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In this study, we report evidences that Mycobacterium tuberculosis (MTB)-induced apoptosis in macrophages is reduced by a broad-spectrum hydroxamic acid-based matrix metalloproteinase (MMP) inhibitor, Batimastat (BB-94). In particular, we show that BB-94 administration to MTB-infected macrophages inhibits apoptosis and the downmodulation of membrane CD14 expression. Moreover, the addition of broad spectrum matrix metalloproteinase inhibitor to cell culture, during MTB infection, decreases the release of soluble TNF-α and leads to a simultaneous increase of membrane TNF-α. These results show that MTB-induced apoptosis in macrophages is reduced by a MMP inhibitor and most probably is related to TNF-α release. This identifies BB-94 as a simultaneous anti-apoptotic and anti-inflammatory molecule during MTB infection. [Copyright &y& Elsevier]

Mycobacterium tuberculosis (MTB) can induce apoptosis in monocytes/macrophages both in vitro and in vivo, and this phenomenon is associated with mycobacterial survival. The present study addresses the possibility that apoptotic and inflammatory pathways could coexist through a caspase-l-mediated mechanism. In this context, a caspase-1 inhibitor (YVAD), but not caspase-3 (DEVD) or caspase-4 (LEVD) inhibitors, was able to strongly inhibit MTBinduced apoptosis. Moreover, caspase-1 activity was confirmed by the increased maturation of interleukin (IL)-1β. Of interest, IL-1β and tumor necrosis factor (TNF)-α were produced massively in the course of infection, and both were inhibited by YVAD pretreatment. To determine whether TNF-α was produced actively by apoptotic cells, the intracytoplasmatic cytokine content and apoptotic phenotype were analyzed at the single-cell level. Results showed a progressive increase of TNF-α production in annexin V-positive cells. These results indicate that MTB-induced apoptosis is associated with proinflammatory cytokine production. [ABSTRACT FROM AUTHOR]

Coinfection with Mycobacterium tuberculosis (Mtb) and the human immunodeficiency virus (HIV) is a significant public health concern. Individuals infected with Mtb who acquire HIV are approximately 16 times more likely to develop active tuberculosis. T cells play an important role as both targets for HIV infection and mediators of the immune response against both pathogens. This review aims to synthesize the current literature and provide insights into the effects of HIV/Mtb coinfection on T cell populations and their contributions to immunity. Evidence from multiple in vitro and in vivo studies demonstrates that T helper responses are severely compromised during coinfection, leading to impaired cytotoxic responses. Moreover, HIV's targeting of Mtb-specific cells, including those within granulomas, offers an explanation for the severe progression of the disease. Herein, we discuss the patterns of differentiation, exhaustion, and transcriptomic changes in T cells during coinfection, as well as the metabolic adaptations that are necessary for T cell maintenance and functionality. This review highlights the interconnectedness of the immune response and the pathogenesis of HIV/Mtb coinfection. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), a chronic infectious disease affecting humans, causes over 1.3 million deaths per year throughout the world. The current preventive vaccine BCG provides protection against childhood TB, but it fails to protect against pulmonary TB. Multiple candidates have been evaluated to either replace or boost the efficacy of the BCG vaccine, including subunit protein, DNA, virus vector-based vaccines, etc., most of which provide only short-term immunity. Several live attenuated vaccines derived from Mycobacterium tuberculosis (Mtb) and BCG have also been developed to induce long-term immunity. Since Mtb mediates its virulence through multiple secreted proteins, these proteins have been targeted to produce attenuated but immunogenic vaccines. In this review, we discuss the characteristics and prospects of live attenuated vaccines generated by targeting the disruption of the genes encoding secretory mycobacterial proteins. [ABSTRACT FROM AUTHOR]

Novel lipid-based nanosystems have been of interest in improving conventional drug release methods. Liposomes are the most studied nanostructures, consisting of lipid bilayers ideal for drug delivery, thanks to their resemblance to the cell plasma membrane. Asymmetric liposomes are vesicles with different lipids in their inner and outer layers; because of this, they can be configured to be compatible with the therapeutic drug while achieving biocompatibility and stability. Throughout this review, topics such as the applications, advantages, and synthesis techniques of asymmetric liposomes will be discussed. Further, an in silico analysis by computational tools will be examined as a helpful tool for designing and understanding asymmetric liposome mechanisms in pharmaceutical applications. The dual-engineered design of asymmetric liposomes makes them an ideal alternative for transdermal drug delivery because of the improved protection of pharmaceuticals without lowering adsorption rates and system biocompatibility. [ABSTRACT FROM AUTHOR]

