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Inhibitory effect of baicalin on bacillary loads. Bacterial CFUs were counted after baicalin treatment for 48 h. **p < 0.01, Data are shown as mean ± SD of three independent experiments.
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Tuberculosis (TB) remains a leading killer worldwide among infectious diseases and the effective control of TB is still challenging. Autophagy is an intracellular self-digestion process which has been increasingly recognized as a major host immune defense mechanism against intracellular microorganisms like Mycobacterium tuberculosis (Mtb) and serve...
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Mycobacterium tuberculosis, responsible for causing tuberculosis (TB) in humans, continues to pose a significant worldwide threat, causing extensive fatalities as the most prominent bacterial disease and urgent attention is required to develop novel anti-TB drugs. Throughout the history of medicine, natural remedies have consistently held a vital p...
Citations
... PI3K, ULK1, and autophagy-related complex ATG are all involved in the induction of autophagy, and it is powerfully induced by starvation, rapamycin, and intracellular infection [34,35]. Regarding M. tb infection, autophagy plays an important antimicrobial role by decreasing bacterial growth and inflammation [34,36]. In this review, we researched various papers studying the mTOR mechanism's role in autophagy generally and during M. tb infection. ...
... Some Chinese herbal plants such as curcumin or larrea tridentata downregulate the mTOR/PI3K/AKT pathway, therefore upregulating autophagy and promoting antimycobacterial effects [34]. Baicalin is a flavonoid which also inhibits the same pathway to activate autophagy and kill intracellular M. tb [34,36]. While the mechanism may be unclear, B and T lymphocyte attenuator (BTLA) has been shown to influence the elimination of M. tb by enhancing autophagy through the PI3K/AKT pathway in macrophages. ...
Background/Objectives: Mycobacterium tuberculosis (M. tb) is a pathogen that causes tuberculosis (TB), an extremely infectious disease which is responsible for millions of deaths worldwide. The severity of this pathogen is further amplified with the emergence of multidrug-resistant strains that are becoming more prevalent at an alarming rate, and novel treatments are needed. Methods: In this paper, we discuss the pathology M. tb infection. We review the literature on the role that mTOR plays in autophagy and the immune system as well as its impact on M. tb infection. Lastly, we discuss the current therapies targeting mTOR and potential routes to explore for future treatments. Results: The mTOR protein acts as a negative regulator of the autophagy pathway and presents as a potent target to establish new treatments for TB. M. tb survival is affected by mTOR, the PI3K/mTOR/AKT pathway, and autophagy. M. tb evades destruction by manipulating host cellular mechanisms, which increases resistance and complicates treatment. Conclusions: Targeting mTOR can enhance autophagy and increase M. tb clearance. Existing drugs such as everolimus, rapamycin + CC214-2, and bazedoxifene are all being currently studied for effectiveness and show positive results. Alternative therapies, including Chinese herbs, baicalin, BTLA, glutathione, and precision medicine can modulate the PI3K/mTOR/AKT pathway and the host’s immune response, resulting in increased M. tb clearance, and these may be the future treatments for M. tb infection.
... All of these pathways ultimately activate mechanistic target of rapamycin (mTOR), the autophagy gateway molecule, which dephosphorylates Atg13, enhances Atg1 kinase activity, and activates autophagy downstream signals to initiate autophagy. The above pathways can induce autophagy directly through upregulation of autophagyrelated protein expression, but it has also been shown that the PI3K/AKT/mTOR signaling pathway can inhibit autophagy [106]. Non-classical autophagy mainly refers to LC3-associated phagocytosis (LAP) targeting intracellular macromolecules [107]. ...
Background
The pathogen responsible for tuberculosis is called Mycobacterium tuberculosis. Its interaction with macrophages has a significant impact on the onset and progression of the disease.
Methods
The respiratory pathway allows Mycobacterium tuberculosis to enter the body's lungs where it battles immune cells before being infected latently or actively. In the progress of tuberculosis, Mycobacterium tuberculosis activates the body's immune system and creates inflammatory factors, which cause tissue inflammation to infiltrate and the creation of granulomas, which seriously harms the body. Toll-like receptors of macrophage can mediate host recognition of Mycobacterium tuberculosis, initiate immune responses, and participate in macrophage autophagy. New host-directed therapeutic approaches targeting autophagy for drug-resistant Mycobacterium tuberculosis have emerged, providing new ideas for the effective treatment of tuberculosis.
Conclusions
In-depth understanding of the mechanisms by which macrophage autophagy interacts with intracellular Mycobacterium tuberculosis, as well as the study of potent and specific autophagy-regulating molecules, will lead to much-needed advances in drug discovery and vaccine design, which will improve the prevention and treatment of human tuberculosis.
