Immunogenetic factors such as human leukocyte antigen (HLA) alleles, have yielded contrasting associations with protection or increased chances of hospitalization due to COVID-19 worldwide. This case-control study included 834 patients with confirmed COVID-19 diagnosis from five Brazilian states: Ceará (n = 110), Mato Grosso (n = 192), Pará (n = 209), Rio de Janeiro (n = 211) and Rio Grande do Sul (n = 112). Genotyping was performed using the Axiom™ Human Genotyping SARS-CoV-2 array, targeting single nucleotide polymorphisms in HLA class I and II genes; HLA alleles were imputed for eight loci. Among the 15 preselected candidate alleles, only DQA1∗05:01 (p = 0.015) in the state of Ceará remained significantly associated with hospitalization. The meta-analysis of the most frequent alleles in all states revealed that HLA-DPA1∗01:03 (p = 0.0229, OR = 0.76, 95 % CI = 0.60-0.96) and HLA-DPB1∗04:01 (p = 0.0474, OR = 0.78, 95 % CI = 0.611.00) were associated with protection against hospitalization, whereas HLA-DPA1∗02:01 (p = 0.0259, OR = 1.37, 95 % CI = 1.04-1.80), HLA-DQA1∗05:01 (p = 0.0133, OR = 1.40, 95 % CI = 1.07-1.82), and HLA-DRB1∗03:01 (p = 0.0276, OR: 1.59, 95 % CI: 1.05-2.40) associated with increased risk of hospitalization. HLA evolutionary divergence (HED) scores were significantly higher among the non-hospitalized group for the HLA-A locus, which has been shown to be a protective factor for the most severe forms and consequently hospitalization due to COVID-19.

Chikungunya virus (CHIKV) is a medically significant arbovirus responsible for Chikungunya fever (CHIKF), a debilitating disease marked by persistent joint and muscle pain. The most severe outcomes of CHIKF, including mortality, are frequently observed in individuals with comorbidities diabetes mellitus (DM). This study aimed to investigate how varying glucose concentrations influence CHIKV infection.

Human umbilical vein endothelial cells (HUVEC) were cultured in normal glucose (NG - 5.5 mM glucose) or high glucose (HG - 25 mM glucose) to mimic normoglycemia and hyperglycemia conditions. Cells were infected with CHIKV and changes in host glucose metabolism were evaluated. Metabolic flux, viral replication, and cellular insulin sensitivity were assessed through biochemical, molecular analyses and metabolomics.

CHIKV infection modulates host cell metabolism in a glucose-dependent manner. Under NG conditions, the virus regulates glucose metabolism to support replication and virion production. In contrast, HG environments enhance viral replication, exploiting the altered metabolic landscape. Notably, CHIKV restores insulin sensitivity in HG conditions, leading to increased glucose uptake. It also promotes anaplerotic reactions by diverting tricarboxylic acid (TCA) cycle intermediates toward amino acid synthesis and upregulates glycolytic flux into the hexosamine biosynthesis pathway (HBP).

These findings provide mechanistic insight into how hyperglycemia associated with DM can exacerbate CHIKV pathogenesis. The virus's ability to hijack and redirect host metabolic processes in high glucose environments may underline the worsened disease severity observed in diabetic patients. Understanding these interactions could inform targeted therapeutic strategies for managing CHIKF in individuals with metabolic comorbidities.

Staphylococcus aureus infection poses a serious threat to the dairy industry and public health safety. The stimulator of interferon gene (STING) signaling pathway has been well established as effective in defending against viral infections. However, the role of STING is controversial during bacterial infections. Herein, we provide an insight into the role of STING during S. aureus infection. Our data revealed that the STING signaling pathway was activated in S. aureus-infected cells. In vitro investigations demonstrated that inhibiting STING reduced inflammation, hypoxia-inducible factor-1 alpha (HIF1α) expression, and mitochondrial reactive oxygen species (mROS) production. Interestingly, blocking HIF1α eliminated the escalation of inflammation associated with STING. Additionally, suppressing mROS production significantly reduced HIF1α expression and inflammation levels, while elevating mROS had the opposite effect. These results indicate that STING promoted inflammation through the mROS-HIF1α pathway. Given that glycolysis is driven by HIF1α, we investigated the role of glycolysis during infection. As expected, STING-elevated inflammation was linked with HIF1α-driven glycolysis. In terms of pathogenesis, STING contributed to S. aureus proliferation within cells and mouse mammary glands. Collectively, our findings demonstrate that STING facilitates infection via the mROS-HIF1α-glycolysis axis, highlighting its potential as a promising anti-inflammatory target.

Corona Virus Disease 2019 (COVID-19) and diabetes interact to influence disease severity, yet their combined immunological characteristics remain unclear. Here, we analyzed Tim-3+ T cells in patients with COVID-19, Type 1 Diabetes (T1D), or both conditions. COVID-19 reduced peripheral T cell subsets but increased Tim-3+ cells, while T1D and COVID-19 with T1D showed the opposite pattern. Patients with Type 2 Diabetes (T2D) exhibited no significant alterations. In human samples and mouse models, Tim-3+ T cells demonstrated impaired activation and cytokine production. RNA-seq analysis in mice and RT-PCR analysis in human samples together identified the dysregulation of the JAK-STAT pathway in Tim-3+ T cells. These findings highlight Tim-3-mediated JAK-STAT dysregulation in T-cells as a potential mechanism linking COVID-19 and T1D, offering insights for therapeutic targeting.

Hypoxia is a hallmark of the tumor microenvironment (TME), and it plays a crucial role in the occurrence and progression in vascular tumors. Under hypoxic conditions, hypoxia-inducible factor 1-alpha (HIF-1α) is stabilized, inducing changes in the expression of various target genes involved in angiogenesis, metabolism, and cell survival. This includes the upregulation of pro-angiogenic factors like VEGF, which promotes the formation of dysfunctional blood vessels, contributing to the worsening of the hypoxic microenvironment. At the same time, hypoxia induces a metabolic shift toward glycolysis, even in the presence of oxygen, supporting tumor cell survival and proliferation by providing necessary energy and biosynthetic precursors. This review discusses the molecular mechanisms by which hypoxia regulates angiogenesis and metabolic reprogramming in vascular tumors, highlighting the intricate link between these processes, and explores potential therapeutic strategies to target these pathways in order to develop effective treatment strategies for patients.

