Immune correlates of protection as a game changer in tuberculosis vaccine development

npj Vaccines, Год журнала: 2024, Номер 9(1)

Опубликована: Окт. 30, 2024

The absence of validated correlates protection (CoPs) hampers the rational design and clinical development new tuberculosis vaccines. In this review, we provide an overview potential CoPs in vaccine research. Major hindrances opportunities are then discussed. Based on recent progress, it is reasonable to anticipate that success ongoing efforts identify would be a game-changer development.

Язык: Английский

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Anthocyanin and phenolic landscape of Syzygium cumini extracts via green extraction

Food Chemistry, Год журнала: 2025, Номер 472, С. 142916 - 142916

Опубликована: Янв. 15, 2025

Язык: Английский

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Host-Mediated Antimicrobial Effects and NLRP3 Inflammasome Modulation by Caulerpin and Its Derivatives in Macrophage Models of Mycobacterial Infections

Microorganisms, Год журнала: 2025, Номер 13(3), С. 561 - 561

Опубликована: Март 1, 2025

Caulerpin, a bis-indole alkaloid isolated from Caulerpa racemosa, has several documented pharmacological activities, including antineoplastic and antiviral properties. This study aimed to evaluate the anti-inflammatory anti-tubercular potentials of caulerpin its analogues in RAW 264.7 macrophages infected with Mycobacterium spp. Additionally, we evaluated cytokine production NLRP3 expression this infection model. Toxicity tests were performed using Vero E6 HepG2 cell lines Artemia salina. Pre-incubation cells decreased internalized M. smegmatis tuberculosis H37Ra. Furthermore, treatment smegmatis-infected reduced bacterial loads. Caulerpin CFU count bacilli H37Ra In addition, diethyl derivative notably found modulate IL-1β TNF-α model after quantifying pro-inflammatory cytokines NLRP3. derivates did not affect viability or nauplii survival toxicity studies. These findings demonstrate that exhibit activity against show promising potential for further efficacy safety evaluation.

Язык: Английский

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Isoniazid and nicotinic hydrazide hybrids mitigate trehalose-6,6’-dimycolate-induced inflammatory responses and pulmonary granulomas via Syk/PI3K pathways: A promising host-directed therapy for tuberculosis

Biomedicine & Pharmacotherapy, Год журнала: 2025, Номер 183, С. 117798 - 117798

Опубликована: Янв. 6, 2025

Язык: Английский

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Identification of novel natural inhibitors of Mycobacterium tuberculosis DNA-directed RNA polymerase via extensive computational screening and MMGBSA

Journal of Molecular Liquids, Год журнала: 2025, Номер unknown, С. 127360 - 127360

Опубликована: Март 1, 2025

Язык: Английский

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Chemokine CXCL14 Inhibits the Survival of Mycobacterium smegmatis inside Macrophages by Upregulating A20 to Promote ROS Production

ACS Infectious Diseases, Год журнала: 2025, Номер unknown

Опубликована: Март 18, 2025

Tuberculosis remains a major global health threat, with traditional antibiotic treatments facing challenges such as drug resistance. Host-directed therapy (HDT) has emerged promising approach to combat tuberculosis by enhancing the host immune response. CXCL14, chemokine family member, plays crucial role in regulating antipathogenic responses. To elucidate of CXCL14 and its key regulatory molecules mycobacterial infections, we identified new targets for host-directed therapy. RAW264.7 macrophages were pretreated infected Mycobacterium smegmatis. CFU, ROS levels, apoptosis assessed. Cell RNA was extracted high-throughput sequencing, significantly differentially expressed genes screened identified. The effects candidate verified using knockdown overexpression techniques. A mouse model infection established validate vivo. pretreatment reduced intracellular mycobacteria increased levels without affecting apoptosis. Transcriptome analysis A20 gene. promoted production decreased mycobacteria, while reversed these effects. combination effectively inhibited survival macrophages. mice organ damage upregulating expression, thereby inhibiting survival. In model, alleviated inflammatory responses histopathological caused infection. These findings suggest that is HDT molecule treatment infections.

Язык: Английский

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N-Acetylcysteine as a Host-Directed Therapy Against Clarithromycin-Resistant Mycobacterium abscessus

