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Progress in Molecular Biology and... 2024Repurposing pharmaceuticals is a technique used to find new, alternate clinical applications for approved drug molecules. It may include altering the drug formulation,... (Review)
Review
Repurposing pharmaceuticals is a technique used to find new, alternate clinical applications for approved drug molecules. It may include altering the drug formulation, route of administration, dose or the dosage regimen. The process of repurposing medicines starts with screening libraries of previously approved drugs for the targeted disease condition. If after an the initial in silico, in vitro or in vivo experimentation, the molecule has been found to be active against a particular target, the molecule is considered as a good candidate for clinical trials. As the safety profile of such molecules is available from the previous data, significant time and resources are saved. These advantages of drug repurposing approach make it especially helpful for finding treatments for rapidly evolving conditions including bacterial infections. An ever-increasing incidence of antimicrobial resistance, owing to the mutations in bacterial genome, leads to therapeutic failure of many approved antibiotics. Repurposing the approved drug molecules for use as antibiotics can provide an effective means for the combating life-threatening bacterial diseases. A number of drugs have been considered for drug repurposing against bacterial infections. These include, but are not limited to, Auranofin, Closantel, and Toremifene that have been repurposed for various infections. In addition, the reallocation of route of administration, redefining dosage regimen and reformulation of dosage forms have also been carried out for repurposing purpose. The current chapter addresses the drug discovery and development process with relevance to repurposing against bacterial infections.
Topics: Drug Repositioning; Humans; Bacterial Infections; Animals; Anti-Bacterial Agents
PubMed: 38942533
DOI: 10.1016/bs.pmbts.2024.03.031 -
Life Sciences Jun 2024The study evaluated the antiviral effect of Verapamil against respiratory syncytial virus (RSV) and investigated its underlying mechanism.
AIMS
The study evaluated the antiviral effect of Verapamil against respiratory syncytial virus (RSV) and investigated its underlying mechanism.
MATERIALS AND METHODS
RSV-infected BALB/c mice were treated with Verapamil. Body weight, survival rates, viral load, lung damage, inflammatory factors, and the expression of RSV fusion (F) protein were analyzed. In cellular studies, intracellular Ca and viral titers were measured in the presence of Verapamil, Calcium Chloride, and EGTA. A time-of-addition assay assessed the antiviral effect of Verapamil.
KEY FINDINGS
Mice infected with RSV and treated with Verapamil exhibited a significant decrease in weight loss, an increase in survival rates, and reductions in viral titers, RSV F protein expression, inflammatory responses, and lung tissue injury. Verapamil reduced intracellular calcium levels, which correlated with reduced viral titers. The addition of calcium chloride reversed the anti-viral effects mediated by Verapamil, while EGTA potentiated them. The antiviral activity of Verapamil was observed during the early phase of RSV infection, likely by blocking Ca channels and inhibiting virus replication.
SIGNIFICANCE
Verapamil effectively inhibits RSV infection by blocking calcium channels and reducing intracellular calcium levels, thereby impeding viral replication. Thus, Verapamil shows promise as a treatment for RSV.
PubMed: 38942358
DOI: 10.1016/j.lfs.2024.122877 -
Biochimica Et Biophysica Acta.... Jun 2024Obesity is a risk factor for developing severe COVID-19. However, the mechanism underlying obesity-accelerated COVID-19 remains unclear. Here, we report results from a...
Obesity is a risk factor for developing severe COVID-19. However, the mechanism underlying obesity-accelerated COVID-19 remains unclear. Here, we report results from a study in which 2-3-month-old K18-hACE2 (K18) mice were fed a western high-fat diet (WD) or normal chow (NC) over 3 months before intranasal infection with a sublethal dose of SARS-CoV2 WA1 (a strain ancestral to the Wuhan variant). After infection, the WD-fed K18 mice lost significantly more body weight and had more severe lung inflammation than normal chow (NC)-fed mice. Bulk RNA-seq analysis of lungs and adipose tissue revealed a diverse landscape of various immune cells, inflammatory markers, and pathways upregulated in the infected WD-fed K18 mice when compared with the infected NC-fed control mice. The transcript levels of IL-6, an important marker of COVID-19 disease severity, were upregulated in the lung at 6-9 days post-infection in the WD-fed mice when compared to NC-fed mice. Transcriptome analysis of the lung and adipose tissue obtained from deceased COVID-19 patients found that the obese patients had an increase in the expression of genes and the activation of pathways associated with inflammation as compared to normal-weight patients (n = 2). The K18 mouse model and human COVID-19 patient data support a link between inflammation and an obesity-accelerated COVID-19 disease phenotype. These results also indicate that obesity-accelerated severe COVID-19 caused by SARS-CoV-2 WA1 infection in the K18 mouse model would be a suitable model for dissecting the cellular and molecular mechanisms underlying pathogenesis.