Patients with coronavirus disease-19 (COVID-19) often develop systemic inflammation, which is associated with increased mortality. Elevated blood glucose levels can exacerbate the cytokine storm, further worsening disease severity and accelerating patient death. Therefore, this study aims to investigate the association between glucose levels and mortality in hospitalized patients, providing insights into the importance of optimizing glucose management in hospitalized COVID-19 patients.

A retrospective cohort study was conducted, involving adult COVID-19 patients in a university hospital. The primary outcome was in-hospital mortality. Propensity score matching (PSM) was utilized to match patients' baseline characteristics. Discrimination capacity of different models was assessed using C-statistics, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Trends in blood glucose over time were detected using the ordinary least squares model.

Among the 4583 COVID-19 patients during the study period, 2147 (46.8%) exhibited normal glycemia, while 2436 (53.2%) had admission hyperglycemia. After adjusting for confounding factors through multivariate regression analysis, patients with hyperglycemia showed significantly higher odds of in-hospital mortality (adjusted odds ratio [aOR]: 3.10, 95% CI: 2.25 to 4.28; P < 0.001). PSM analysis yielded similar results (aOR: 2.66, 95% CI: 2.09 to 3.41; P < 0.001). The incorporation of admission glucose significantly improved C-statistics (P < 0.001), IDI (P < 0.001), and NRI (P < 0.001) for predicting mortality.

This study concludes that blood glucose levels ≥ 6.1 mmol/L can independently predict all-cause mortality and clinical sequelae in COVID-19 patients. Furthermore, even a mild increase in blood glucose was associated with a significantly higher risk of mortality in these patients. These findings underscore the importance of managing hyperglycemia and monitoring blood glucose in individuals with COVID-19.

The complex interplay between protein palmitoylation, mitochondrial dynamics, and inflammatory responses plays a pivotal role in respiratory diseases. One significant feature of post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) is the occurrence of a storm of inflammatory cytokines related to the NOD-like receptor protein 3 (NLRP3). However, the specific mechanisms via which palmitoylation affects mitochondrial function and its impact on the NLRP3 inflammasome under pathological respiratory conditions remain to be elucidated.

This study aimed to investigate how protein palmitoylation influences inflammatory responses and mitochondrial dynamics in respiratory diseases, such as those induced by the SARS-CoV-2 spike S protein in PACS, thereby providing a therapeutic target for inflammatory lung injury.

In vivo experiments were conducted using AdV5-pADM-CMV-COVID-19-S (AdV5-S) nasal drip-treated C57BL/6 mice to assess NLRP3 inflammasome activation and inflammatory response. In vitro experiments were performed using pCMV-S-transfected human lung epithelial BEAS-2B cells to analyze the effects of DHHC5-mediated palmitoylation of cyclooxygenase-2 (COX-2) at cysteine 555 (COX-2Cys555) on mitochondrial metabolism and NLRP3 inflammasome activation.

Palmitoylation of COX-2Cys555 enhanced its interaction with hexokinase 2 (HK2) to regulate mitochondrial metabolic reprogramming, leading to NLRP3 inflammasome activation and pyroptosis. Pharmacological and genetic suppression of palmitoylation diminished the mitochondrial localization of palmitoylated COX-2 and its interaction with HK2, thereby reducing mitochondrial metabolic reprogramming. Furthermore, genetic intervention targeting DHHC5 (shDhhc5) alleviated NLRP3 activation and pyroptosis, mitigating the chronic inflammatory damage associated with PACS.

This study highlights the regulatory role of COX-2Cys555 palmitoylation in mitochondrial metabolism and lung inflammatory injury, and suggests potential therapeutic targets to combat respiratory pathogenesis linked to palmitoylated COX-2.

Syphilis, caused by Treponema pallidum (Tp), represents a significant public health challenge. The clinical manifestations of syphilis are attributed to local inflammatory responses induced by Tp, notably monocyte infiltration into local lesions and the secretion of inflammatory cytokines. However, the mechanisms driving cytokine production in response to Tp infection remain largely unknown. Given that increased glycolysis is associated with inflammatory responses, we aimed to investigate the role of glycolysis in Tp-induced secretion of inflammatory cytokines. In this study, we found that Tp promotes the secretion of inflammatory cytokines IL-6, IL-8, and CCL2 from monocytes while enhancing glycolysis through increased GLUT1 plasma membrane expression and glucose uptake. Importantly, inhibiting glycolysis and GLUT1 reduced the Tp-induced secretion of monocyte inflammatory cytokines. Additionally, Tp significantly increased HIF-1α expression and induced its nuclear translocation, thereby promoting glycolysis by upregulating the expression of GLUT1 and LDHA glycolytic enzymes. Knockdown of HIF-1α inhibits Tp-induced monocyte cytokine secretion, highlighting the crucial role of HIF-1α-mediated glycolysis in the cytokine response to Tp. Also, expression of HIF-1α and an increase in glycolysis were confirmed in patients with syphilis. In conclusion, we demonstrated that HIF-1α-regulated GLUT1-mediated glycolysis enhances inflammatory cytokine secretion following Tp infection. Our findings not only elucidate the mechanism of glycolysis in Tp-induced inflammatory responses in monocytes but also contribute to the development of a potential biomarker in syphilis diagnosis and treatment.