Liposome-based drug delivery systems are nanosized spherical lipid bilayer carriers that can encapsulate a broad range of small drug molecules (hydrophilic and hydrophobic drugs) and large drug molecules (peptides, proteins, and nucleic acids). They have unique characteristics, such as a self-assembling bilayer vesicular structure. There are several FDA-approved liposomal-based medicines for treatment of cancer, bacterial, and viral infections. Most of the FDA-approved liposomal-based therapies are in the form of conventional "symmetric" liposomes and they are administered mainly by injection. Arikace® is the first and only FDA-approved liposomal-based inhalable therapy (amikacin liposome inhalation suspension) to treat only adults with difficult-to-treat Mycobacterium avium complex (MAC) lung disease as a combinational antibacterial treatment. To date, no "asymmetric liposomes" are yet to be approved, although asymmetric liposomes have many advantages due to the asymmetric distribution of lipids through the liposome's membrane (which is similar to the biological membranes). There are many challenges for the formulation and stability of asymmetric liposomes. This review will focus on asymmetric liposomes in contrast to conventional liposomes as a potential clinical intervention drug delivery system as well as the formulation techniques available for symmetric and asymmetric liposomes. The review aims to renew the research in liposomal nanovesicle delivery systems with particular emphasis on asymmetric liposomes as future potential carriers for enhancing drug delivery including pulmonary nanotherapeutics. [ABSTRACT FROM AUTHOR]

Examines the intracellular mycobacterial viability of mycobacterium tuberculosis (MTB)-induced apoptosis in monocytes. Association of MTB- induces apoptosis with CD14 expression; Correlation between MTB high doses and parasite survival; Role of monocytes on cytokines and chemokines release.

This study aims to fabricate smart insoles using wireless Flexi force and bend sensing technology. Polyvinyl chloride (PVC) film was chosen as the substrate to hold all the sensors. The developed smart insole has a three-layer structure (insole-PVC layer-fabric layer) and is calibrated in an isolation laboratory to evaluate its measurement performance. One male volunteer subject exhibited four different body postures, namely tree pose, forward-leaning, squatting, and forward folding pose. Changes in pressure distribution were considered to be similar for the forward, squat, and forward-folded positions. When subjects performed a full squat, the flex sensor exhibited maximum flexion during the squat position, and the flex sensor response against the squat pose was found to be higher by about 18.18% than in the forward lean, respectively. The tree pose has the highest error rate at the first metatarsal, about 18.6%, of which the maximum absolute relative error of the sensor is less than 5%. Plantar pressure distribution and body posture measurements were successfully validated using Flexi force and flex sensors embedded in the smart insole. The smart insole proposed in this research work has broader prospects for clinical application. [ABSTRACT FROM AUTHOR]

Mycobacterium abscessus (M. abscessus) is an opportunistic pathogen usually colonizing abnormal lung airways and is often seen in patients with cystic fibrosis. Currently, there is no vaccine available for M. abscessus in clinical development. The treatment of M. abscessus-related pulmonary diseases is peculiar due to intrinsic resistance to several commonly used antibiotics. The development of either prophylactic or therapeutic interventions for M. abscessus pulmonary infections is hindered by the absence of an adequate experimental animal model. In this review, we outline the critical elements related to M. abscessus virulence mechanisms, host–pathogen interactions, and treatment challenges associated with M. abscessus pulmonary infections. The challenges of effectively combating this pathogen include developing appropriate preclinical animal models of infection, developing proper diagnostics, and designing novel strategies for treating drug-resistant M. abscessus. [ABSTRACT FROM AUTHOR]

The review considers liposomes as systems of substantial interest as adjuvant carriers in vaccinology due to their versatility and maximal biocompatibility. Research and development on the use of liposomes and lipid nanoparticles to create subunit vaccines for the prevention and treatment of infectious diseases has been going on for several decades. In recent years, the area has seen serious progress due to the improvement of the technology of industrial production of various high-grade lipids suitable for parenteral administration and the emergence of new technologies and equipment for the production of liposomal preparations. When developing vaccines, it is necessary to take into account how the body's immune system (innate and adaptive immunity) functions. The review briefly describes some of the fundamental mechanisms underlying the mobilization of immunity when encountering an antigen, as well as the influence of liposome carriers on the processes of internalization of antigens by immunocompetent cells and ways of immune response induction. The results of the studies on the interactions of liposomes with antigen-presenting cells in function of the liposome size, charge, and phase state of the bilayer, which depends on the lipid composition, are often contradictory and should be verified in each specific case. The introduction of immunostimulant components into the composition of liposomal vaccine complexes—ligands of the pathogen-associated molecular pattern receptors—permits modulation of the strength and type of the immune response. The review briefly discusses liposome-based vaccines approved for use in the clinic for the treatment and prevention of infectious diseases, including mRNA-loaded lipid nanoparticles. Examples of liposomal vaccines that undergo various stages of clinical trials are presented. [ABSTRACT FROM AUTHOR]

