Membrane Atg8ylation, stress granule formation, and MTOR regulation during lysosomal damage.

The functions of mammalian Atg8 proteins (mATG8s) expand beyond canonical autophagy and include processes collectively referred to as Atg8ylation. Global modulation of protein synthesis under stress conditions is governed by MTOR and liquid-liquid phase separated condensates containing ribonucleoprotein particles known as stress granules (SGs). We report that lysosomal damage induces SGs acting as a hitherto unappreciated inhibitor of protein translation via EIF2A/eIF2α phosphorylation while favoring an ATF4-dependent integrated stress response. SGs are induced by lysosome-damaging agents, SARS-CoV-2 open reading frame 3a protein (ORF3a) expression, Mycobacterium tuberculosis infection, and exposure to proteopathic MAPT/tau. Proteomic studies revealed recruitment to damaged lysosomes of the core SG proteins NUFIP2 and G3BP1 along with the GABARAPs of the mATG8 family. The recruitment of these proteins is independent of SG condensates or canonical autophagy. GABARAPs interact directly with NUFIP2 and G3BP1 whereas Atg8ylation is needed for their recruitment to damaged lysosomes. At the lysosome, NUFIP2 contributes to MTOR inactivation together with LGALS8 (galectin 8) via the Ragulator-RRAGA-RRAGB complex. The separable functions of NUFIP2 and G3BP1 in SG formation vis-a-vis their role in MTOR inactivation are governed by GABARAP and Atg8ylation. Thus, cells employ membrane Atg8ylation to control and coordinate SG and MTOR responses to lysosomal damage.Abbreviations: Atg8: autophagy related 8; ATG: autophagy related; ATF4: activating transcription factor 4; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; GABARAP: GABA type A receptor-associated protein; G3BP1: G3BP stress granule assembly factor 1; LLOMe: L-leucyl-L-leucine methyl ester; LysoIP: lysosome immunopurification; mRNA: messenger ribonucleic acid; MTOR: mechanistic target of rapamycin kinase; NUFIP2: nuclear FMR1 interacting protein 2; ORF3a: open reading frame 3a protein; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SG: stress granule; TIA1: TIA1 cytotoxic granule associated RNA binding protein.

Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System.

It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer's disease (AD) and DM, promote healthy aging, facilitate clearance of ß-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.

Respiratory Syncytial Virus (RSV) infections in children: recent concepts in immunopathogenesis and diagnostic dilemma