The concept of macrophage polarization has been largely used in human diseases to define a typology of activation of myeloid cells reminiscent of lymphocyte functional subsets. In COVID-19, several studies have investigated myeloid compartment dysregulation and macrophage polarization as an indicator of disease prognosis and monitoring. SARS-CoV-2 induces an in vitro activation state in monocytes and macrophages that does not match the polarization categories in most studies. In COVID-19 patients, monocytes and macrophages are activated but they do not show a polarization profile. Therefore, the investigation of polarization under basic conditions was not relevant to assess monocyte and macrophage activation. The analysis of monocytes and macrophages with high-throughput methods has allowed the identification of new functional subsets in the context of COVID-19. This approach proposes an innovative stratification of myeloid cell activation. These new functional subsets of myeloid cells would be better biomarkers to assess the risk of complications in COVID-19, reserving the concept of polarization for pharmacological programme evaluation. This review reappraises the polarization of monocytes and macrophages in viral infections, particularly in COVID-19.

The COVID-19 pandemic, driven by SARS-CoV-2, has led to a global health crisis, highlighting the virus's unique molecular mechanisms that distinguish it from other respiratory pathogens. It is known that the Hypoxia-Inducible Factor 1α (HIF-1α) activates a complex network of intracellular signaling pathways regulating cellular energy metabolism, angiogenesis, and cell survival, contributing to the wide range of clinical manifestations of COVID-19, including Post-Acute COVID-19 Syndrome (PACS). Emerging evidence suggests that dysregulation of HIF-1α is a key driver of systemic inflammation, silent hypoxia, and pathological tissue remodeling in both the acute and post-acute phases of the disease. This scoping review was conducted following PRISMA-ScR guidelines and registered in INPLASY. It involved a literature search in Scopus and PubMed, supplemented by manual reference screening, with study selection facilitated by Rayyan software. Our analysis clarifies the dual role of HIF-1α, which may either worsen inflammatory responses and viral persistence or support adaptive mechanisms that reduce cellular damage. The potential for targeting HIF-1α therapeutically in COVID-19 is complex, requiring further investigation to clarify its precise role and translational applications. This review deepens the molecular understanding of SARS-CoV-2-induced cellular and tissue dysfunction in hypoxia, offering insights for improving clinical management strategies and addressing long-term sequelae.

Despite the early recognition that individuals living with obesity are more prone to develop adverse outcomes during COVID-19, the mechanisms underlying these conditions are still unclear. During obesity, an accumulation of free fatty acids (FFAs) in the circulation promotes low-grade inflammation. Here, we show that FFAs induce epigenetic reprogramming of monocytes, exacerbating their inflammatory profile after SARS-CoV-2 infection, a mechanism named metabolic-primed immunity. Monocytes from people with obesity or primed with palmitate, a central component of circulating FFAs, presented elevated viral load and higher gene expression of IL-6. Palmitate-primed monocytes upregulate fatty acid oxidation and FFAs entry into the mitochondria. FFA-derived acetyl-CoA is then converted into citrate, exiting the mitochondria and is used to support H3K18 histone acetylation, which regulates IL-6 accessibility. Ingestion of palm oil by lean and healthy individuals increased circulating FFAs levels and was sufficient to exacerbate the inflammatory profile of monocytes upon SARS-CoV-2 infection. Our findings demonstrate that obesity-derived FFAs induce the metabolic priming of monocytes, which exacerbates the inflammatory response observed in people with severe COVID-19.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been recognized not only for its acute effects but also for its ability to cause LongCOVID Syndrome (LCS), a condition characterized by persistent symptoms affecting multiple organ systems. This review examines the molecular and immunological mechanisms underlying LCS, with a particular focus on autophagy inhibition, chronic inflammation, oxidative, nitrosative and calcium stress, viral persistence and autoimmunology. Potential pathophysiological mechanisms involved in LCS include (1) autoimmune activation, (2) latent viral persistence, where SARS-CoV-2 continues to influence host metabolism, (3) reactivation of latent pathogens such as Epstein-Barr virus (EBV) or cytomegalovirus (CMV), exacerbating immune and metabolic dysregulation, and (4) possible persistent metabolic and inflammatory dysregulation, where the body fails to restore post-infection homeostasis. The manipulation of cellular pathways by SARS-CoV-2 proteins is a critical aspect of the virus' ability to evade immune clearance and establish long-term dysfunction. Viral proteins such as NSP13, ORF3a and ORF8 have been shown to disrupt autophagy, thereby impairing viral clearance and promoting immune evasion. In addition, mitochondrial dysfunction, dysregulated calcium signaling, oxidative stress, chronic HIF-1α activation and Nrf2 inhibition create a self-sustaining inflammatory feedback loop that contributes to tissue damage and persistent symptoms. Therefore understanding the molecular basis of LCS is critical for the development of effective therapeutic strategies. Targeting autophagy and Nrf2 activation, glycolysis inhibition, and restoration calcium homeostasis may provide novel strategies to mitigate the long-term consequences of SARS-CoV-2 infection. Future research should focus on personalized therapeutic interventions based on the dominant molecular perturbations in individual patients.

The TMPRSS2 cell surface protease is used by a broad range of respiratory viruses to facilitate entry into target cells. Together with ACE2, TMPRSS2 represents a key factor for SARS-CoV-2 infection, as TMPRSS2 mediates cleavage of viral spike protein, enabling direct fusion of the viral envelope with the host cell membrane. Since the start of the COVID-19 pandemic, TMPRSS2 has gained attention as a therapeutic target for protease inhibitors which would inhibit SARS-CoV-2 infection, but little is known about TMPRSS2 regulation, particularly in cell types physiologically relevant for SARS-CoV-2 infection. Here, we performed an unbiased genome-wide CRISPR-Cas9 library screen, together with a library targeted at epigenetic modifiers and transcriptional regulators, to identify cellular factors that modulate cell surface expression of TMPRSS2 in human colon epithelial cells. We find that endogenous TMPRSS2 is regulated by the Elongin BC-VHL complex and HIF transcription factors. Depletion of Elongin B or treatment of cells with PHD inhibitors resulted in downregulation of TMPRSS2 and inhibition of SARS-CoV-2 infection. We show that TMPRSS2 is still utilised by SARS-CoV-2 Omicron variants for entry into colonic epithelial cells. Our study enhances our understanding of the regulation of endogenous surface TMPRSS2 in cells physiologically relevant to SARS-CoV-2 infection.

