mTOR Research Articles

Impact of oxytosis on the cross-talk of mTORC with mitochondrial proteins in drug-resistant cancer stem cells.

By delivering the environmental inputs to transport nutrients and growth factors, Mechanistic Target of Rapamycin (mTOR) plays a significant role in the growth and metabolism of eukaryotic cells through the regulation of numerous elementary cellular processes such as autophagy, protein synthesis, via translation of mitochondrial protein transcription factor A mitochondrial, mitochondrial ribosomal proteins, and mitochondrial respiratory complexes I &V that are encoded in the nucleus with the help of translation initiation factor 4E-BP. These mitochondrial proteins are involved in cell signaling to regulate proper cell growth, proliferation, and death which are essential for tumor growth and proliferation. This suggests that tumor cells are dependent on mTORC1 for various metabolic pathways. However, this crucial regulator is activated and regulated by calcium homeostasis. Mounting evidence suggests the role of calcium ions in regulating mitochondrial enzymes and proteins. Hence, disrupting calcium homeostasis leads to calcium-dependent cell death called "Oxytosis" through hampering the expression of various mitochondrial proteins. "Oxytosis" is a novel non-apoptotic cell death characterized by glutamate cytotoxicity and ferritin degradation. The present review focuses on the crosstalk between mTORC1 and mitochondrial proteins in the cancer pathophysiology and the impact of calcium ions on disrupting mTORC1 leading to the induction of "Oxytosis."

Porcine granulosa cell transcriptomic analyses reveal the differential regulation of lncRNAs and mRNAs in response to all-trans retinoic acid in vitro.

The active metabolite of vitamin A, all-trans retinoic acid (ATRA), is involved in the proliferation and differentiation of granulosa cells, and promotes the follicular development, oocyte maturation, and ovulation in mammals. This study aims to investigate the ATRA induced potential long noncoding RNAs (lncRNAs) that regulate the expression of genes associated with granulosa cell proliferation and follicular development. The lncRNA and mRNA profiles of porcine granulosa cells from ATRA treatment and control group in vitro were constructed through RNA sequencing. Meanwhile, the sequencing data were verified using quantitative polymerase chain reaction (qPCR). A total of 86 differentially expressed lncRNAs and 128 differentially expressed genes (DEGs) were detected in granulosa cells after ATRA treatment. The qRT-PCR results were consistent with the RNA-seq data. Functional annotation analysis revealed that the DEGs were remarkably enriched in ovary function and reproduction which contained FoxO, Hippo, Oocyte meiosis, mTOR signaling pathway, as well as several pathways associated with hormone regulation like Oxytocin signaling pathway and Steroid hormone biosynthesis. Moreover, an interaction network of lncRNAs and their cis-target DEGs was constructed, and 7 differentially expressed lncRNAs and 6 cis-target DEGs were enriched in ovarian steroidogenesis and reproduction. These findings expand the lncRNA catalogue and provide a basis for further studies on the mechanism of ATRA-mediated lncRNA regulation of follicular development in pigs.

POU2F1 inhibits miR-29b1/a cluster-mediated suppression of PIK3R1 and PIK3R3 expression to regulate gastric cancer cell invasion and migration.

The transcription factor POU2F1 regulates the expression levels of microRNAs in neoplasia. However, the miR-29b1/a cluster modulated by POU2F1 in gastric cancer (GC) remains unknown. Gene expression in GC cells was evaluated using reverse-transcription polymerase chain reaction (PCR), western blotting, immunohistochemistry, and RNA in situ hybridization. Co-immunoprecipitation was performed to evaluate protein interactions. Transwell migration and invasion assays were performed to investigate the biological behavior of GC cells. MiR-29b1/a cluster promoter analysis and luciferase activity assay for the 3'-UTR study were performed in GC cells. In vivo tumor metastasis was evaluated in nude mice. POU2F1 is overexpressed in GC cell lines and binds to the miR-29b1/a cluster promoter. POU2F1 is upregulated, whereas mature miR-29b-3p and miR-29a-3p are downregulated in GC tissues. POU2F1 promotes GC metastasis by inhibiting miR-29b-3p or miR-29a-3p expression in vitro and in vivo. Furthermore, PIK3R1 and/or PIK3R3 are direct targets of miR-29b-3p and/or miR-29a-3p, and the ectopic expression of PIK3R1 or PIK3R3 reverses the suppressive effect of mature miR-29b-3p and/or miR-29a-3p on GC cell metastasis and invasion. Additionally, the interaction of PIK3R1 with PIK3R3 promotes migration and invasion, and miR-29b-3p, miR-29a-3p, PIK3R1, and PIK3R3 regulate migration and invasion via the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in GC cells. In addition, POU2F1, PIK3R1, and PIK3R3 expression levels negatively correlated with miR-29b-3p and miR-29a-3p expression levels in GC tissue samples. The POU2F1-miR-29b-3p/miR-29a-3p-PIK3R1/PIK3R1 signaling axis regulates tumor progression and may be a promising therapeutic target for GC.