Respiratory viral infections are important cause of morbidity and mortality in early life. The relative influence of host and viral factors possibly contribute to the disease pathogenesis. Predisposing conditions like prematurity, Low birth weight and congenital heart diseases etc. have been incriminated in the disease progression. The development of cough, wheezing, and tachypnea, usually peaking on days 4 to 5, go parallel with host cytokine responses and viral load. Various host cytokines, chemokines and molecules involved in the immune response against RSV infection might be responsible for the outcome of the disease process. Nasopharyngeal aspirates (NPAs) from children (n = 349) between 2013-2017 were subjected for IL-17A, IFN-gamma, TNF-alpha, IL-10, IL-6 levels by CBA and MMP-9 and TIMP-1 levels by ELISA. The viral load in RSV positive samples and cytokine levels were correlated with the WHO criteria for acute lower respiratory tract illness (ALRTI). RSV viral load, Pro-inflammatory cytokine (TNF-alpha) levels in severe ALRTI patients were significantly higher than the ALRTI patients [p<0.001]. Whereas Th17 cytokine (IL-17) was found to be significantly higher (p<0.05) in ALRTI patients than severe patients. MMP-9 is secreted in higher levels in severe ALRTI patients (n = 77) in comparison to Acute LRTI patients (n = 35) with an increase of thirty seven fold (p<0.001). Thus, the study highlights the role of TNF -alpha, IL-17 and Th2 cytokine biasness in the pathogenesis of RSV disease with the possible contribution of higher MMP-9/TIMP-1 ratio as a bad prognostic marker towards disease severity. To study the gene expression of autophagy and mTOR signalling pathways in RSV infected children with ALRTI. Nasopharyngeal aspirate (NPA) samples (n = 145) from children suffering from ALRTI were subjected for detection of RSV (Oct 2019 to March 2020). Semi-quantitative gene expression analysis for 5 representative genes each of mTOR signalling and autophagy pathway were performed in respiratory tract epithelial cells using 25 RSV positive cases and 10 healthy controls subjects. Autophagy gene expression analysis revealed significant upregulation in NPC1 and ATG3 autophagy genes. mTOR, AKT1 and TSC1 genes of mTOR pathway were significantly down-regulated in RSV positive patients except RICTOR gene which was significantly upregulated. Thus, survival of RSV within autophagosome might have been facilitated by upregulation of autophagy and downregulation of mTOR signalling genes. To assess the impact of SARS-CoV2 pandemic on RSV, samples were collected from children with ALRTIs admitted to emergency, PICU and indoor admissions during pre-pandemic period (October 2019 to February 2020;n = 166) and during COVID-19 Pandemic (July 2021 to July 2022;n = 189, SARS-CoV2 negative). These NP swabs were analyzed for pdm InfA H1N1, InfA H3N2, Inf B, RSV, hMPV, hBoV, hRV, PIV-2 and PIV-3 by PCR. Higher proportion of children with ALRTIs have had virus/es isolated during pre-pandemic period than during pandemic period (p<0.001). During pre-pandemic period, significantly higher proportion of children had RSV positivity (p<0.001);and significantly lower positivity for hRV (p<0.05), hMPV (p<0.05), and hBoV (p <= 0.005). The occurrence of COVID-19 pandemic has significantly impacted the frequency and pattern of detection of RSV among hospitalized children with LRTIs. RSV Fusion protein plays a critical role in the entry of the virus into the host cell by initiating the fusion of host and viral membranes. It happens to be a target of neutralizing antibodies paving the way as a vaccine candidate. Hence effort was made to introduce point mutation in hRSV fusion protein which can confer stability in its prefusion form. In-silico a stable structure of RSV fusion protein was generated making it a potential vaccine candidate. The timely diagnosis of RSV infection in this population is important for initiating therapy and instituting appropriate infection prevention measures. Serological testing is not widely used for the diagnosis of RSV. C ll Cultures including shell vial culture were used for RSV diagnosis. However, culture approaches lack sensitivity, often quite significantly, compared to nucleic acid amplification assays for the diagnosis of RSV infections. Molecular multiplex assays now offer increased sensitivity for a more accurate diagnosis. However issues with the use of these types of commercial panel assays include the requirement for substantial training, quality systems, and infrastructure to maintain and run these assays and many a times identification of viruses where the true pathogenic potential of those multiple viruses are debatable. Studies are available with laboratory- developed nucleic acid amplification test systems for the detection of RSVA and RSVB in clinical specimens either by PCRbased technologies or RT-LAMP. Gene targets of laboratory-developed molecular assays point towards M gene and the N gene in RSVA and -B with the benefits of flexibility to modify assays when targets are under evolutionary pressure to change, as well as a perceived initial low cost to carry out testing.

Pan-cancer landscape of CENPO and its underlying mechanism in LUAD.