Excessive mitochondrial fission and a shift to a Warburg phenotype are hallmarks of pulmonary hypertension (PH), although the mechanistic link between these processes remains unclear. We show that in pulmonary arterial endothelial cells (PAEC), Drp1 overexpression induces mitochondrial fission and increases glycolytic ATP production and glycolysis. This is due to mitochondrial reactive oxygen species (mito-ROS)-mediated activation of hypoxia-inducible factor-1α (HIF-1α) signaling, and this is linked to hydrogen peroxide (H2O2)-mediated inhibition of prolyl hydroxylase domain-2 (PHD2) due to its cysteine 326 oxidation and dimerization. Furthermore, these findings are validated in PAEC isolated from a lamb model of PH, which are glycolytic (Shunt PAEC), exhibit increases in both H2O2 and PHD2 dimer levels. The overexpression of catalase reversed the PHD2 dimerization, decreased HIF-1α levels, and attenuated glycolysis in Shunt PAEC. Our data suggest that reducing PHD2 dimerization could be a potential therapeutic target for PH.

SARS-CoV-2 poses significant challenges to people living with diabetes (PLWD). This systematic review aimed to explore the impact of COVID-19 on mortality, complications associated with diabetes and haematological parameters among PLWD.

Systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE).

EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials and LILACS were searched between 1 December 2019 and 14 January 2025.

Eligible studies included case-control and cohort studies involving PLWD categorised into two groups: those with confirmed SARS-CoV-2 infection and those without.

Meta-analyses estimated the odds ratios (ORs) and mean differences (MDs) of outcomes including mortality, intensive care unit (ICU) admission, diabetic ketoacidosis (DKA), acute kidney injury, hospitalisation length and haematological parameters. We pooled results using random-effects models and assessed study quality with the Newcastle-Ottawa Scale. A funnel plot was used to detect potential publication bias. The overall certainty of evidence was assessed using GRADE.

25 of 7266 unique studies were eligible, including 1 154674 PLWD (561 558 with COVID-19 and 593 116 without COVID-19). SARS-CoV-2 infection in PLWD was associated with significantly increased mortality (OR 2.52, 95% CI 1.45 to 4.36, I2=99%), acute kidney injury (3.69, 95% CI 2.75 to 4.94, I2=0%), random plasma glucose in subjects with type 1 diabetes (MD 20.38 mg/dL, 95% CI 7.39 to 33.36, I2=0%), haemoglobin A1C in subjects with type 2 diabetes (0.21%, 95% CI 0.05 to 0.38, I2=13%), creatinine (0.12 mg/dL, 95% CI 0.04 to 0.19, I2=0%), C reactive protein (38.30 mg/L, 95% CI 4.79 to 71.82, I2=82%) and D-dimer (1.52 µg/mL, 95% CI 0.73 to 2.31, I2=0%). No significant differences were observed in the incidence of ICU admission and DKA, hospitalisation length, haemoglobin, leucocyte, lymphocyte, neutrophil to lymphocyte ratio, platelet, blood urea nitrogen, estimated glomerular filtration rate, procalcitonin, albumin, ferritin and bilirubin among PLWD with and without SARS-CoV-2 infection.

SARS-CoV-2 infection is associated with elevated risks of mortality and acute kidney injury and poor glycaemic control in PLWD, alongside increased levels of inflammatory and coagulation biomarkers. These findings underscore the urgent need for tailored clinical management strategies for PLWD with COVID-19.

CRD42023418039.

The potential implications of Coronavirus disease-2019 (COVID-19) on oral squamous cell carcinoma (OSCC) development, chemo-resistance, tumor recurrence, and patient outcomes are explored, emphasizing the urgent need for tailored therapeutic strategies to mitigate these risks. The role of hypoxia-inducible factor 1-alpha (HIF-1α) in OSCC studies has highlighted HIF-1α as a crucial prognostic marker in OSCC, with implications for disease prognosis and patient survival. Its overexpression has been linked to aggressive subtypes in early OSCC stages, indicating its significance as an early biomarker for disease progression. Moreover, dysplastic lesions with heightened HIF-1α expression exhibit a greater propensity for malignant transformation, underscoring its role in early oral carcinogenesis. Cancer patients, including those with OSCC, face an elevated risk of severe COVID-19 complications, which may further impact cancer progression and treatment outcomes. Understanding the interplay between COVID-19 infection, HIF-1α activation, and OSCC pathogenesis is crucial for enhancing clinical management strategies. So, insights from this review shed light on the significance of HIF-1α in OSCC tumorigenesis, metastasis formation, and patient prognosis. The review underscores the need for further research to elucidate the precise mechanisms through which HIF-1α modulates cancer progression and chemo-resistance in the context of COVID-19 infection. Such knowledge is essential for developing targeted therapeutic interventions to improve outcomes for OSCC patients.

Respiratory viral infections, such as those caused by rhinoviruses (RVs) and human corona viruses (HCoV), result in a serious strain on healthcare systems and public health, underscoring an urgent need for inhaled broad-spectrum antiviral therapies. However, their development is challenging, as no standardized in vitro methodologies that can fully replicate the in vivo environment have been established. In this work, we aimed to investigate the antiviral and anti-inflammatory effect of three 2-deoxylated glucose analogues (2-DGA): 2-deoxy-D-glucose, 2-fluoro-2-deoxy-D-glucose and 2-fluoro-2-deoxy-D-mannose (2-FDM), by utilizing advanced in vitro air-liquid interface (ALI) airway models. We demonstrated that commonly used ALI models have variable susceptibility to RV, HCoV and influenza A virus (IAV) infection. Further, we showed that 2-DGA have an anti-inflammatory effect and suppress respiratory viral replication in models mimicking the upper and lower respiratory airways. Moreover, we confirmed that 2-DGA can be delivered via nebulization in vitro, highlighting their potential to be used as broad-spectrum inhaled antivirals. Finally, our results demonstrate the importance of incorporating complex in vitro methodologies, such as primary cell ALI cultures and aerosol exposure, at an early stage of drug development.