Carthamus tinctorius L. inhibits hepatic fibrosis and hepatic stellate cell activation by targeting the PI3K/Akt/mTOR pathway.

Hepatic fibrosis (HF) is a process that occurs during the progression of several chronic liver diseases, for which there is a lack of effective treatment options. Carthamus tinctorius L. (CTL) is often used in Chinese or Mongolian medicine to treat liver diseases. However, its mechanism of action remains unclear. In the present study, CTL was used to treat rats with CCl4‑induced HF. The histopathological, biochemical and HF markers of the livers of the rats were analyzed, and CTL‑infused serum was used to treat hepatic stellate cells (HSCs) in order to detect the relevant markers of HSC activation. Protein expression pathways were detected both in vitro and in vivo. Histopathological results showed that CTL significantly improved CCl4‑induced liver injury, reduced aspartate aminotransferase and alanine aminotransferase levels, promoted E‑cadherin expression, and decreased α‑smooth muscle actin (SMA), SOX9, collagen I and hydroxyproline expression. Moreover, CTL‑infused serum was found to decrease α‑SMA and collagen I expression in HSCs. Further studies showed that CTL inhibited the activity of the PI3K/Akt/mTOR pathway in the rat livers. Following the administration of the PI3K agonist 740Y‑P to HSCs, the inhibitory effect of CTL on the PI3K/Akt//mTOR pathway was blocked. These results suggested that CTL can inhibit HF and HSC activation by inhibiting the PI3K/Akt/mTOR pathway.

New and future perspectives in familial Mediterranean fever and other autoinflammatory diseases

Systemic autoinflammatory diseases are a group of disorders characterized by sterile episodes of inflammation resulting from defects in the innate immune system. In contrast to classical autoimmune diseases, where circulating autoantibodies and the adaptive immune system are involved, these conditions involve excessive presence of proinflammatory cytokines leading to inflammatory attacks. Excessive cytokine production, functional mutations in regulatory pathways, excessive interferon production, defects in the nuclear factor-kappa B signaling pathway, abnorARCHmal protein folding, and complement activation are the mechanisms leading to autoinflammatory diseases. A defect in the mTOR pathway and trained immunity are newly discovered possible causes in pathogenesis. Early onset and severe forms of classical rheumatological diseases have been more frequently associated with autoinflammatory diseases in the last decade. Therefore, monogenic autoinflammatory diseases should be considered in rheumatic diseases with family history, consanguinity, early onset, and severe disease. The combination of functional and genotyping research will help to identify unclassified patients. The optimal treatment strategy remains uncertain, functional studies such as interferon signature and cytokine profiling, may prove valuable in guiding the treatment process. Stem cell transplantation strategies in autoinflammatory diseases with partial response to biological therapies can be considered. Autoinflammatory diseases are becoming increasingly complex and are bringing new perspectives to already known rheumatic diseases. Although we have effective treatments, we are still far from personalized recommendations.

A severe asthma phenotype of excessive airway Haemophilus influenzae relative abundance associated with sputum neutrophilia.