... We and others have previously demonstrated that autophagy serves as an important host immune defense mechanism during infection with Mycobacterium tuberculosis and BCG and functions as a key regulator of inflammation [58][59][60][61]. Therefore, autophagy-associated proteins were investigated in vivo and in vitro. ...
... This further limited the generation of inflammation-associated NLRP3 inflammasome and IL-1b. Thus, baicalin exhibited antiinflammatory and anti-MTB functions with HDT potency (110). Baicalein promoted autophagy by inhibiting the Akt/mTOR pathway, downregulating AIM2 and NLRP3 inflammasomes, and inhibiting pyroptosis in MTB-infected macrophages (111). ...
Tuberculosis (TB) is caused by the bacterial pathogen Mycobacterium tuberculosis (MTB) and is one of the principal reasons for mortality and morbidity worldwide. Currently, recommended anti-tuberculosis drugs include isoniazid, rifampicin, ethambutol, and pyrazinamide. TB treatment is lengthy and inflicted with severe side-effects, including reduced patient compliance with treatment and promotion of drug-resistant strains. TB is also prone to other concomitant diseases such as diabetes and HIV. These drug-resistant and complex co-morbid characteristics increase the complexity of treating MTB. Host-directed therapy (HDT), which effectively eliminates MTB and minimizes inflammatory tissue damage, primarily by targeting the immune system, is currently an attractive complementary approach. The drugs used for HDT are repositioned drugs in actual clinical practice with relative safety and efficacy assurance. HDT is a potentially effective therapeutic intervention for the treatment of MTB and diabetic MTB, and can compensate for the shortcomings of current TB therapies, including the reduction of drug resistance and modulation of immune response. Here, we summarize the state-of-the-art roles and mechanisms of HDT in immune modulation and treatment of MTB, with a special focus on the role of HDT in diabetic MTB, to emphasize the potential of HDT in controlling MTB infection.
... Previous studies have revealed that some medicinal plants like Semecarpus anacardium, Adhatoda vasica, Camchaya calcarea, and Zanthoxylum capense for promising antimycobacterial activity. The various phytoconstituents like quinazoline alkaloids; vasicine and vasicinone isolated from Justicia adhatoda; pinocembrin, a flavanone from Cryptocarya chinensis; and a glycosyloxyflavone baicalin from Scutellaria baicalensis showed significant anti-mycobacterial activity (Chou et al., 2011;Ignacimuthu & Shanmugam, 2010;Zhang et al., 2017). ...
... Moreover, in vivo autophagy experiments have shown that the autophagy protein Atg5 in macrophages is required to inhibit Mtb infection in mice [10], and autophagy inhibitors enhance mycobacterial burden in zebrafish embryonic models [11]. In vitro studies have also demonstrated the antibacterial and anti-inflammatory mechanism of autophagy [12]. Besides, our research group has shown that the recovery of autophagy is conducive to the inhibition of pyroptosis. ...
... Our previous studies have proved that Mtb-infected macrophages can promote the activation of the NLRP3 inflammasome, thereby causing pyroptosis and leading to the spread of bacteria and a severe inflammatory reaction [8,12,22]. In the present study, we found that UA significantly inhibited the expression of NLRP3 in a timeand concentration-dependent manner ( Fig. 3a-d) and inhibited the formation of apoptosis-associated specklike protein containing a caspase recruitment domain (ASC) oligomerization (Fig. 3e, f), thereby inhibiting the assembly of the NLRP3 inflammasome (Fig. 3g, h), effectively suppressing the activity of caspase-1, blocking N-terminal fragment of GSDMD (GSDMD-N), and inhibiting the occurrence of pyroptosis (Fig. 3i, j). ...
... The ability of Mtb to survive and replicate in host macrophages is the core of the TB mechanism [9,26]. Some studies have demonstrated that Mtb clearance can be enhanced by targeting the macrophage autophagy mechanism to reduce inflammation [12,27]. To evaluate the ability of UA to induce autophagy in Mtb infection, we measured the expressions of p62 and LC3 II at the protein level when exposed to different concentrations of UA (0, 5, 10, or 20 μM) and at different times of treatment. ...