Coronaviruses hijack host cell metabolic pathways and resources to support their replication. They induce extensive host endomembrane remodeling to generate viral replication organelles and exploit host membranes for assembly and budding of their enveloped progeny virions. Because of the overall significance of host membranes, we sought to gain insight into the role of host factors involved in lipid metabolism in cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV). We employed a single-cycle infection approach in combination with pharmacological inhibitors, biochemical assays, lipidomics, and light and electron microscopy. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), key host factors in de novo fatty acid biosynthesis, led to pronounced inhibition of MERS-CoV particle release. Inhibition of ACC led to a profound metabolic switch in Huh7 cells, altering their lipidomic profile and inducing lipolysis. However, despite the extensive changes induced by the ACC inhibitor, the biogenesis of viral replication organelles remained unaffected. Instead, ACC inhibition appeared to affect the trafficking and post-translational modifications of the MERS-CoV envelope proteins. Electron microscopy revealed an accumulation of nucleocapsids in early budding stages, indicating that MERS-CoV assembly is adversely impacted by ACC inhibition. Notably, inhibition of palmitoylation resulted in similar effects, while supplementation of exogenous palmitic acid reversed the compound's inhibitory effects, possibly reflecting a crucial need for palmitoylation of the MERS-CoV spike and envelope proteins for their role in virus particle assembly.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a zoonotic respiratory disease of limited transmissibility between humans. However, MERS-CoV is still considered a high-priority pathogen and is closely monitored by WHO due to its high lethality rate of around 35% of laboratory-confirmed infections. Like other positive-strand RNA viruses, MERS-CoV relies on the host cell's endomembranes to support various stages of its replication cycle. However, in spite of this general reliance of MERS-CoV replication on host cell lipid metabolism, mechanistic insights are still very limited. In our study, we show that pharmacological inhibition of acetyl-CoA carboxylase (ACC), a key enzyme in the host cell's fatty acid biosynthesis pathway, significantly disrupts MERS-CoV particle assembly without exerting a negative effect on the biogenesis of viral replication organelles. Furthermore, our study highlights the potential of ACC as a target for the development of host-directed antiviral therapeutics against coronaviruses.

Coronavirus infection (COVID-19), designated a global health emergency by the World Health Organization in 2020, continues to spur the search for effective therapeutics. The causative agent, SARS-CoV-2, depends on viral proteins and host metabolic reprogramming for replication. This study explores the potential of glycolytic inhibitors as dual-action agents against SARS-CoV-2, explicitly targeting the main protease and the spike protein due to their critical roles in viral replication and cellular entry. These inhibitors disrupt the activity of viral proteins and host cell glycolysis, thereby preventing viral propagation. Through a combination of virtual screening, molecular docking, and molecular dynamics simulations, fluoro-deoxy-glucose folate (FDGF) and N-(2-fluoro-3-(6-O-glucosylpropyl-azomycin)) were identified as potent candidates. The docking results showed strong binding affinities, with scores of -8.6 and -7.1 kcal/mol for main protease and -9.9 and - 7.5 kcal/mol for spike receptor-binding domain bound to ACE2. Further molecular dynamic simulations confirmed the stability of the FDGF complexes, with RMSD fluctuations consistently remained within 1.6-2.9 Å over a 100 ns trajectory. Additionally, MM-GBSA binding free energy calculations revealed favorable binding energies, underscoring the stability and potential efficacy of these compounds. Overall, the findings suggest that FDGF and N-(2-fluoro-3-(6-O-glucosylpropyl-azomycin)) show promise as SARS-CoV-2 therapeutics, warranting further in vitro and in vivo validation to confirm their antiviral potential.

The online version contains supplementary material available at 10.1007/s40203-025-00336-2.

Post-acute SarS-Cov2 (PASC), Myalgia encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Post-acute infection syndrome (PAIS) consist of chronic post-acute infectious syndromes, sharing exhaustive fatigue, post exertional malaise, intermittent pain, postural tachycardia and neuro-cognitive-psychiatric dysfunction. However, the concerned shared pathophysiology is still unresolved in terms of upstream drivers and transducers. Also, risk factors which may determine vulnerability/progression to the chronic phase still remain to be defined. In lack of drivers and a cohesive pathophysiology, the concerned syndromes still remain unmet therapeutic needs. 'mTORC1 Syndrome' (TorS) implies an exhaustive disease entity driven by sustained hyper-activation of the mammalian target of rapamycin C1 (mTORC1), and resulting in a variety of disease aspects of the Metabolic Syndrome (MetS), non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, some cancers, neurodegeneration and other [Bar-Tana in Trends Endocrinol Metab 34:135-145, 2023]. TorS may offer a cohesive insight of PASC, ME/CFS and PAIS drivers, pathophysiology, vulnerability and treatment options.

Comorbidities, including obesity and type 2 diabetes mellitus (T2DM), are associated with increased disease severity and mortality following SARS-CoV-2 infection. Here, we investigated virus-host interactions under the effects of these comorbidities in diet-induced obesity (DIO) and leptin receptor-deficient (T2DM) mice following infection with SARS-CoV-2. DIO mice, as well as their lean counterparts, showed limited susceptibility to SARS-CoV-2 infection. In contrast, T2DM mice showed exacerbated pulmonary SARS-CoV-2 replication and delayed viral clearance associated with down-regulation of innate and adaptative immune gene signatures, ineffective type I interferon response, and delayed SARS-CoV-2-specific cell-mediated immune responses. While T2DM mice showed higher and prolonged SARS-CoV-2-specific immunoglobulin isotype responses compared to their lean counterparts, neutralizing antibody levels were equivalent. By silencing the leptin receptor in vitro using a human alveolar epithelial cell line, we observed an increase in SARS-CoV-2 replication and type I interferons. Altogether, our data provides for the first time evidence that disruption of leptin receptor signaling leading to obesity and T2DM induces altered type I interferon and cell-mediated responses against SARS-CoV-2, mediating increased viral replication and delayed clearance. These data shed light on the alteration of the innate immune pathway in the lung using in-depth transcriptomic analysis and on adaptive immune responses to SARS-CoV-2 under T2DM conditions. Finally, this study provides further insight into this risk factor aggravating SARS-CoV-2 infection and understanding the underlying cellular mechanisms that could help identify potential intervention points for this at-risk population.