BACKGROUND: Centromere protein O (CENPO) is a newly discovered constitutive centromeric protein, associated with cell death. However, little is known about how CENPO expression is associated with human cancers or immune infiltration. Here, we assessed the function of CENPO in pan-cancer and further verified the results in lung adenocarcinoma (LUAD) through in vitro and in vivo experiments. METHODS: Sangerbox and TCGA databases were used to evaluate the CENPO expression level in different human cancer types. A subsequent evaluation of the potential role of CENPO as a diagnostic and prognostic biomarker in pancancer was conducted. The CENPO mutations were analyzed using the cBioPortal database and its function was analyzed using the LinkedOmics and CancerSEA databases. The TIMER2 and TISIDB websites were used to find out how CENPO affects immune infiltration. The expression level of CENPO in LUAD was revealed by TCGA database and immunohistochemical (IHC) staining. Targetscan, miRWalk, miRDB, miRabel, LncBase databases, and Cytoscape tool were used to identify microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) that regulate expression and construct ceRNA network. Subsequently, loss-of-function assays were performed to identify the functions of CENPO on the malignant behavior and tumor growth of LUAD in vitro and in vivo experiments. RESULTS: In most cancers, CENPO was upregulated and mutated, which predicted a poorer prognosis. Furthermore, infiltration of CENPO and myeloid-derived suppressor cells (MDSC) showed a significant positive correlation, while T-cell NK infiltration showed a significant negative correlation in most cancers. CENPO was expressed at high levels in LUAD and was correlated with p-TNM stage. Furthermore, CENPO knockdown suppressed the malignant phenotypes of LUAD cells, manifested by slower proliferation, cycle in G2, increased apoptosis, decreased migration, and attenuated tumorigenesis. Furthermore, CENPO knockdown decreased CDK1/6, PIK3CA, and inhibited mTOR phosphorylation, suggesting that the mTOR signaling pathway may be involved in CENPO-mediated regulation of LUAD development. CONCLUSIONS: In pan-cancer, especially LUAD, CENPO may be a potential biomarker and oncogene. Furthermore, CENPO has been implicated in immune cell infiltration in pan-cancer and represents a potential immunotherapeutic target for tumor therapy.

Unilateral multiple facial angiofibromas as a solitary manifestation of tuberous sclerosis

We describe the case of a 12-year-old boy who presented via teledermatology with a 5-6-year history of multiple lesions on the right side of his face. They were unchanged since their initial appearance at 6 years of age but were slowly increasing in number across his right cheek and extending onto the chin. Although the lesions were asymptomatic, growing older had made him feel increasingly self-conscious. He was otherwise fit and well, and attended mainstream school, with no past medical history or family history of note. Perinatal and birth history were also uneventful. On examination, he had multiple, 1-2-mm, erythematous papules confined to the right cheek and right chin. Dermoscopy showed an unusual pattern of vessels with nonspecific globules in between. The rest of the skin, hair and nails were entirely normal in appearance. There were no systemic symptoms and a detailed general and systemic examination, as well as radiological imaging, did not reveal any abnormality. An excisional biopsy was taken of one of the lesions, with histological examination demonstrating focal superficial telangiectasia with associated bland round-tospindle cell proliferation, appearances most in keeping with an angiofibroma. This correlated well clinically, apart from unilateral facial angiofibromas being the solitary finding in our patient. Facial angiofibromas - also called adenoma sebaceum - are well described as part of the cutaneous manifestations of tuberous sclerosis (TSC). Classically, these appear as a facial rash in the form of small pink or red spots across the cheeks and nose in a butterfly distribution, at between 3 and 10 years of age, increasing in size and number until adolescence. TSC is an autosomal dominant disorder with defective mammalian target of rapamycin (mTOR) signalling, characterized by hamartomas in many organs, particularly the skin, central nervous system, renal and cardiovascular systems. The clinical presentation is variable, with other well known and frequently reported cutaneous findings such as shagreen patches, ash-leaf macules and periungual fibromas. Unilateral multiple facial angiofibromas in the absence of other cutaneous or systemic manifestations of TSC - as in our patient - are rare, with only 13 reported cases. These may form part of the clinical spectrum of TSC as a probable consequence of cutaneous mosaicism in which a postzygotic genetic mutation has occurred. Our patient was referred for genetic testing, but this has been delayed as a result of the COVID-19 pandemic. Topical sirolimus 1% - an mTOR inhibitor - has been used with good effect for facial angiofibromas, and our patient also responded well to this.

