Roles of HIF-1α signaling in Mycobacterium tuberculosis infection: New targets for anti-TB therapeutics?

Tuberculosis (TB), a deadly infectious disease induced by Mycobacterium tuberculosis (Mtb), continues to be a global public health issue that kill millions of patents every year. Despite significant efforts have been paid to identify effective TB treatments, the emergence of drug-resistant strains of the disease and the presence of comorbidities in TB patients urges us to explore the detailed mechanisms involved in TB immunity and develop more effective innovative anti-TB strategies. HIF-1α, a protein involved in regulating cellular immune responses during TB infection, has been highlighted as a promising target for the development of novel strategies for TB treatment due to its critical roles in anti-TB host immunity. This review provides a summary of current research progress on the roles of HIF-1α in TB infection, highlighting its importance in regulating the host immune response upon Mtb infection and summarizing the influences and mechanisms of HIF-1α on anti-TB immunological responses of host cells. This review also discusses the various challenges associated with developing HIF-1α as a target for anti-TB therapies, including ensuring specificity and avoiding off-target effects on normal cell function, determining the regulation and expression of HIF-1α in TB patients, and developing drugs that can inhibit HIF-1α. More deep understanding of the molecular mechanisms involved in HIF-1α signaling, its impact on TB host status, and systematic animal testing and clinical trials may benefit the optimization of HIF-1α as a novel therapeutic target for TB.

Exploring Novel Antidepressants Targeting G Protein-Coupled Receptors and Key Membrane Receptors Based on Molecular Structures.

Major Depressive Disorder (MDD) is a complex mental disorder that involves alterations in signal transmission across multiple scales and structural abnormalities. The development of effective antidepressants (ADs) has been hindered by the dominance of monoamine hypothesis, resulting in slow progress. Traditional ADs have undesirable traits like delayed onset of action, limited efficacy, and severe side effects. Recently, two categories of fast-acting antidepressant compounds have surfaced, dissociative anesthetics S-ketamine and its metabolites, as well as psychedelics such as lysergic acid diethylamide (LSD). This has led to structural research and drug development of the receptors that they target. This review provides breakthroughs and achievements in the structure of depression-related receptors and novel ADs based on these. Cryo-electron microscopy (cryo-EM) has enabled researchers to identify the structures of membrane receptors, including the N-methyl-D-aspartate receptor (NMDAR) and the 5-hydroxytryptamine 2A (5-HT2A) receptor. These high-resolution structures can be used for the development of novel ADs using virtual drug screening (VDS). Moreover, the unique antidepressant effects of 5-HT1A receptors in various brain regions, and the pivotal roles of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and tyrosine kinase receptor 2 (TrkB) in regulating synaptic plasticity, emphasize their potential as therapeutic targets. Using structural information, a series of highly selective ADs were designed based on the different role of receptors in MDD. These molecules have the favorable characteristics of rapid onset and low adverse drug reactions. This review offers researchers guidance and a methodological framework for the structure-based design of ADs.

Identification and Validation of Genes Related to Macrophage Polarization and Cell Death Modes Under Mycobacterium tuberculosis Infection.

Purpose: To investigate the correlation between M1/M2 macrophages (M1/M2 Mφ) and cell death mode under Mycobacterium tuberculosis (Mtb) infection. Methods: Raw gene expression profiles were collected from the Gene Expression Omnibus (GEO) database. Genes related to different cell death modes were collected from the KEGG, FerrDb and GSEA databases. The differentially expressed genes (DEGs) of the gene expression profiles were identified using the limma package in R. The intersection genes of M1/M2 Mφ with different cell death modes were obtained by the VennDiagram package. Hub genes were obtained by constructing the protein-protein interactions (PPI) network and Receiver Operating Characteristic (ROC) curve analysis. The expression of cell death modes marker genes and Hub genes were verified by Western Blot and Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Results: Bioinformatics analysis was performed to screen Hub genes of Mtb-infected M1 Mφ and different cell death modes, naming NFKB1, TNF, CFLAR, TBK1, IL6, RELA, SOCS1, AIM2; Hub genes of Mtb-infected M2 Mφ and different cell death modes, naming TNF, BIRC3, MAP1LC3C, DEPTOR, UVRAG, SOCS1. Combined with experimental validation, M1 Mφ under Mtb infection showed higher expression of death (including apoptosis, autophagy, ferroptosis, and pyroptosis) genes compared to M2 Mφ and genes such as NFKB1, TNF, CFLAR, TBK1, IL6, RELA, AIM2, BIRC3, DEPTOR show differential expression. Conclusion: NFKB1, TNF, CFLAR, TBK1, IL6, RELA, AIM2 in Mtb-infected M1 Mφ, and TNF, BIRC3, DEPTOR in Mtb-infected M2 Mφ might be used as potential diagnostic targets for TB. At early stage of Mtb infection, apoptosis, autophagy, ferroptosis, and pyroptosis occurred more significantly in M1 Mφ than that in M2 Mφ, which may contribute to the transition of Mtb-infected Mφ from M1-dominant to M2-dominant and contribute to the immune escape mechanisms of Mtb.