Approximately 10-30% of individuals continue to experience symptoms classified as post-acute sequelae of coronavirus disease 2019 (COVID-19 (PASC)). PASC is a multisystem condition primarily characterized by respiratory symptoms, such as reduced diffusing capacity for carbon monoxide (DLco). Although many studies have investigated the pathogenesis of acute COVID-19, the long-term molecular changes in COVID-19 convalescents with PASC remain poorly understood.

We prospectively recruited 70 individuals who had been diagnosed with COVID-19 from 7 January 2020 to 29 May 2020 (i.e., COVID-19 convalescents); we performed follow-up visits at 6 months, 1 year, 2 years, and 3 years after hospital discharge. Thirty-five healthy controls (CONs), recruited from a physical examination center before the COVID-19 pandemic, served as a comparison group. We explored the proteomic and metabolomic profiles of 174 plasma samples from the 70 COVID-19 convalescents and 35 CONs.

We performed a comprehensive molecular analysis of COVID-19 convalescents to investigate host changes up to 3 years after hospital discharge. Our multi-omics analysis revealed activation of cytoskeletal organization and glycolysis/gluconeogenesis, as well as suppression of gas transport and adaptive immune responses, in COVID-19 convalescents. Additionally, metabolites involved in glutathione metabolism; alanine, aspartate, and glutamate metabolism; and ascorbate and aldarate metabolism were significantly upregulated in COVID-19 convalescents. Pulmonary and molecular abnormalities persisted for 3 years in COVID-19 convalescents; impaired diffusing capacity for carbon monoxide (DLco) was the most prominent feature. We used this multi-omics profile to develop a model involving one protein (heterogeneous nuclear ribonucleoprotein K (HNRNPK)) and two metabolites (arachidonoyl-EA and 1-O-(2r-hydroxy-pentadecyl)-sn-glycerol)) for identification of COVID-19 convalescents with abnormal DLco.

These data provide insights concerning molecular sequelae among COVID-19 convalescents up to 3 years after hospital discharge, clarify mechanisms driving respiratory sequelae, and support the development of a novel model to predict reduced DLco. This longitudinal multi-omics analysis may illuminate the trajectory of altered lung function in COVID-19 convalescents.

Background: Hyperbaric Oxygen Therapy (HBOT) is a medical treatment that involves administering 100% oxygen at increased atmospheric pressure to enhance oxygen delivery to tissues. Initially developed for decompression sickness, HBOT has since been utilized for a wide range of medical conditions, including severe infections, non-healing wounds, and, more recently, COVID-19. Objective: This review explores the historical development of HBOT, its principles, its emerging role in the management of and its outcome as treatment in COVID-19, particularly in mitigating inflammation, hypoxemia, and oxidative stress. Methods: A comprehensive review of the literature was conducted, analyzing case reports and case series that examined the effectiveness of HBOT in various clinical scenarios, with a focus on COVID-19. Results: HBOT has been shown to enhance tissue oxygenation, reduce inflammation, and modulate oxidative stress, thereby improving clinical outcomes in patients with severe COVID-19. The therapy's ability to increase dissolved oxygen levels in blood and tissues, independent of hemoglobin, makes it particularly beneficial in conditions like COVID-19, where hypoxemia and inflammation are prominent. Conclusion: HBOT offers a promising adjunctive treatment for severe COVID-19, with the potential to reduce mortality and improve recovery by targeting key pathophysiological processes such as hypoxemia, inflammation, and oxidative stress. Further research is warranted to optimize treatment protocols and confirm long-term benefits.

In the context of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), metabolic research has become crucial for in-depth exploration of viral infection mechanisms and in searching for therapeutic strategies. This paper summarizes the interrelationships between carbohydrate, lipid, and amino acid metabolism and COVID-19 infection, discussing their roles in infection progression. SARS-CoV-2 infection leads to insulin resistance and increased glycolysis, reducing glucose utilization and shifting metabolism to use fat as an energy source. Fat is crucial for viral replication, and imbalances in amino acid metabolism may interfere with immune regulation. Consequently, metabolic changes such as hyperglycemia, hypolipidemia, and deficiency of certain amino acids following SARS-CoV-2 infection can contribute to progression toward severe conditions. These metabolic pathways not only have potential value in prediction and diagnosis but also provide new perspectives for the development of therapeutic strategies. By monitoring metabolic changes, infection severity can be predicted early, and modulating these metabolic pathways may help reduce inflammatory responses, improve immune responses, and reduce the risk of thrombosis. Research on the relationship between metabolism and SARS-CoV-2 infection provides an important scientific basis for addressing the global challenge posed by COVID-19, however, further studies are needed to validate these findings and provide more effective strategies for disease control.

The specific pathogenesis of acute lung injury (ALI) is complex and not yet clear, and the clinical treatment methods are relatively limited. It is of great clinical significance to explore its pathogenesis and effective molecular targets. Here, we identified an ALI biomarker (UPP1) associated with uridine metabolism by a systematic bioinformatics approach. It was also confirmed to be associated with the glycolytic pathway in the mouse ALI model. In addition, drug sensitivity analysis based on the CMAP database identified three UPP1-associated drugs (CAY10585, XL147 and IOX2) that may be useful in the treatment of ALI. Molecular docking and molecular dynamics simulations further confirmed the stability of the binding between UPP1 and the three drugs. In conclusion, this study confirms that the uridine metabolism gene UPP1 associated with glycolysis is a key biomarker of ALI and provides valuable insights into the potential application of CAY10585, XL147 and IOX2 in ALI.