SARS-CoV-2 Therapy: Old Drugs as New Interventions

An outburst of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a grave threat to global health and the economy. As of May 13, 2020, a total of 42,81,838 cases have been confirmed, with over 2,92,376 deaths worldwide. In India, 75,048 cases have been reported to date with 2,440 deaths. Management of this new coronavirus (COVID19) has mainly focused on infection prevention, case detection, monitoring, and supportive care. As there is no vaccine or specific antiviral treatment for human SARS-CoV-2, therefore identifying the drug treatment options as soon as possible is critical for the response to the COVID19 outbreak. Pro-inflammatory cascade and cytokine storm play a key role in the pathogenesis of new coronavirus. A large number of therapeutic interventions such as antiviral, antimalarial, convalescent plasma therapy, BCG vaccine, mTOR inhibi-tors, Tissue Plasminogen Activator, Human monoclonal antibodies, Anti-parasitic agents, Immunoen-hancers, Nutritional interventions, JAK-STAT signaling inhibitors, ACE2 receptor modulators, and An-giotensin II receptor blockers have been either tried or suggested for effective treatment of patients with SARS-CoV-2 disease. Hence, we recommend that all the above potential interventions must be imple-mented in terms of their safety and efficacy through proper clinical experiments to control the emerging SARS-CoV-2 disease.Copyright © 2021 Bentham Science Publishers.

Therapeutic role of mTOR inhibitors in control of SARS-CoV-2 viral replication.

By the end of 2019, COVID-19 was reported in Wuhan city of China, and through human-human transmission, this virus spread worldwide and became a pandemic. Initial symptoms of the disease include fever, cough, loss of smell, taste, and shortness of breath, but a decrease in the oxygen levels in the body leads, and pneumonia may ultimately lead to the patient's death. However, the symptoms vary from patient to patient. To understand COVID-19 disease pathogenesis, researchers have tried to understand the cellular pathways that could be targeted to suppress viral replication. Thus, this article reviews the markers that could be targeted to inhibit viral replication by inhibiting the translational initiation complex/regulatory kinases and upregulating host autophagic flux that may lead to a reduction in the viral load. The article also highlights that mTOR inhibitors may act as potential inhibitors of viral replication. mTOR inhibitors such as metformin may inhibit the interaction of SARS-CoV-2 Nsp's and ORFs with mTORC1, LARP1, and 4E-BP. They may also increase autophagic flux by decreasing protein degradation via inhibition of Skp2, further promoting viral cell death. These events result in cell cycle arrest at G1 by p27, ultimately causing cell death.

Role of mTOR inhibitor in the cellular and humoral immune response to a booster dose of SARS-CoV-2 mRNA-1273 vaccine in kidney transplant recipients.

Background: Immunocompromised patients have an increased risk of developing severe COVID disease, as well as a tendency to suboptimal responses to vaccines. The objective of this study was to evaluate the specific cellular and humoral adaptive immune responses of a cohort of kidney transplant recipients (KTR) after 3 doses of mRNA-1273 vaccine and to determinate the main factors involved. Methods: Prospective observational study in 221 KTR (149 non infected), 55 healthy volunteers (HV) and 23 dialysis patients (DP). We evaluated anti-spike (by quantitative chemiluminescence immunoassay) and anti-nucleocapsid IgG (ELISA), percentage of TCD4+ and TCD8+ lymphocytes producing IFNγ against S-protein by intracellular flow cytometry after Spike-specific 15-mer peptide stimulation and serum neutralizing activity (competitive ELISA) at baseline and after vaccination. Results: Among COVID-19 naïve KTR, 54.2% developed cellular and humoral response after the third dose (vs 100% in DP and 91.7% in HV), 18% only showed cell-mediated response, 22.2% exclusively antibody response and 5.6% none. A correlation of neutralizing activity with both the IgG titer (r=0.485, p<0.001) and the percentage of S-protein-specific IFNγ-producing CD8-T cells (r=0.198, p=0.049) was observed. Factors related to the humoral response in naïve KTR were: lymphocytes count pre-vaccination >1000/mm3 [4.68 (1.72-12.73, p=0.003], eGFR>30 mL/min [7.34(2.72-19.84), p<0.001], mTOR inhibitors [6.40 (1.37-29.86), p=0.018]. Infected KTR developed a stronger serologic response than naïve patients (96.8 vs 75.2%, p<0.001). Conclusions: KTR presented poor cellular and humoral immune responses following vaccination with mRNA-1273. The immunosuppression degree and kidney function of these patients play an important role, but the only modifiable factor with a high impact on humoral immunogenicity after a booster dose was an immunosuppressive therapy including a mTOR inhibitor. Clinical trials are required to confirm these results.

