinforces the need for further research on the neuroendocrinology of obesity and circadian rhythms using this biological model.

"Evening chronotype associates with increased triglyceride levels in young adults in two independent populations".

BACKGROUND & AIMS: Evening chronotype has been linked with obesity, diabetes and metabolic syndrome (MetS) in middle-aged and older adults. However, few studies have analyzed this association in young adults. The aim of this study was to assess potential associations between individual chronotype and cardiometabolic outcomes in young adults of two independent populations from Europe and America. METHODS: Total population comprised 2 223 young adults (18-29 years old), 525 from Spain (Europe) and 1 698 from Mexico (America). Anthropometric, body composition and biochemical analyses were performed. Circadian preference was determined using the Morningness-Eveningness Questionnaire (MEQ). RESULTS: In these two young adult populations, a higher metabolic risk was found in those individuals with evening chronotypes, whereas those with neither or morning chronotypes showed lower cardiometabolic risk. Evening chronotypes showed lipid alterations with increased levels of triglycerides in both populations, VLDL-c in Spaniards and total cholesterol and LDL-c in Mexicans. Among the Mexican population, evening chronotypes showed higher MetS risk and more obesity traits than the other two chronotypes; no significant differences for the same comparison were found among the equivalent Spanish chronotypes. Evening chronotypes showed lower carbohydrates and higher fat intake in Spaniards, while they had lower fiber intake in Mexicans. The associations between MEQ score and cardiometabolic risk were independent of the dietary characteristics. Lifestyle factors differed among chronotypes with more smokers and habitual drinkers among evening chronotypes than in neither or morning chronotypes (P < 0.05). CONCLUSIONS: This study performed in two American and European independent populations shows that even in apparently healthy young adults, evening chronotypes have increased cardiometabolic risk and lipid alterations as compared to neither or morning chronotypes.

Persistent high levels of immune activation and their correlation with the HIV-1 proviral DNA and 2-LTR circles loads, in a cohort of Mexican individuals following long-term and fully suppressive treatment.

OBJECTIVES: The aim of this study was to investigate the correlation between the HIV-1 reservoir and the levels of immune activation in chronic patients under fully suppressive cART. METHODS: We quantified the HIV proviral DNA and 2-LTR circles loads from PBMCs, the levels of CD38+ and Ki-67+ T-cells, and the levels of IL-7 in a cohort of patients with more than 5 years of ART at enrollment and after 1 year. RESULTS: In 29 participants with a median of 8 years (IQR, 6.9-9.4) under suppressive cART we found higher levels of CD8+ CD38+ T-cells after 1-year (P = .000). There was a non-statistically significant poor correlation between the levels of immune activation and the proviral DNA of CD4+ and CD8+ T-cells. Ki-67+ T-cells declined without significant differences, and there was no significant correlation with the proportion of CD38+. IL-7 decreased at the follow-up observation (P = .094), but there was no correlation with the levels of CD38+ and Ki-67+ T-cells. CONCLUSIONS: We found a weak but non-statistically significant correlation of the levels of T-cell activation with the proviral DNA and 2-LTR circles. This suggests the likely occurrence of further mechanisms driving chronic versus early immune activation other than viral replication by itself in chronic patients.

Regulation of Cas9 by viral proteins Tat and Rev for HIV-1 inactivation.

While combined antiretroviral therapy (cART) has had a great impact on the treatment of HIV-1 infection, the persistence of long-lived cells with an intact provirus precludes virus eradication and sterilizing cure. CRISPR/Cas9 genome editing has become an efficient tool to eradicate HIV-1 genome or prevent replication. Furthermore, regulation of Cas9 gene expression by HIV can induce mutations that could inactivate the proviral genome, making a gene therapy safe by preventing the induction of non-specific mutations, which could compromise the integrity of healthy cells. In this study, isolated HIV-1 LTR, INS and RRE sequences were used to regulate Cas9 expression in HEK293 cells, and guide RNAs (gRNAs) were designed to target mutations in HIV-1 conserved regions such as tat and rev regulatory genes. We demonstrate that Cas9 expression in our system is controlled by the HIV-1 Tat and Rev proteins, leading to self-regulation of gene edition, and showing a strong antiviral effect by inactivating HIV-1 replication. Sequencing analysis confirmed that viral genome was partially excised by multiplex editing (90% efficiency), and viral capsid protein (CA-p24) was undetectable. In conclusion, the self-regulated CRISPR/Cas9 system may be a reliable and accurate strategy for eliminating HIV-1 infection whose effect will be restricted to infected cells.

Daily cycle in hepatic lipid metabolism in obese mice, Neotomodon alstoni: Sex differences.

Disruption of circadian rhythms influences the pathogenesis of obesity, particularly with the basic regulation of food intake and metabolism. A link between metabolism and the circadian clock is the peroxisome proliferator-activated receptors (PPARs). The Neotomodon alstoni mouse, known as the "Mexican volcano mouse," may develop obesity if fed a normo-caloric diet. This manuscript documents the changes in part of the hepatic lipid homeostasis in both sexes of lean and obese N. alstoni mice, comparing the daily changes in the BMAL1 clock protein, in regulators of lipid metabolism (PGC-1α, PPARα-γ, SREBP-1c, and CPT-1α) and in free fatty acid (FFA) and hepatic triacylglyceride (TAG) metabolites in light-dark cycles. Hepatic tissue and blood were collected at 5, 10, 15, 19, and 24 h. Samples were analyzed by western blotting to determine the relative presence of protein. The results indicate that obesity affects daily changes in lipid metabolism and the BMAL1 profile in females considerably more than in males. These results suggest that the impact of obesity on lipid metabolism has important differences according to sex.