During the Omicron infection wave, diabetic patients are susceptible to COVID-19, which is linked to a poor prognosis. However, research on the real-world effectiveness and safety of Azvudine, a common medication for COVID-19, is insufficient in those with pre-existing diabetes.

In this retrospective study, we included 32,864 hospitalized COVID-19 patients from 9 hospitals in Henan Province. Diabetic patients were screened and divided into the Azvudine group and the control group, via 1:1 propensity score matching. The primary outcome was all-cause mortality, and the secondary outcome was composite disease progression. Laboratory abnormal results were used for safety evaluation.

A total of 1,417 patients receiving Azvudine and 1,417 patients receiving standard treatment were ultimately included. Kaplan-Meier curves suggested that all-cause mortality (P = 0.0026) was significantly lower in the Azvudine group than in the control group, but composite disease progression did not significantly differ (P = 0.1). Cox regression models revealed Azvudine treatment could reduce 26% risk of all-cause mortality (95% CI: 0.583-0.942, P = 0.015) versus controls, and not reduce the risk of composite disease progression (HR: 0.91, 95% CI: 0.750-1.109, P = 0.355). The results of subgroup analysis and three sensitivity analyses were consistent with the previous findings. Safety analysis revealed that the incidence rates of most adverse events were similar between the two groups.

In this study, Azvudine demonstrated good efficacy in COVID-19 patients with diabetes, with a lower all-cause mortality rate. Additionally, the safety was favorable. This study may provide a new strategy for the antiviral management of COVID-19 patients with diabetes.

The long-term health impacts of COVID-19, including post-acute sequelae of SARS-CoV-2, remain insufficiently explored, especially concerning pre-existing cardiovascular risk factors in older adults. This study examines the association between these risk factors and post-acute sequelae of SARS-CoV-2 in this population.

A retrospective study of Brazilian adults aged = 60 years assessed the persistence of post-acute sequelae of SARS-CoV-2 three months after infection in 2020. Cardiovascular risk factors (obesity, smoking, high blood pressure, diabetes mellitus, hypercholesterolemia, and chronic kidney disease) were analyzed in relation to sequelae and adjusting for sociodemographic variables. Data were obtained from the Department of Epidemiological Surveillance in Roraima, Brazil.

Of the 1,322 participants (55% female; mean age 70.4 years, SD = 7.87), 61.7% (95% CI: 59.1-63.9) reported at least one post-acute sequelae of SARS-CoV-2 at the three-month follow-up. The likelihood of post-acute sequelae of SARS-CoV-2 was significantly higher in participants with diabetes mellitus (OR = 4.39; 95% CI: 3.42-5.66), tobacco use (OR = 3.93; 95% CI: 2.47-6.23), hypertension (OR = 3.62; 95% CI: 2.73-4.78), or hypercholesterolemia (OR = 3.58; 95% CI: 2.80-4.59). Chronic kidney disease (OR = 2.28; 95% CI: 1.59-3.25) and obesity (OR = 1.83; 95% CI: 1.28-2.61) were less strongly associated.

Pre-existing cardiovascular risk factors are linked to a higher likelihood of long-term COVID-19 sequelae in adults aged = 60 years old. Preventing and managing these factors are crucial for reducing the long-term effects of COVID-19, particularly during a pandemic.

This review article discusses the role of vascular endothelial growth factor A (VEGF-A) in the pathogenesis of SARS-CoV-2 and HIV infection, both conditions being renowned for their impact on the vascular endothelium. The processes involved in vascular homeostasis and angiogenesis are reviewed briefly before exploring the interplay between hypoxia, VEGF-A, neuropilin-1 (NRP-1), and inflammatory pathways. We then focus on SARS-CoV-2 infection and show how the binding of the viral pathogen to the angiotensin-converting enzyme 2 receptor, as well as to NRP-1, leads to elevated levels of VEGF-A and consequences such as coagulation, vascular dysfunction, and inflammation. HIV infection augments angiogenesis via several mechanisms, most prominently, by the trans-activator of transcription (tat) protein mimicking VEGF-A by binding to its receptor, VEGFR-2, as well as upregulation of NRP-1, which enhances the interaction between VEGF-A and VEGFR-2. We propose that the elevated levels of VEGF-A observed during HIV/SARS-CoV-2 co-infection originate predominantly from activated immune cells due to the upregulation of HIF-1α by damaged endothelial cells. In this context, a few clinical trials have described a diminished requirement for oxygen therapy during anti-VEGF treatment of SARS-CoV-2 infection. The currently available anti-VEGF therapy strategies target the binding of VEGF-A to both VEGFR-1 and VEGFR-2. The blocking of both receptors could, however, lead to a negative outcome, inhibiting not only pathological, but also physiological angiogenesis. Based on the examination of published studies, this review suggests that treatment targeting selective inhibition of VEGFR-1 may be beneficial in the context of SARS-CoV-2 infection.

The Coronavirus Disease 2019 (COVID-19) pandemic has disproportionately affected individuals with Type 2 Diabetes Mellitus (T2DM), making them more susceptible to viral infections. Additionally, COVID-19 and the associated lockdown restrictions have influenced metabolic regulatory mechanisms in this population. This study aims to evaluate the impact of COVID-19 infection and lockdown measures on physiological parameters in individuals with T2DM.

This retrospective cohort study included 118 individuals with a prior diagnosis of T2DM. Medical records were reviewed for laboratory tests conducted within three months before the onset of the COVID-19 pandemic in Iran. Fifty-nine patients with confirmed COVID-19 infection during the first three months of the pandemic underwent follow-up laboratory tests six months post-diagnosis. An age- and gender-matched group of 59 noninfected individuals underwent follow-up tests six months after the pandemic's onset. Clinical and laboratory parameters were analyzed and compared within each group.