Severe asthma (SA) encompasses several clinical phenotypes with a heterogeneous airway microbiome. We determined the phenotypes associated with a low α-diversity microbiome. Metagenomic sequencing was performed on sputum samples from SA participants. A threshold of 2 standard deviations below the mean of α-diversity of mild-moderate asthma and healthy control subjects was used to define those with an abnormal abundance threshold as relative dominant species (RDS). Fifty-one out of 97 SA samples were classified as RDSs with Haemophilus influenzae RDS being most common (n=16), followed by Actinobacillus unclassified (n=10), Veillonella unclassified (n=9), Haemophilus aegyptius (n=9), Streptococcus pseudopneumoniae (n=7), Propionibacterium acnes (n=5), Moraxella catarrhalis (n=5) and Tropheryma whipplei (n=5). Haemophilus influenzae RDS had the highest duration of disease, more exacerbations in previous year and greatest number on daily oral corticosteroids. Hierarchical clustering of RDSs revealed a C2 cluster (n=9) of highest relative abundance of exclusively Haemophilus influenzae RDSs with longer duration of disease and higher sputum neutrophil counts associated with enrichment pathways of MAPK, NF-κB, TNF, mTOR and necroptosis, compared to the only other cluster, C1, which consisted of 7 Haemophilus influenzae RDSs out of 42. Sputum transcriptomics of C2 cluster compared to C1 RDSs revealed higher expression of neutrophil extracellular trap pathway (NETosis), IL6-transignalling signature and neutrophil activation. We describe a Haemophilus influenzae cluster of the highest relative abundance associated with neutrophilic inflammation and NETosis indicating a host response to the bacteria. This phenotype of severe asthma may respond to specific antibiotics.

Propyl acetate protects intestinal barrier during parenteral nutrition in mice and Caco-2 cells.

Gut microbiota dysbiosis induces intestinal barrier damage during parenteral nutrition (PN). However, the underlying mechanisms remain unclear. This study aimed to investigate gut microbiota dysbiosis, luminal short-chain fatty acids, and autophagy in a mouse model and how these short-chain fatty acids regulate autophagy. Eight-week-old male specific-pathogen-free mice were randomly divided into a Chow group (standard diet and intravenous normal saline infusion) and a PN group (continuous infusion of PN nutrient solution) for 7 days. Caco-2 cells were also treated with intestinal rinse solutions from Chow and PN mouse models. Compared with the Chow group, the PN group exhibited increased Proteobacteria and decreased Firmicutes, correlating with decreased propyl acetate. In the PN group, intestinal tissue exhibited elevated adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, LC3II protein levels, and Atg3 and Atg7 messenger RNA levels. P62 protein levels were decreased, indicating an increase of autophagy flux in the PN group. In the Caco-2 cell model, cells treated with PN solution plus propyl acetate exhibited increased Claudin-1 and occluding along with decreased interleukin-6 and tumor necrosis factor α compared with those treated with PN solution alone. Propyl acetate addition inhibited the AMPK-mammalian target of rapamycin (mTOR) pathway, mitigating the excessive autophagy induced by the PN intestinal rinse solution in Caco-2 cells. PN led to a significant reduction in propyl acetate levels in the intestine, excessive activation of autophagy, and barrier dysfunction. Propyl acetate inhibited excessive autophagy via the AMPK/mTOR signaling pathway and protected the intestinal barrier during PN.

Potential roles of voltage-gated ion channel disruption in Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is a lynchpin disorder, as it results in overactive mammalian target of rapamycin (mTOR) signaling, which has been implicated in a multitude of disease states. TSC is an autosomal dominant disease where 90% of affected individuals develop epilepsy. Epilepsy results from aberrant neuronal excitability that leads to recurring seizures. Under neurotypical conditions, the coordinated activity of voltage-gated ion channels keep neurons operating in an optimal range, thus providing network stability. Interestingly, loss or gain of function mutations in voltage-gated potassium, sodium, or calcium channels leads to altered excitability and seizures. To date, little is known about voltage-gated ion channel expression and function in TSC. However, data is beginning to emerge on how mTOR signaling regulates voltage-gated ion channel expression in neurons. Herein, we provide a comprehensive review of the literature describing common seizure types in patients with TSC, and suggest possible parallels between acquired epilepsies with known voltage-gated ion channel dysfunction. Furthermore, we discuss possible links toward mTOR regulation of voltage-gated ion channels expression and channel kinetics and the underlying epileptic manifestations in patients with TSC.