Resveratrol attenuates staphylococcal enterotoxin B-activated immune cell metabolism via upregulation of miR-100 and suppression of mTOR signaling pathway.

Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of insults, such as bacterial and viral infections, including SARS-CoV-2, leading to high mortality. In the murine model of ARDS induced by Staphylococcal enterotoxin-B (SEB), our previous studies showed that while SEB triggered 100% mortality, treatment with Resveratrol (RES) completely prevented such mortality by attenuating inflammation in the lungs. In the current study, we investigated the metabolic profile of SEB-activated immune cells in the lungs following treatment with RES. RES-treated mice had higher expression of miR-100 in the lung mononuclear cells (MNCs), which targeted mTOR, leading to its decreased expression. Also, Single-cell RNA-seq (scRNA seq) unveiled the decreased expression of mTOR in a variety of immune cells in the lungs. There was also an increase in glycolytic and mitochondrial respiration in the cells from SEB + VEH group in comparison with SEB + RES group. Together these data suggested that RES alters the metabolic reprogramming of SEB-activated immune cells, through suppression of mTOR activation and its down- and upstream effects on energy metabolism. Also, miR-100 could serve as novel potential therapeutic molecule in the amelioration of ARDS.

Modeling the effects of SARS-CoV-2 infection on the mTOR signaling pathway

The spread of COVID-19 caused by SARS-CoV-2 leads to global emergent health crisis and has a major impact on medical capacity. Novel drugs and therapeutic strategies are being developed to against COVID- 19. The mTOR pathway is one of the most pathogenesis-related signaling pathway of COVID- 19. SARS-CoV-2 can hijack the mTOR signaling pathway to promote its own replication and transmission. However, SARS-CoV-2 acts different at the early and late stages, which repress and induce apoptosis, respectively. This phenomenon results in two completely opposite treatment strategies between the early and late stages of infection. To precisely understand the pathogenetic progress and estimate the best administration time and therapeutic strategy at different stages of SARS-CoV-2 infection, we developed the first comprehensive dynamic quantitative model of the mTOR signaling pathway with SARS-CoV-2 infection in lung. This model incorporates systematic gene expression data and gives a more comprehensive and precise understanding of COVID-19 pathogenesis. This model can be used as a platform for investigating novel therapeutic strategies and administration times against COVID-19.

Increased mTOR Signaling and Impaired Autophagic Flux Are Hallmarks of SARS-CoV-2 Infection.

The COVID-19 (Coronavirus Disease 2019), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), severely affects mainly individuals with pre-existing comorbidities. Here our aim was to correlate the mTOR (mammalian/mechanistic Target of Rapamycin) and autophagy pathways with the disease severity. Through western blotting and RNA analysis, we found increased mTOR signaling and suppression of genes related to autophagy, lysosome, and vesicle fusion in Vero E6 cells infected with SARS-CoV-2 as well as in transcriptomic data mining of bronchoalveolar epithelial cells from severe COVID-19 patients. Immunofluorescence co-localization assays also indicated that SARS-CoV-2 colocalizes within autophagosomes but not with a lysosomal marker. Our findings indicate that SARS-CoV-2 can benefit from compromised autophagic flux and inhibited exocytosis in individuals with chronic hyperactivation of mTOR signaling.