In the COVID-19 positive group, significant reductions were observed in triglycerides (TG) (P = 0.001), total cholesterol (TC) (P = 0.028), body mass index (BMI) (P = 0.034), atherogenic index of plasma (AIP) (P = 0.027), triglyceride-glucose (TyG) index (P = 0.001), and triglyceride-glucose-BMI (TyG-BMI) index (P < 0.001) during the six months following infection compared to pre-pandemic levels. Other variables remained unchanged. In the COVID-19 negative group, significant reductions were noted in TC (P = 0.001) and low-density lipoprotein cholesterol (LDL-C) (P = 0.01).

T2DM patients with mild to moderate COVID-19 infection exhibited improvements in TC, TG, BMI, and insulin-related indices. Lockdown restrictions were associated with decreased TC and LDL-C levels in T2DM patients without a history of COVID-19 infection.

COVID-19, a complex multisystem disorder affecting the central nervous system, can also have psychiatric sequelae. In addition, clinical evidence indicates that a diagnosis of a schizophrenia spectrum disorder is a risk factor for mortality in patients with COVID-19. In this study, we aimed to explore brain-specific molecular aspects of COVID-19 by using a proteomic approach. We analyzed the brain proteome of fatal COVID-19 cases and compared it with differentially regulated proteins found in postmortem schizophrenia brains. The COVID-19 proteomic dataset revealed a strong enrichment of proteins expressed by glial and neuronal cells and processes related to diseases with a psychiatric and neurodegenerative component. Specifically, the COVID-19 brain proteome enriches processes that are hallmark features of schizophrenia. Furthermore, we identified shared and distinct molecular pathways affected in both conditions. We found that brain ageing processes are likely present in both COVID-19 and schizophrenia, albeit possibly driven by distinct processes. In addition, alterations in brain cell metabolism were observed, with schizophrenia primarily impacting amino acid metabolism and COVID-19 predominantly affecting carbohydrate metabolism. The enrichment of metabolic pathways associated with astrocytic components in both conditions suggests the involvement of this cell type in the pathogenesis. Both COVID-19 and schizophrenia influenced neurotransmitter systems, but with distinct impacts. Future studies exploring the underlying mechanisms linking brain ageing and metabolic dysregulation may provide valuable insights into the complex pathophysiology of these conditions and the increased vulnerability of schizophrenia patients to severe outcomes.

Coronavirus Disease 2019, caused by severe acute respiratory coronavirus 2, has been an ever-evolving disease and pandemic, profoundly impacting clinical care, drug treatments, and understanding. In response to this global health crisis, there has been an unprecedented increase in research exploring new and repurposed drugs and advancing available clinical interventions and treatments. Given the widespread interest in this topic, this review aims to provide a current summary-for interested professionals not specializing in COVID-19-of the clinical characteristics, recommended treatments, vaccines, prevention strategies, and epidemiology of COVID-19. The review also offers a historical perspective on the pandemic to enhance understanding.

The aim of this study was to investigate the impact of diabetes on mortality and adverse outcomes in COVID-19 patients and to analyse the associated risk factors.

This is a retrospective cohort study in 500 hospitalized patients with COVID-19 infection (214 with diabetes and 286 without diabetes) admitted to a tertiary hospital in China from December 2022 to February 2023. Demographic information, clinical characteristics and outcomes were collected. Survival status was investigated at discharge and at 6 months after discharge.

The mortality rate of COVID-19 patients with diabetes was higher than the rate of non-diabetic COVID-19 patients, both at discharge, and at 6 months after discharge. Body mass index (BMI), C-reactive protein (CRP), pH, D-dimer, blood osmotic pressure, serum creatinine, white blood cell count, creatine kinase and hospitalization expenses were significantly different between diabetic group and non-diabetic group (p < 0.05). Compared with the survivors, non-survived COVID-19 patients with diabetes had worse diabetes control indicators, with random blood glucose increased by 3.58 mmol/L (p < 0.05), and fasting blood glucose increased by 2.77 mmol/L (p < 0.01). In addition, there were significant differences in age, heart rate, CRP, pH, potassium (K+), serum creatinine, white blood cell count, creatine kinase, the proportion with diabetic complications, treatment in ICU and mechanical ventilation between survivors and non-survivors of COVID-19 patients with diabetes. By multivariate logistic regression analysis, the death of COVID-19 patients with diabetes is positively correlated with age and CRP (p < 0.05), and has a trend towards significance with fasting blood glucose (p < 0.1).

Infection with COVID-19 on the basis of diabetes can significantly increase mortality, which was further associated with diabetes control indicators.

Immunometabolism is an emerging field that explores the intricate interplay between immune cells and metabolism. Regulatory T cells (Tregs), which maintain immune homeostasis in immunometabolism, play crucial regulatory roles. The activation, differentiation, and function of Tregs are influenced by various metabolic pathways, such as the Mammalian targets of rapamycin (mTOR) pathway and glycolysis. Correspondingly, activated Tregs can reciprocally impact these metabolic pathways. Tregs also possess robust adaptive capabilities, thus enabling them to adapt to various microenvironments, including the tumor microenvironment (TME). The complex mechanisms of Tregs in metabolic diseases are intriguing, particularly in conditions like MASLD, where Tregs are significantly upregulated and contribute to fibrosis, while in diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), they show downregulation and reduced anti-inflammatory capacity. These phenomena suggest that the differentiation and function of Tregs are influenced by the metabolic environment, and imbalances in either can lead to the development of metabolic diseases. Thus, moderate differentiation and inhibitory capacity of Tregs are critical for maintaining immune system balance. Given the unique immunoregulatory abilities of Tregs, the development of targeted therapeutic drugs may position them as novel targets in immunotherapy. This could contribute to restoring immune system balance, resolving metabolic dysregulation, and fostering innovation and progress in immunotherapy.