PubMed: 38942338
DOI: 10.1016/j.bbadis.2024.167322 -
Journal of Infection and Chemotherapy :... Jun 2024Drug resistance is an important factor in the fight against influenza A virus (IAV). Natural products offer a rich source of lead compounds for the discovery of novel...
BACKGROUND
Drug resistance is an important factor in the fight against influenza A virus (IAV). Natural products offer a rich source of lead compounds for the discovery of novel antiviral drugs. In a previous study, we isolated the sorbicillinoid polyketide HSL-2 from the mycelium of fungus Trichoderma sp. T-4-1. Here, we show that this compound exerts strong antiviral activity against a panel of IAVs.
METHODS
The immunofluorescence and qRT-PCR assays were used to detect the inhibitory effect of HSL-2 toward the replication of influenza virus and IAV-induced expression of the pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β.
RESULTS
The results indicated that HSL-2 inhibited influenza virus replication, and it significantly inhibited IAV-induced overexpression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β through modulating the PPAR-γ/NF-κB pathway. Notably, this effect was decreased when cells were transfected with PPAR-γ siRNA or treated with the PPAR-γ inhibitor T0070907. In addition, HSL-2 was able to attenuate lung inflammatory responses and to improve lung lesions in a mouse model of IAV infection.
CONCLUSIONS
In this paper, we identified a microbial secondary metabolite, HSL-2, with anti-influenza virus activity. This report is the first to describe the antiviral activity and mechanism of action of HSL-2, and it provides a new strategy for the development of novel anti-influenza virus drugs from natural sources.
PubMed: 38942291
DOI: 10.1016/j.jiac.2024.06.013 -
Journal of Proteomics Jun 2024Tuberculosis (TB) is an infectious disease that remains one of the major global public health concerns. Early detection of Active Pulmonary TB is therefore of utmost... (Review)
Review
Tuberculosis (TB) is an infectious disease that remains one of the major global public health concerns. Early detection of Active Pulmonary TB is therefore of utmost importance for controlling lethality and disease spreading. Currently available TB diagnostics can be broadly categorized into microscopy, culture-based, and molecular approaches, all of which come with compromised sensitivity, limited efficacy, and high expenses. Hence, rapid, sensitive, and affordable diagnostic methods for TB is the current prerequisite for disease management. This review summarizes the proteomics investigations for host-specific biomarkers from serum, sputum, saliva, and urine samples of TB patients, along with patients having comorbidity. Thorough data mining from available literature led us to conclude that the host-specific proteins involved in immunity and defense, metabolic regulation, cellular adhesion, and motility, inflammatory responses, and tissue remodelling have shown significant deregulation upon Mycobacterium tuberculosis (Mtb) infection. Notably, the immunoregulatory protein orosomucoid (ORM) was up-regulated in active TB compared to non-TB individuals, as observed in multiple studies from diverse sample types. Mannose receptor C type 2 (MRC2) was identified as an upregulated, treatment response biomarker in two independent serum proteomics investigations. Thorough mechanistic investigation on these candidate proteins would be fascinating to dig into potential drug targets and customized therapeutics for TB patients, along with their diagnostic potentials.
PubMed: 38942234
DOI: 10.1016/j.jprot.2024.105245 -
British Journal of Hospital Medicine... Jun 2024Systemic lupus erythematosus (SLE) is a complex autoimmune disease where the body loses tolerance to its own antigens, particularly nuclear antigens. Abnormal responses...
Systemic lupus erythematosus (SLE) is a complex autoimmune disease where the body loses tolerance to its own antigens, particularly nuclear antigens. Abnormal responses from T and B cells lead to the production of autoantibodies and the formation of immune complexes in tissues, triggering complement activation, inflammation, and irreversible organ damage. SLE can affect any part of the body, resulting in diverse clinical symptoms. One rare manifestation of SLE is lupus mesenteric vasculitis (LMV), which presents with vague symptoms, abnormal laboratory findings, and specific imaging features. LMV, although uncommon, can progress to severe complications such as bowel perforation, haemorrhage, and even mortality. Here, we report a case of LMV with the involvement of multiple organ systems (including mucocutaneous, musculoskeletal, serosal cavities, and haematological systems), presenting initially with life-threatening intractable gastrointestinal bleeding, and complicated by severe pulmonary infection. By sharing this case, we aim to enhance clinicians' confidence in managing critical SLE cases and raise awareness about disease surveillance.
Topics: Humans; Gastrointestinal Hemorrhage; Lupus Erythematosus, Systemic; Vasculitis; Female; Mesentery; Tomography, X-Ray Computed; Adult
PubMed: 38941968
DOI: 10.12968/hmed.2024.0108 -
Cancer Epidemiology Jun 2024Data on social inequalities in cancer mortality are sparse, especially in low- and middle-income countries. We aimed to analyze the socioeconomic inequalities in cancer...
INTRODUCTION
Data on social inequalities in cancer mortality are sparse, especially in low- and middle-income countries. We aimed to analyze the socioeconomic inequalities in cancer mortality in Costa Rica between 2010 and 2018.