Pathogens, Год журнала: 2025, Номер 14(4), С. 302 - 302

Опубликована: Март 21, 2025

(1) Background: The treatment of Mycobacterium abscessus (M. abscessus) infections resistant to clarithromycin (CLR) is highly challenging. Traditional non-tuberculous mycobacteria (NTM) chemotherapy may disturb the immune homeostasis host by increasing oxidative stress; therefore, host-directed immunotherapy an alternative option for caused M. abscessus. (2) Method: A clinical isolate CLR-resistant was screened, and then therapeutic effects N-acetylcysteine (NAC) against infection were evaluated in Tohoku Hospital Pediatrics-1 (THP-1) cells murine models. RNA sequencing Western blot used profile protective responses induced NAC. contribution candidate signaling pathways confirmed corresponding inhibitor agonist. (3) Results: NAC led a significant reduction bacterial loads both THP-1 models, which associated with enhanced antioxidant downregulation apoptosis signal-regulating kinase 1 (ASK1)–mitogen-activated protein ki-nase/extracellular signal-regulated 3/6 (MKK3/6)–p38 mitogen-activated (MAPK)-mediated inflammatory responses. p38 mimicked effect NAC, while agonist attenuated it, suggesting that pathway crucial NAC-mediated protection infection. (4) Conclusion: Our study suggests could be as therapy agent drug-resistant

Язык: Английский

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Effect of urolithin A on intracellular survival of Mycobacterium tuberculosis by regulating AKT-FOXO1-mediated autophagy

mSphere, Год журнала: 2025, Номер unknown

Опубликована: Апрель 10, 2025

ABSTRACT Tuberculosis (TB), resulting from Mycobacterium tuberculosis (Mtb), is one of the leading causes morbidity and mortality in humans worldwide. Host-directed therapy (HDT) a novel approach for treating TB, particularly those with drug resistance. Urolithin A (UroA) produced through bioconversion plant-derived ellagic acid by gut microbes has been proven to have multiple beneficial effects variety diseases without showing undesired adverse reactions. However, whether UroA antimycobacterial effect underlying mechanism not yet reported. Here, we found that significantly inhibited Mtb growth within both macrophages mice. Moreover, promoted activation autophagy Mtb-infected via protein kinase B–Forkhead box O1 signaling pathway, which contributed UroA. Additionally, suppressed survival clinically isoniazid (INH)-resistant (C2) macrophages, combination INH synergistically enhanced host elimination H37Rv. Therefore, may be utilized as potential candidate HDT an adjunctive first-line anti-TB drugs. IMPORTANCE We (Mtb) macrophages.

Язык: Английский

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Discovery of anti-infective compounds againstMycobacterium marinumafter biotransformation of simple natural stilbene scaffolds by a fungal secretome

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 22, 2024

ABSTRACT This study evaluated the efficacy of a high-throughput Dictyostelium discoideum – Mycobacterium marinum Dd-Mm infection system by first benchmarking it against set antibiotics and second in screening library natural product (NP) derivatives for anti-infective activity intracellular (Mm). The observed no pyrazinamide Mm, consistent with known resistance patterns, confirmed other antibiotics, such as rifampicin bedaquiline, below defined antibacterial susceptibility breakpoints. From small NP derivatives, trans -δ-viniferins emerged promising scaffolds, particularly two compounds which exhibited an on Mm during but not broth, 17 IC 50 18.1 µM, 19 9 µM). Subsequent exploration via halogenation structure-activity relationship (SAR) studies led to identification improved selectivity potency. phenotype may involve mechanisms blocking mycobacterial virulence factors or boosting host defense. Furthermore, highlights potential product-inspired derivatization approaches drug discovery underscores utility identifying novel compounds. IMPORTANCE significance leveraging innovative models search By employing - small, focused identified scaffolds , opening therapeutic avenues combating tuberculosis. findings highlight value exploring nature-inspired chemistry addressing global health challenges.

Язык: Английский

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Discovery of anti-infective compounds against Mycobacterium marinum after biotransformation of simple natural stilbenes by a fungal secretome

Frontiers in Microbiology, Год журнала: 2024, Номер 15

Опубликована: Сен. 17, 2024

Introduction Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, remains a serious threat to human health worldwide and quest for new anti-tubercular drugs is an enduring demanding journey. Natural products (NPs) have played significant role in advancing drug therapy infectious diseases. Methods This study evaluated suitability high-throughput infection system composed host amoeba Dictyostelium discoideum (Dd) marinum (Mm), close relative Mtb, identify anti-infective compounds. Growth Dd intracellular Mm were quantified by using luminescence fluorescence readouts phenotypic assays. The was first benchmarked with set therapeutic anti-Mtb antibiotics then used screen library biotransformed stilbenes. Results confirmed both efficacy established such as rifampicin bedaquiline, activities below defined anti-mycobacterium susceptibility breakpoints, lack activity pyrazinamide against Mm. screening revealed promising trans -δ-viniferins particular two compounds 17 19 IC 50 18.1 μM, 9 respectively. Both had no on broth. Subsequent exploration via halogenation structure-activity relationship studies led identification derivatives improved selectivity potency. modes action may involve inhibition mycobacterial virulence factors or boosting defense. Discussion highlights potential biotransformation NP-inspired derivatization approaches discovery underscores utility Dd-Mm identifying novel

Язык: Английский

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