MTOR hypermethylation may associate with the susceptibility and survival of SARS-CoV-2 infections to lung adenocarcinoma patients based on multi-omics data and machine learning

Recent studies have shown that lung adenocarcinoma (LUAD) patients have a higher risk and worse prognosis of COVID-19 caused by SARS-CoV-2 compared to normal samples. Whereas, in addition to the receptor for SARS-CoV-2, other genes also deserve attention. In our study, we identified 19 differentially methylated genes (DMGs) that were co-upregulated in LUAD and COVID-19 samples. These 19 DMGs mainly regulated the immune-related and multiple viral infection signaling pathways. Gene Ontology and pathway enrichment analysis were applied with these genes. Then, 6 key DMGs (MTOR, ACE, IGF1, PTPRC, C3, and PTGS2) were identified by constructing and analyzing the protein-protein interaction (PPI) network. Besides, MTOR was significantly associated with 5 prognostic markers (CDO1, NEURL4, SMAP1, NPEPPS, IQCK) identified by survival analysis based on machine learning. In total, MTOR hypermethylation may be related to the susceptibility of LUAD patients to SARS-CoV-2 and the prognosis of LUAD patients suffering from COVID-19. © 2022 IEEE.

Molecular and therapeutic insights of rapamycin: a multi-faceted drug from Streptomyces hygroscopicus.

The advancement in pharmaceutical research has led to the discovery and development of new combinatorial life-saving drugs. Rapamycin is a macrolide compound produced from Streptomyces hygroscopicus. Rapamycin and its derivatives are one of the promising sources of drug with broad spectrum applications in the medical field. In recent times, rapamycin has gained significant attention as of its activity against cytokine storm in COVID-19 patients. Rapamycin and its derivatives have more potency when compared to other prevailing drugs. Initially, it has been used exclusively as an anti-fungal drug. Currently rapamycin has been widely used as an immunosuppressant. Rapamycin is a multifaceted drug; it has anti-cancer, anti-viral and anti-aging potentials. Rapamycin has its specific action on mTOR signaling pathway. mTOR has been identified as a key regulator of different pathways. There will be an increased demand for rapamycin, because it has lesser adverse effects when compared to steroids. Currently researchers are focused on the production of effective rapamycin derivatives to combat the growing demand of this wonder drug. The main focus of the current review is to explore the origin, development, molecular mechanistic action, and the current therapeutic aspects of rapamycin. Also, this review article revealed the potential of rapamycin and the progress of rapamycin research. This helps in understanding the exact potency of the drug and could facilitate further studies that could fill in the existing knowledge gaps. The study also gathers significant data pertaining to the gene clusters and biosynthetic pathways involved in the synthesis and production of this multi-faceted drug. In addition, an insight into the mechanism of action of the drug and important derivatives of rapamycin has been expounded. The fillings of the current review, aids in understanding the underlying molecular mechanism, strain improvement, optimization and production of rapamycin derivatives.

WWOX activates autophagy to alleviate lipopolysaccharide-induced acute lung injury by regulating mTOR.

Acute lung injury (ALI) is characterized by acute systemic inflammatory responses that may lead to severe acute respiratory distress syndrome (ARDS). The clinical course of ALI/ARDS is variable; however, it has been reported that lipopolysaccharides (LPS) play a role in its development. The fragile chromosomal site gene WWOX is highly sensitive to genotoxic stress induced by environmental exposure and is an important candidate gene for exposure-related lung disease research. However, the expression of WWOX and its role in LPS-induced ALI still remain unidentified. This study investigated the expression of WWOX in mouse lung and epithelial cells and explored the role of WWOX in LPS-induced ALI model in vitro and in vivo. In addition, we explored one of the possible mechanisms by which WWOX alleviates ALI from the perspective of autophagy. Here, we observed that LPS stimulation reduced the expression of WWOX and the autophagy marker microtubule-associated protein 1 light chain 3ß-II (MAP1LC3B/LC3B) in mouse lung epithelial and human epithelial (H292) cells. Overexpression of WWOX led to the activation of autophagy and inhibited inflammatory responses in LPS-induced ALI cells and mouse model. More importantly, we found that WWOX interacts with mechanistic target of rapamycin [serine/threonine kinase] (mTOR) and regulates mTOR and ULK-1 signaling-mediated autophagy. Thus, reduced WWOX levels were associated with LPS-induced ALI. WWOX can activate autophagy in lung epithelial cells and protect against LPS-induced ALI, which is partly related to the mTOR-ULK1 signaling pathway.