METHODS
We linked 9-years of data from the National Electoral Rolls, National Birth Index and National Death Index to classify deaths due to cancer and socioeconomic characteristics of the district of residence, as measured by levels of urbanicity and wealth. We analyzed the fifteen most frequent cancer sites in Costa Rica among the 2.7 million inhabitants aged 20 years and older. We used a parametric survival model based on a Gompertz distribution.
RESULTS
Compared to urban areas, mixed and rural area residents had lower mortality from pancreas, lung, breast, prostate, kidney, and bladder cancers, and higher mortality from stomach cancer. Mortality from stomach, lung and cervical cancer was higher, and mortality from colorectal cancer, non-Hodgkin lymphoma and leukemia was lower in the most disadvantaged districts, compared to the wealthiest ones.
CONCLUSION
We observed marked disparities in cancer mortality in Costa Rica in particular from infection- and lifestyle- related cancers. There are important opportunities to reduce disparities in cancer mortality by targeting cancer prevention, early detection and opportune treatment, mainly in urban and disadvantaged districts.
PubMed: 38941875
DOI: 10.1016/j.canep.2024.102604 -
Heart & Lung : the Journal of Critical... Jun 2024Bradycardia and dysautonomia observed during SARS-Cov2 infection suggests involvement of the autonomic nervous system (ANS). Limited data exists on ANS dysregulation and...
BACKGROUND
Bradycardia and dysautonomia observed during SARS-Cov2 infection suggests involvement of the autonomic nervous system (ANS). Limited data exists on ANS dysregulation and its association with outcomes in patients with acute respiratory distress syndrome (ARDS) related to COVID-19 (C-ARDS) or other etiologies (NC-ARDS).
OBJECTIVES
We aimed to explore sympathovagal balance, assessed by heart rate variability (HRV), and its clinical prognostic value in C-ARDS compared with NC-ARDS.
METHODS
A single-center, prospective case-control study was conducted. Consecutive patients meeting ARDS criteria between 2020 and 2022 were included. HRV was assessed using 1-hour electrographic tracing during a stable, daytime period.
RESULTS
Twenty-four patients with C-ARDS and 19 with NC-ARDS were included. Age, sex and ARDS severity were similar between groups. The median heart rate was markedly lower in the C-ARDS group than in the NC-ARDS group (60 [53-72] versus 101 [91-112] bpm, p<.001). Most of HRV parameters were significantly increased in patients with C-ARDS. HRV correlated with heart rate only in patients with C-ARDS. A positive correlation was found between the low-to high-frequency ratio (LF/HF) and length of intensive care unit stay (r = 0.576, p<.001).
CONCLUSION
This study confirmed that C-ARDS was associated with marked bradycardia and severe ANS impairment, suggesting a sympathovagal imbalance with vagal overtone. Poor outcomes appeared to be more related to sympathetic rather than parasympathetic hyperactivation.
PubMed: 38941770
DOI: 10.1016/j.hrtlng.2024.06.014 -
Current Opinion in Virology Jun 2024
PubMed: 38941708
DOI: 10.1016/j.coviro.2024.101425 -
Scientific Reports Jun 2024Helminth infections lead to an overdispersion of the parasites in humans as well as in animals. We asked whether early immune responses against migrating Ascaris larvae...
Helminth infections lead to an overdispersion of the parasites in humans as well as in animals. We asked whether early immune responses against migrating Ascaris larvae are responsible for the unequal distribution of worms in natural host populations and thus investigated a susceptible versus a resistant mouse strain. In mice, the roundworm larvae develop until the lung stage and thus early anti-Ascaris immune responses against the migrating larvae in the liver and lung can be deciphered. Our data show that susceptible C57BL/6 mice respond to Ascaris larval migration significantly stronger compared to resistant CBA mice and the anti-parasite reactivity is associated with pathology. Increased eosinophil recruitment was detected in the liver and lungs, but also in the spleen and peritoneal cavity of susceptible mice on day 8 post infection compared to resistant mice. In serum, eosinophil peroxidase levels were significantly higher only in the susceptible mice, indicating functional activity of the recruited eosinophils. This effect was associated with an increased IL-5/IL-13 production by innate lymphoid cells and CD4 T cells and a pronounced type 2 macrophage polarization in the lungs of susceptible mice. Furthermore, a comparison of wildtype BALB/c and eosinophil-deficient dblGATA-1 BALB/c mice showed that eosinophils were not essential for the early control of migrating Ascaris larvae. In conclusion, in primary infection, a strong local and systemic type 2 immune response during hepato-tracheal helminth larval migration is associated with pathology rather than protection.
Topics: Animals; Ascariasis; Larva; Mice; Th2 Cells; Mice, Inbred BALB C; Lung; Ascaris; Eosinophils; Mice, Inbred C57BL; Mice, Inbred CBA; Liver; Female
PubMed: 38942904
DOI: 10.1038/s41598-024-65281-0