Unveiling the Mechanisms of Apoptosis Induction by Deep‐Sea‐Derived Polyketide‐Terpenoid Hybrids from Penicillium allii‐sativi: A Focus on Mitochondrial and mTOR Pathways

Comprehensive SummaryA chemical investigation of the deep‐sea‐derived fungus Penicillium allii‐sativi MCCC 3A00580 resulted in the discovery of four new meroterpenoids (1—4) and one related known co‐metabolite (5). These meroterpenoids showcase unique carbon skeletons featuring a common drimane sesquiterpene part with highly diverse polyketide units. Particularly, compound 1 incorporates a salicylic acid moiety while 2 possesses a rare peroxide bridge in the polyketide part. The structures of new compounds were assigned by extensive spectroscopic analysis, quantum calculations, and biogenetic considerations. Notably, 3 significantly blocked the mTOR signaling pathway, resulting in the arrest of cell cycle at G0‐G1 phase and triggering mitochondrial apoptosis in Hela cells. While the previously reported co‐metabolite macrophorin A (MPA) effectively triggered cell death in MDA‐MB‐231 cancer cells by activating apoptosis pathways involving death receptors, mitochondria, mTOR, and TNF.

Effects of Intermittent and Chronic Hypoxia on Fish Size and Nutrient Metabolism in Tiger Puffer (Takifugu rubripes).

Intermittent and chronic hypoxia are common stresses to marine fish, but the different responses of fish to intermittent and chronic hypoxia have not been well-known. In this study, tiger puffers were farmed in normoxia conditions (NO, 6.5 ± 0.5 mg/L), intermittent hypoxia (IH, 6.5 ± 0.5 mg/L in the day and 3.5 ± 0.5 mg/L in the night), or choric hypoxia (CH, 3.5 ± 0.5 mg/L) conditions for 4 weeks, after which the growth, nutrient metabolism and three hifα isoforms expression were measured. Both intermittent and chronic hypoxia decreased the fish growth and visceral weight but increased the feed conversion ratio and blood hemoglobin content. Chronic hypoxia but not intermittent hypoxia promoted protein synthesis and whole-fish protein content by activating mtor gene expression and promoted the glycolysis pathway by activating gene expression of hif1α and hif2α. Intermittent hypoxia but not chronic hypoxia decreased the hepatic lipid synthesis by inhibiting fasn and srebf1 gene expression. Meanwhile, intermittent hypoxia reduced the monounsaturated fatty acid content but increased the n-3 polyunsaturated fatty acids percentage. The results of this study clarified the adaptive mechanism of tiger puffer to intermittent and chronic hypoxia, which provides important information about mechanisms of hypoxia adaption in fish.

BCAA mediated microbiota-liver-heart crosstalk regulates diabetic cardiomyopathy via FGF21

BackgroundDiabetic cardiomyopathy (DCM) is one of leading causes of diabetes-associated mortality. The gut microbiota-derived branched-chain amino acids (BCAA) have been reported to play a central role in the onset and progression of DCM, but the potential mechanisms remain elusive.ResultsWe found the type 1 diabetes (T1D) mice had higher circulating BCAA levels due to a reduced BCAA degradation ability of the gut microbiota. Excess BCAA decreased hepatic FGF21 production by inhibiting PPARα signaling pathway and thereby resulted in a higher expression level of cardiac LAT1 via transcription factor Zbtb7c. High cardiac LAT1 increased the levels of BCAA in the heart and then caused mitochondrial damage and myocardial apoptosis through mTOR signaling pathway, leading to cardiac fibrosis and dysfunction in T1D mice. Additionally, transplant of faecal microbiota from healthy mice alleviated cardiac dysfunction in T1D mice, but this effect was abolished by FGF21 knockdown.ConclusionsOur study sheds light on BCAA-mediated crosstalk among the gut microbiota, liver and heart to promote DCM and FGF21 serves as a key mediator.BVPaWWrrqVUsPwxN3tcRV1Video

Hsa-miR-483-5p/mRNA network that regulates chemotherapy resistance in locally advanced rectal cancer identified through plasma exosome transcriptomics.