Impact of immunosuppression regimen on COVID-19 mortality in kidney transplant recipients: Analysis from a Colombian transplantation centers registry.

BACKGROUND: The impact of immunosuppression in solid organ transplant recipients with SARS-CoV-2 infection is unknown. The knowledge about the behavior of different immunosuppression schemes in clinical outcomes is scarce. This study aimed to determine the risk of death in kidney transplant recipients with COVID-19 under two different schemes of immunosuppression. METHODS: We describe our experience in kidney transplant recipients with SARS-CoV-2 infection in seven transplant centers during the first year of the pandemic before starting the vaccination programs in the city of Bogotá. Demographic characteristics, clinical presentation, immunosuppression schemes at presentation, and global treatment strategies were compared between recovered and dead patients; survival analysis was carried out between calcineurin inhibitors based regimen and free calcineurin inhibitors regimen. RESULTS: Among 165 confirmed cases, 28 died (17%); the risk factors for mortality identified in univariate analysis were age older than 60 years (p=.003) diabetes (p=.001), immunosuppression based on calcineurin inhibitors (CNI) (p=.025) and patients receiving steroids (p=.041). In multivariable analysis, hypoxemia (p=.000) and calcineurin inhibitors regimen (p=.002) were predictors of death. Survival analysis showed increased mortality risk in patients receiving CNI based immunosuppression regimen vs. CNI free regimens mortality rates were, respectively, 21.7% and 8.5% (p=.036). CONCLUSIONS: Our results suggest that the calcineurin inhibitors probably do not provide greater protection compared to calcineurin inhibitor free schemes being necessary to carry out analyzes that allow us to evaluate the outcomes with different immunosuppression schemes in solid organ transplant recipients with SARS-CoV-2 infection.

Modeling the effects of SARS-CoV-2 infection on the mTOR signaling pathway

The spread of COVID-19 caused by SARS-CoV-2 leads to global emergent health crisis and has a major impact on medical capacity. Novel drugs and therapeutic strategies are being developed to against COVID-19. The mTOR pathway is one of the most pathogenesis-related signaling pathway of COVID-19. SARS CoV-2 can hijack the mTOR signaling pathway to promote its own replication and transmission However, SARS-CoV-2 acts different at the early and late stages, which repress and induce apoptosis, respectively. This phenomenon results in two completely opposite treatment strategies between the early and late stages of infection. To precisely understand the pathogenetic progress and estimate the best administration time and therapeutic strategy at different stages of SARS-CoV-2 infection, we developed the first comprehensive dynamic quantitative model of the mTOR signaling pathway with SARS-CoV-2 infection in lung. This model incorporates systematic gene expression data and gives a more comprehensive and precise understanding of COVID-19 pathogenesis. This model can be used as a platform for investigating novel therapeutic strategies and administration times against COVID-19. © 2022 IEEE.

Diabetes and SARS-CoV-2 Infection: The Potential Role of Antidiabetic Therapy in the Evolution of COVID-19.

Diabetes mellitus represents one of the most frequent comorbidities among patients with COVID-19, constituting a risk factor for a more severe prognosis than that of non-diabetic patients. However, the pathophysiological mechanism underlying this unfavorable outcome is still not completely clear. The goal of our study was to evaluate the potential role of antidiabetic therapy in the evolution of COVID-19.

MERS-CoV nsp1 regulates autophagic flux via mTOR signalling and dysfunctional lysosomes.