Iron, Copper, and Zinc Homeostasis in the Battle between Macrophage and Mycobacterium Tuberculosis.

Iron, copper, and zinc play integral roles in the battle against Mycobacterium tuberculosis (Mtb) infection; however, they are often trapped between nutrients and toxins, posing a significant challenge to macrophages and Mtb to utilize them. Due to this two-sided effect, macrophages and Mtb strictly regulate metal uptake, storage, and excretion. This review discusses the balanced regulation of iron, copper, and zinc in macrophages and Mtb during infection, focusing on the intracellular metal regulatory system. Macrophages typically use the two-sided effect of metals to limit Mtb access to nutrients or poison them. Mtb has developed a metal metabolism regulatory mechanism compatible with the nutritional immune strategy. This includes the mediation of relevant metalloproteins and metalloenzymes to maintain the multimetal balance. This review also explored the regulation of metal metabolism homeostasis in macrophages resistant to Mtb infection, providing a theoretical foundation for identifying potential clinical targets for Mtb infection, developing metalloid anti-tuberculosis drugs, and understanding the immune mechanisms against intracellular Mtb infection.

Intratracheal Administration of Stem Cell Membrane-Cloaked Naringin-Loaded Biomimetic Nanoparticles Promotes Resolution of Acute Lung Injury.

Cytokine storm and ROS overproduction in the lung always lead to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in a very short time. Effectively controlling cytokine storm release syndrome (CRS) and scavenging ROS are key to the prevention and treatment of ALI/ARDS. In this work, the naringin nanoparticles (Nar-NPs) were prepared by the emulsification and evaporation method; then, the mesenchymal stem cell membranes (CMs) were extracted and coated onto the surface of the Nar-NPs through the hand extrusion method to obtain the biomimetic CM@Nar-NPs. In vitro, the CM@Nar-NPs showed good dispersity, excellent biocompatibility, and biosafety. At the cellular level, the CM@Nar-NPs had excellent abilities to target inflamed macrophages and the capacity to scavenge ROS. In vivo imaging demonstrated that the CM@Nar-NPs could target and accumulate in the inflammatory lungs. In an ALI mouse model, intratracheal (i.t.) instillation of the CM@Nar-NPs significantly decreased the ROS level, inhibited the proinflammatory cytokines, and remarkably promoted the survival rate. Additionally, the CM@Nar-NPs increased the expression of M2 marker (CD206), and decreased the expression of M1 marker (F4/80) in septic mice, suggesting that the Nar-modulated macrophages polarized towards the M2 subtype. Collectively, this work proves that a mesenchymal stem cell membrane-based biomimetic nanoparticle delivery system could efficiently target lung inflammation via i.t. administration; the released payload inhibited the production of inflammatory cytokines and ROS, and the Nar-modulated macrophages polarized towards the M2 phenotype which might contribute to their anti-inflammation effects. This nano-system provides an excellent pneumonia-treated platform with satisfactory biosafety and has great potential to effectively deliver herbal medicine.

Oral delivery of pH-sensitive nanoparticles loaded Celastrol targeting the inflammatory colons to treat ulcerative colitis.

The incidence of ulcerative colitis (UC) is rapidly rising worldwide. Oral drug delivery system is a promising approach for treating UC, but it often fails to accumulate to the inflammatory lesions, thus, it is impressive to develop a colon-targeted oral delivery system for preventing systemic toxicity and maintaining UC therapeutics. Here, a negative-charged PLGA nanoparticle system was designed to encapsulate celastrol (Cel), and then chitosan and mannose were coated on the surface of the nanoparticles (MC@Cel-NPs) to endow these nanoparticles with the mucosal adsorption and macrophage targeting abilities. MC@Cel-NPs demonstrate excellent resist decomposition ability against the strong acidic gastrointestinal environment, and accumulates in the specific inflammatory sites through the affinity of electrostatic reaction. After releasing the payload, MC@Cel-NPs could remarkably alleviate the colon inflammation, which was evidenced by the decrease in pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 in both blood and colon sections, and scavenging reactive oxygen species (ROS) in colon cells, including macrophage, neutrophil, T cell, and B cell. This nanoparticle system provided a new approach for treating UC through a Chinese herbal ingredient-related oral delivery manner.