Neotomodon alstoni mice present sex differences between lean and obese in daily hypothalamic leptin signaling.

This article compared the effects of spontaneous obesity on the daily profile in the relative amount of the leptin receptor (LepRb), and its output. That is the precursor Pro-opiomelanocortin (POMC) over a 24-hour period and compared with differences in locomotion and food intake in periods of artificial light. Differences between lean and obese mice were examined, as were sex differences. Body weight, food intake and locomotor activity were monitored in freely moving lean and obese mice. Hypothalamic tissue was collected at 5 h, 10 h, 15 h, 19 h and 24 h. Samples were analyzed by western blotting to determine the relative presence of protein for LepRb, STAT3 phosphorylation (by pSTAT3/STAT3 ratio) and POMC. Obese mice were 60% less active in locomotion than lean mice during the night. While both locomotor activity and food intake were noticeably greater during the day in obese mice than in lean mice, the hypothalamus in obese mice showed a lower relative abundance of POMC and reduced pSTAT3/STAT3 ratio and leptin receptors. Behavioral and biochemical differences were more evident in obese females than in obese males. These results indicate that obesity in N. alstoni affects hypothalamic leptin signaling according to sex.

Restricted feeding modulates the daily variations of liver glutamate dehydrogenase activity, expression, and histological location.

Glutamate dehydrogenase is an important enzyme in the hepatic regulation of nitrogen and energy metabolism. It catalyzes one of the most relevant anaplerotic reactions. Although its relevance in liver homeostasis has been widely described, its daily pattern and responsiveness to restricted feeding protocols has not been studied. We explored the daily variations of liver glutamate dehydrogenase transcription, protein, activity, and histochemical and subcellular location in a protocol of daytime food synchronization in rats. Restricted feeding involved food access for 2 h each day for three weeks. Control groups included food ad libitum as well as acute fasting (21 h fasting) and refeeding (22 h fasting followed by 2 h of food access). Glutamate dehydrogenase mRNA, protein, activity, and histological location were measured every 3 h by qPCR, Western blot, spectrophotometry, and immunohistochemistry, respectively, to generate 24-h profiles. Restricted feeding promoted higher levels of mitochondrial glutamate dehydrogenase protein and activity, as well as a loss of 24-h rhythmicity, in comparison to ad libitum conditions. The rhythmicity of glutamate dehydrogenase activity detected in serum was changed. The data demonstrated that daytime restricted feeding enhanced glutamate dehydrogenase protein and activity levels in liver mitochondria, changed the rhythmicity of its mRNA and serum activity, but without effect in its expression in hepatocytes surrounding central and portal veins. These results could be related to the adaptation in nitrogen and energy metabolism that occurs in the liver during restricted feeding and the concomitant expression of the food entrainable oscillator. Impact statement For the first time, we are reporting the changes in daily rhythmicity of glutamate dehydrogenase (GDH) mRNA, protein and activity that occur in the liver during the expression of the food entrained oscillator (FEO). These results are part of the metabolic adaptations that modulate the hepatic timing system when the protocol of daytime restricted feeding is applied. As highlight, it was demonstrated higher GDH protein and activity in the mitochondrial fraction. These results contribute to a better understanding of the influence of the FEO in the energy and nitrogen handling in the liver. They could also be significant in the pathophysiology of hepatic diseases related with circadian abnormalities.

Desarrollo y uso de una interfaz de programación de aplicaciones modificada de GoogleMaps© para la georreferenciación de pacientes con enfermedad glomerular / Development and use of an application programming interface modified from GoogleMaps© for the georeferencing of patients with glomerular disease

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Daytime restricted feeding modifies the daily variations of liver gluconeogenesis: adaptations in biochemical and endocrine regulators.

Daytime restricted feeding (DRF) promotes circadian adaptations in the metabolic processing of nutrients. We explored the hepatic gluconeogenic response in DRF rats by the temporal profiles of the following: (1) the activity of glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), as well as the periportal and pericentral distribution of PEPCK; (2) conversion of alanine to glucose; (3) glycemia and liver glycogen content; (4) presence of glycogen synthase (GYS) and its phosphorylated form (at Ser641, pGYS); (5) circulating levels of corticosterone, glucagon and insulin; (6) glucose-tolerance test; and (7) sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-coactivator 1α (PGC-1α). The results showed that DRF promoted: (1) a phase shift in G6Pase activity and an increase in PEPCK activity as well as a change of PEPCK from periportal to pericentral hepatocytes, (2) a net conversion of alanine to circulating glucose, (3) a decrease in glycemic values and a phase shift in the liver glycogen content, (4) a phase shift in GYS and an increase of pGYS, (5) an increase in the daily levels of corticosterone and glucagon, but a reduction in the levels of insulin, (6) normal glucose homeostasis in all groups and (7) an enhanced presence of SIRT1 and PGC-1α. It is proposed that the increased gluconeogenic in DRF group promotes synthesis of hepatic glycogen and the production of glucose. These results could be a modulation of the gluconeogenic process due to rheostatic adaptations in the endocrine, metabolic and timing regulation of liver and could be associated with the physiology of the food entrained oscillator.