Autophagy, a cellular surveillance mechanism, plays an important role in combating invading pathogens. However, viruses have evolved various strategies to disrupt autophagy and even hijack it for replication and release. Here, we demonstrated that Middle East respiratory syndrome coronavirus (MERS-CoV) non-structural protein 1(nsp1) induces autophagy but inhibits autophagic activity. MERS-CoV nsp1 expression increased ROS and reduced ATP levels in cells, which activated AMPK and inhibited the mTOR signalling pathway, resulting in autophagy induction. Meanwhile, as an endonuclease, MERS-CoV nsp1 downregulated the mRNA of lysosome-related genes that were enriched in nsp1-located granules, which diminished lysosomal biogenesis and acidification, and inhibited autophagic flux. Importantly, MERS-CoV nsp1-induced autophagy can lead to cell death in vitro and in vivo. These findings clarify the mechanism by which MERS-CoV nsp1-mediated autophagy regulation, providing new insights for the prevention and treatment of the coronavirus.

Therapeutics That Can Potentially Replicate or Augment the Anti-Aging Effects of Physical Exercise.

Globally, better health care access and social conditions ensured a significant increase in the life expectancy of the population. There is, however, a clear increase in the incidence of age-related diseases which, besides affecting the social and economic sustainability of countries and regions around the globe, leads to a decrease in the individual's quality of life. There is an urgent need for interventions that can reverse, or at least prevent and delay, the age-associated pathological deterioration. Within this line, this narrative review aims to assess updated evidence that explores the potential therapeutic targets that can mimic or complement the recognized anti-aging effects of physical exercise. We considered pertinent to review the anti-aging effects of the following drugs and supplements: Rapamycin and Rapamycin analogues (Rapalogs); Metformin; 2-deoxy-D-glucose; Somatostatin analogues; Pegvisomant; Trametinib; Spermidine; Fisetin; Quercetin; Navitoclax; TA-65; Resveratrol; Melatonin; Curcumin; Rhodiola rosea and Caffeine. The current scientific evidence on the anti-aging effect of these drugs and supplements is still scarce and no recommendation of their generalized use can be made at this stage. Further studies are warranted to determine which therapies display a geroprotective effect and are capable of emulating the benefits of physical exercise.

mTOR Inhibitor Use Is Associated With a Favorable Outcome of COVID-19 in Patients of Kidney Transplant: Results of a Retrospective Study.

Introduction: In solid organ transplant recipients, COVID-19 is associated with a poor prognosis because of immunosuppression. Some studies suggest a potential therapeutic role of mammalian Target of Rapamycin (mTOR) inhibitors in SARS-CoV-2 infection. This study aimed to assess the impact of mTOR employment on the evolution and outcome of SARS-CoV-2 infection in solid organ transplant recipients. Methods: We enrolled kidney transplant patients attending the Azienda Ospedaliera Universitaria Federico II in Naples and followed up on these patients from March 2020 to June 2021. We evaluated the risk of acquiring the SARS-CoV-2 infection, the clinical presentation of the disease, and its outcome together with the type of immunosuppressive therapy. Finally, we assessed the impact of mTOR inhibitors on relevant clinical metrics of SARS-CoV-2 infection. Results: We enrolled 371 patients, of whom 56 (15.1%) contracted SARS-CoV-2 infection during the period of the study. There were no differences observed among the different immunosuppressive therapies concerning the risk of acquiring SARS-CoV-2 infection. In contrast, the type of immunosuppressive therapy had a significant impact on the outcome of the disease. In detail, patients who received mTOR inhibitors, as part of their immunosuppressive therapy, compared to other regimens had a lower chance of developing a moderate or severe form of the disease (OR = 0.8, 95, CI: (0.21-0.92), P = 0.041). Conclusion: In kidney transplant patients, the use of mTOR inhibitors as part of an immunosuppressive regimen is associated with a better prognosis in the case of COVID-19.