Inhalation is required for respiration and life in all vertebrates. This process is not without risk, as it potentially exposes the host to environmental pathogens with every breath. This makes the upper respiratory tract one of the most common routes of infection and one of the leading causes of morbidity and mortality in the world. To combat this, the lung relies on the innate immune defenses. In contrast to the adaptive immune system, the innate immune system does not require sensitization, previous exposure or priming to attack foreign particles. In the lung, the innate immune response starts with the epithelial barrier and mucus production and is reinforced by phagocytic cells and T cells. These cells are vital for the production of cytokines, chemokines and anti-microbial peptides that are critical for clearance of infectious agents. In this review, we discuss all aspects of the innate immune response, with a special emphasis on ways to target aspects of the immune response to combat antibiotic resistant bacteria. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite substantial theoretical and experimental support for using vascular normalization as cancer therapy, effectively achieving this strategy in the clinic remains complex. In the present paper, we propose a novel potential approach for the induction of tumor vascular normalization, reduction of hypoxia, and improvement of conventional treatment in cancer patients. This approach consists of the pharmacological modulation of a patient's plasma S1P levels which through a PDGF signaling can enhance tumor vasculature functionality and reduce hypoxia. This approach is proposed following a clinical observation in pancreatic adenocarcinoma patients and pre-clinical data in different in vivo tumor models, and is supported by a review of the literature describing the biological role of S1P in vascular functionality regulation. Increasing evidence indicates that tumor vasculature normalization could be an appropriate strategy to increase therapies' efficacy in solid tumors by decreasing hypoxia and improving drug delivery. We searched for a novel approach that reduces hypoxia and enhances chemotherapy efficacy in pancreatic adenocarcinoma which is characterized by disrupted blood vasculature associated with poor patient survival. Clinical significance of plasma levels of the angiogenic lipid sphingosine-1-phosphate (S1P) was assessed at baseline in 175 patients. High plasma S1P concentration was found to be a favorable prognostic/predictive marker in advanced/metastatic pancreatic adenocarcinoma patients treated by gemcitabine alone but not in patients receiving a combination gemcitabine and PDGFR-inhibitor. In pancreatic adenocarcinoma PDX models, oral administration of an S1P lyase inhibitor (LX2931) significantly increased plasma S1P levels, decreased tumor expression of the hypoxia marker (CA IX), and enhanced chemotherapy efficacy when combined with gemcitabine treatment. The direct effect of S1P on tumor oxygenation was assessed by administration of S1P onto tumor-grafted CAM model and measuring intra-tumoral pO2 using a tissue oxygen monitor. S1P increased pO2 in a tumor-CAM model. Thus, increasing plasma S1P is a promising strategy to decrease tumor hypoxia and enhance therapy efficacy in solid tumors. S1P may act as a tumor vasculature normalizer. [ABSTRACT FROM AUTHOR]

Summary [ABSTRACT FROM AUTHOR]

Discusses the characteristics of mycobacterium tuberculosis. Epidemiology of the disease; Pathology of the infection; Progression of the disease.

The present study addresses the differential ability of macrophages to control intracellular growth of non-pathogenic Mycobacterium smegmatis (Msm) and pathogenic M . tuberculosis (MTB). Results reported herein show that 3 h post infection, intracellular Msm , but not MTB, was significantly killed by macrophages. As the role of human macrophage phospholipase D (PLD) in the activation of antimicrobial mechanisms has been documented, we hypothesised the role of such enzyme in antimycobacterial mechanisms. To this aim, macrophage PLD activity was analysed at different times after exposure with either pathogenic MTB or non-pathogenic Msm. Results showed that, starting from 15 min after mycobacterial exposure, MTB did not induce macrophage PLD activity, whereas the environmental non-pathogenic Msm stably increased it. The direct contribution of PLD in intracellular mycobacterial killing was also analysed by inhibiting enzymatic activity with ethanol or calphostin C. Results show that PLD inhibition significantly increases intracellular Msm replication. In order to see whether the innate PLD-mediated antimicrobial mechanisms against MTB are also induced after CpG ODN stimulation, the role of PLD has been analysed in the course of CpG-mediated intracellular MTB killing. CpG DNA increased PLD activity in both uninfected and MTB-infected macrophages, and the inhibition of PLD activity resulted in a significant reduction of CpG-induced MTB killing. Taken together, our data suggest a relationship between host PLD activation and the macrophage ability to control intracellular mycobacterial growth. [ABSTRACT FROM AUTHOR]