Chemoresistance is the primary contributor to distant metastasis in the context of neoadjuvant chemoradiotherapy (nCRT) for rectal cancer. However, the underlying mechanisms remain elusive. To detect the differential expression profiles of plasma exosomal microRNAs (miRNAs) in poor and good responders and explore the potential mechanisms of chemoresistance. In this study, the profiles of plasma exosomal miRNAs were compared in two dimensions according to treatment responses (poor/good responders) and treatment courses (pre/post-nCRT) using RNA sequencing. Exosome hsa-miR-483-5p was up-regulated in good responders post-nCRT. Bioinformatics analysis revealed that the target genes of hsa-miR-483-5p were mainly enriched in tumor-specific pathways, such as the MAPK signaling pathway, EGFR tyrosine kinase inhibitor resistance, Toll-like receptor signaling pathway, VEGF signaling pathway, and mTOR signaling pathway. Further analysis indicated that MAPK3, RAX2, and RNF165 were associated with inferior recurrence-free survival in patients with rectal cancer, and the profiles of MAPK3, TSPYL5, and ZNF417 were correlated with tumor stage. In addition, the expression profiles of MAPK3, RNF165, and ZNF417 were negatively correlated with inhibitory concentration 50 values. Accordingly, an hsa-miR-483-5p/MAPK3/RNF 165/ZNF417 network was constructed. This study provides insights into the mechanism of chemoresistance in terms of exosomal miRNAs. However, further research is required within the framework of our established miRNA-mRNA network.

Impaired energy expenditure following exposure to either DDT or DDE in mice may be mediated by DNA methylation changes in brown adipose.

The insecticide dichlorodiphenyltrichloroethane (DDT) and its persistent metabolite, dichlorodiphenyldichloroethylene (DDE), have been associated with increased adiposity and obesity in multiple generations of rodents and humans. These lipophilic pollutants accumulate in adipose tissue and appear to decrease energy expenditure through the impairment of thermogenesis in brown adipose tissue (BAT). We hypothesized that impaired thermogenesis is due to persistent epigenetic modifications of BAT. To address this, we exposed C57BL/6 J mice to DDT or DDE from gestational day (GD) 11.5 to postnatal day (PND) 5, evaluated longitudinal body temperature, and performed reduced representation bisulfite sequencing and RNA sequencing of BAT from infant and adult offspring. Exposure to DDT or DDE reduced core body temperature in adult mice, and differential methylation at the pathway and gene level was persistent from infancy to adulthood. Furthermore, thermogenesis and biological pathways essential for thermogenic function, such as oxidative phosphorylation and mechanistic target of rapamycin kinase (mTOR) signaling, were enriched with differential methylation and RNA transcription in adult mice exposed to DDT or DDE. PAZ6 human brown preadipocytes were differentiated in the presence of DDT or DDE to understand the brown adipocyte-autonomous effect of these pollutants. In vitro exposure led to limited changes in RNA expression; however, mitochondrial membrane potential was decreased in vitro with 0.1 µM and 1 µM doses of DDT or DDE. These results demonstrate that concentrations of DDT and DDE relevant to human exposure have a significant effect on thermogenesis, the transcriptome, and DNA methylome of mouse BAT and the mitochondrial function of human brown adipocytes.

Gene mutation characteristics of clinical stage ⅠA lung adenocarcinoma and their relations with patients' long-term prognosis

Objective: To explore the gene mutation characteristics and the relationship between gene mutations and long-term prognosis in clinical stage ⅠA lung adenocarcinoma patients. Methods: A retrospective analysis was conducted on 63 clinical stage ⅠA lung adenocarcinoma patients who underwent surgical resection at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2007 to October 2012, with documented postoperative recurrence or metastasis, as well as those who had a follow-up duration of 10 years or more without recurrence or metastasis. Whole exome sequencing (WES) technology was used to analyze the gene mutation profiles in tumor tissues and univariate and multivariate Cox regression analysis were used to clarify the influencing factors for patient prognosis. Results: After long term follow-up, 13 out of the 63 patients (21%) experienced recurrence or metastasis. WES technology analysis revealed that the most common tumor related gene mutations occurred in epidermal growth factor receptor (EGFR), with a mutation rate of 65.1% (41/63), followed by tumor protein p53 (TP53), fatatypical cadherin 1 (FAT1), low density lipoprotein receptor-related protein 1B (LRP1B), mechanistic target of rapamycin (MTOR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG), and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), with mutation rates of 30.2% (19/63), 20.6% (13/63), 15.9% (10/63), 15.9% (10/63), 15.9% (10/63), and 15.9% (10/63), respectively. Multivariate Cox regression analysis showed that PIK3CG mutations (HR=21.52, 95% CI: 3.19-145.01),smoothened (SMO) mutations (HR=35.28, 95% CI: 3.12-398.39), catenin beta 1 (CTNNB1) mutations (HR=332.86, 95% CI: 15.76-7 029.05), colony stimulating factor 1 receptor (CSF1R) mutations (HR=8 109.60, 95% CI: 114.19-575 955.17), and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations (HR=23.65, 95% CI: 1.86-300.43) were independent risk factors affecting the prognosis of clinical stage ⅠA lung adenocarcinoma patients. Conclusions: PIK3CG, SMO, CTNNB1, CSF1R, BRAF gene mutations are closely related to long-term recurrence or metastasis in clinical stage ⅠA lung adenocarcinoma. Patients with these gene mutations should be given closer clinical attention.

Antagonism of β-arrestins in IL-4-driven microglia reactivity via the Samd4/mTOR/OXPHOS axis in Parkinson's disease.

Interleukin-4 (IL-4)-exposed microglia acquire neuroprotective properties, but their functions and regulation in Parkinson's disease (PD) are poorly understood. In this study, we demonstrate that IL-4 enhances anti-inflammatory microglia reactivity, ameliorates the pathological features of PD, and reciprocally affects expression of β-arrestin 1 and β-arrestin 2 in microglia in PD mouse models. We also show that manipulation of two β-arrestins produces contrary effects on the anti-inflammatory states and neuroprotective action of microglia induced by IL-4 in vivo and in vitro. We further find that the functional antagonism of two β-arrestins is mediated through sequential activation of sterile alpha motif domain containing 4 (Samd4), mammalian target of rapamycin (mTOR), and mitochondrial oxidative phosphorylation (OXPHOS). Collectively, these data reveal opposing functions of two closely related β-arrestins in regulating the IL-4-induced microglia reactivity via the Samd4/mTOR/OXPHOS axis in PD mouse models and provide important insights into the pathogenesis and therapeutics of PD.

Global microRNA profiling of bone marrow-MSC derived extracellular vesicles identifies miRNAs associated with hematopoietic dysfunction in aplastic anemia

Recently, we have reported that extracellular vesicles (EVs) from the bone marrow mesenchymal stromal cells (BM-MSC) of aplastic anemia (AA) patients inhibit hematopoietic stem and progenitor cell (HSPC) proliferative and colony-forming ability and promote apoptosis. One mechanism by which AA BM-MSC EVs might contribute to these altered HSPC functions is through microRNAs (miRNAs) encapsulated in EVs. However, little is known about the role of BM-MSC EVs derived miRNAs in regulating HSPC functions in AA. Therefore, we performed miRNA profiling of EVs from BM-MSC of AA (n = 6) and normal controls (NC) (n = 6) to identify differentially expressed miRNAs. The Integrated DEseq2 analysis revealed 34 significantly altered mature miRNAs, targeting 235 differentially expressed HSPC genes in AA. Hub gene analysis revealed 10 HSPC genes such as IGF-1R, IGF2R, PAK1, PTPN1, etc., which are targeted by EV miRNAs and had an enrichment of chemokine, MAPK, NK cell-mediated cytotoxicity, Rap1, PI3k-Akt, mTOR signalling pathways which are associated with hematopoietic homeostasis. We further showed that miR-139-5p and its target, IGF-1R (hub-gene), might regulate HSPC proliferation and apoptosis, which may serve as potential therapeutic targets in AA. Overall, the study highlights that AA BM-MSC EV miRNAs could contribute to impaired HSPC functions in AA.

Activated phosphoinositide 3‐kinase delta syndrome: Pathogenesis, clinical manifestations, and treatment

AbstractActivated phosphoinositide 3‐kinase delta syndrome (APDS) is an autosomal dominant inborn errors of immunity resulting from gain of function mutations in the PIK3CD gene or loss of function mutations in the PIK3R1 gene. These mutations lead to hyperactivation of the phosphoinositide 3‐kinase/Akt/mammalian target of rapamycin (mTOR) signaling pathways, causing complex deficiencies in cellular and humoral immunity. APDS patients exhibit diverse clinical manifestations including recurrent respiratory infections, nonneoplastic lymphoproliferation, an increasing risk of malignancy, and autoimmune diseases. Neurodevelopmental abnormalities, short stature, failure to thrive, and psychological disorders are also observed. Management strategies for APDS involve antibiotic prophylaxis and immunoglobulin replacement therapy, immunosuppressive therapies, and hematopoietic stem cell transplantation for severe cases. Targeted therapies, such as the mTOR inhibitor sirolimus and the elective Phosphoinositide 3‐kinase delta inhibitor leniolisib, have emerged as promising options, demonstrating both safety and effectiveness. Continuous monitoring and further research are essential to optimize treatment strategies and understand the long‐term implications of these interventions. This review aims to summarize the pathogenesis, clinical manifestations, and treatment of APDS.

Establishing network pharmacology between natural polyphenols and Alzheimer’s disease using bioinformatic tools – An advancement in Alzheimer’s research

Alzheimer’s disease (AD) is a major cause of disability and one of the top causes of mortality globally. AD remains a major public health challenge due to its prevalence, impact on patients and caregivers, and the current lack of a cure. In recent years, polyphenols have garnered attention for their potential therapeutic effects on AD. The objective of the study was to establish network pharmacology between selected polyphenols of plant origin and AD. Insilico tools such as SwissADME, ProTox3.0, pkCSM, Swiss Target Prediction, DisGeNET, InterActiVenn, DAVID database, STRING database, Cytoscape/CytoHubba were employed to establish the multi-target potential of the polyphenolic compounds. The present study revealed that out of 17 polyphenols, 10 ligands were found to possess a drug-likeness nature along with desirable pharmacokinetic parameters and a lesser toxicity profile. Also, the results highlighted the possible interactions between the polyphenols and the disease targets involved in AD. Further, this study has shed light on the mTOR pathway and its impact on AD through the autophagic mechanism. Overall, this study indicated that polyphenols could be a better therapeutic option for treating AD. Hence, the consumption of polyphenolic cocktails as a part of the diet could produce more effective outcomes against the disease. Additional studies are warranted in the future to explore additional pathways and genes to provide a comprehensive understanding regarding the usage of the shortlisted polyphenols and their derivatives for the prevention and treatment of AD.

Sodium Tungstate Promotes Neurite Outgrowth and Confers Neuroprotection in Neuro2a and SH-SY5Y Cells.

Sodium tungstate (Na2WO4) normalizes glucose metabolism in the liver and muscle, activating the Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Because this pathway controls neuronal survival and differentiation, we investigated the effects of Na2WO4 in mouse Neuro2a and human SH-SY5Y neuroblastoma monolayer cell cultures. Na2WO4 promotes differentiation to cholinergic neurites via an increased G1/G0 cell cycle in response to the synergic activation of the Phosphatidylinositol 3-kinase (PI3K/Akt) and ERK1/2 signaling pathways. In Neuro2a cells, Na2WO4 increases protein synthesis by activating the mechanistic target of rapamycin (mTOR) and S6K kinases and GLUT3-mediated glucose uptake, providing the energy and protein synthesis needed for neurite outgrowth. Furthermore, Na2WO4 increased the expression of myocyte enhancer factor 2D (MEF2D), a member of a family of transcription factors involved in neuronal survival and plasticity, through a post-translational mechanism that increases its half-life. Site-directed mutations of residues involved in the sumoylation of the protein abrogated the positive effects of Na2WO4 on the MEF2D-dependent transcriptional activity. In addition, the neuroprotective effects of Na2WO4 were evaluated in the presence of advanced glycation end products (AGEs). AGEs diminished neurite differentiation owing to a reduction in the G1/G0 cell cycle, concomitant with lower expression of MEF2D and the GLUT3 transporter. These negative effects were corrected in both cell lines after incubation with Na2WO4. These findings support the role of Na2WO4 in neuronal plasticity, albeit further experiments using 3D cultures, and animal models will be needed to validate the therapeutic potential of the compound.

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer's disease.

Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well-known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient-induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock-in (APPSAA) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. NiMA is inhibited in APPSAA mice before other defects are detected in these Aβ-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice. NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APPSAA mice, and may represent an early stage in human AD. Amyloid beta blocks communication between lysosomes and mitochondria in vivo. Nutrient-induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer's disease (AD) histopathology in heterozygous amyloid precursor protein knock-in (APPSAA/+) mice. NiMA is disrupted long before learning and memory deficits in APPSAA/+ mice. Pharmacological interventions can rescue AD-related NiMA disruption in vivo.