As a lethal infectious disease, tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb). Its complex pathophysiological process limits the effectiveness of many clinical treatments. By regulating host cell death, Mtb manipulates macrophages, the first line of defense against invading pathogens, to evade host immunity and promote the spread of bacteria and intracellular inflammatory substances to neighboring cells, resulting in widespread chronic inflammation and persistent lung damage. Autophagy, a metabolic pathway by which cells protect themselves, has been shown to fight intracellular microorganisms, such as Mtb, and they also play a crucial role in regulating cell survival and death. Therefore, host-directed therapy (HDT) based on antimicrobial and anti-inflammatory interventions is a pivotal adjunct to current TB treatment, enhancing anti-TB efficacy. In the present study, we showed that a secondary plant metabolite, ursolic acid (UA), inhibited Mtb-induced pyroptosis and necroptosis of macrophages. In addition, UA induced macrophage autophagy and enhanced intracellular killing of Mtb. To investigate the underlying molecular mechanisms, we explored the signaling pathways associated with autophagy as well as cell death. The results showed that UA could synergistically inhibit the Akt/mTOR and TNF-α/TNFR1 signaling pathways and promote autophagy, thus achieving its regulatory effects on pyroptosis and necroptosis of macrophages. Collectively, UA could be a potential adjuvant drug for host-targeted anti-TB therapy, as it could effectively inhibit pyroptosis and necroptosis of macrophages and counteract the excessive inflammatory response caused by Mtb-infected macrophages via modulating the host immune response, potentially improving clinical outcomes.
... Moreover, in vivo autophagy experiments have shown that the autophagy protein Atg5 in macrophages is required to inhibit Mtb infection in mice [10], and autophagy inhibitors enhance mycobacterial burden in zebra sh embryonic models [11]. In vitro studies have also demonstrated the antibacterial and antiin ammatory mechanism of autophagy [12]. Besides, our research group has shown that the recovery of autophagy is conducive to the inhibition of pyroptosis. ...
... Our previous studies have proved that Mtb-infected macrophages can promote the activation of the NLRP3 in ammasome, thereby causing pyroptosis and leading to the spread of bacteria and a severe in ammatory reaction [8, 12,22]. In the present study, we found that UA signi cantly inhibited the expression of NLRP3 in a time-and concentration-dependent manner (Fig. 3a-3d) and inhibited the formation of Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomerization (Fig. 3e, 3f), thereby inhibiting the assembly of the NLRP3 in ammasome (Fig. 3g, 3h), effectively suppressing the activity of caspase-1, blocking N-terminal fragment of GSDMD (GSDMD-N), and inhibiting the occurrence of pyroptosis (Fig. 3i, 3j). ...
... The ability of Mtb to survive and replicate in host macrophages is the core of the TB mechanism [9,26]. Some studies have demonstrated that Mtb clearance can be enhanced by targeting the macrophage autophagy mechanism to reduce in ammation [12,27]. To evaluate the ability of UA to induce autophagy in Mtb infection, we measured the expressions of p62 and LC3 II at the protein level when exposed to different concentrations of UA (0, 5, 10, or 20 μM) and at different times of treatment. ...
As a lethal infectious disease, tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb). Its complex pathophysiological process limits the effectiveness of many clinical treatments. By regulating host cell death, Mtb manipulates macrophages, the first line of defense against invading pathogens, to evade host immunity and promote the spread of bacteria and intracellular inflammatory substances to neighboring cells, resulting in widespread chronic inflammation and persistent lung damage. Autophagy, a metabolic pathway by which cells protect themselves, has been shown to fight intracellular microorganisms, such as Mtb, and they also play a crucial role in regulating cell survival and death. Therefore, host-directed therapy (HDT) based on antimicrobial and anti-inflammatory interventions is a pivotal adjunct to current TB treatment, enhancing anti-TB efficacy. In the present study, we showed that a secondary plant metabolite, ursolic acid (UA), inhibited Mtb-induced pyroptosis and necroptosis of macrophages. In addition, UA induced macrophage autophagy and enhanced intracellular killing of Mtb. To investigate the underlying molecular mechanisms, we explored the signaling pathways associated with autophagy as well as cell death. The results showed that UA could synergistically inhibit the Akt/mTOR and TNF-α/TNFR1 signaling pathways and promote autophagy, thus achieving its regulatory effects on pyroptosis and necroptosis of macrophages. Collectively, UA could be a potential adjuvant drug for host-targeted anti-TB therapy, as it could effectively inhibit pyroptosis and necroptosis of macrophages and counteract the excessive inflammatory response caused by Mtb-infected macrophages via modulating the host immune response, potentially improving clinical outcomes.
... Tuberculosis (TB) has been reported to be one of the most prevalent infectious diseases which gets transmitted through the nasal and salivary droplets of the affected person via air. The literature reported that tuberculosis is caused due to the infectious agent Mycobacterium tuberculosis and is considered one of the cardinal causes of death due to infectious diseases across the globe [1]. As per the official report of the World Health Organization (WHO), around 4.1 million people are suffering from TB globally [2]. ...
... The various metallic nanoparticles are also been reported to have notable cognizance against Mycobacterium tuberculosis [18]. Metals like zinc, silver, gold, etc. have been widely adopted as nanoparticles to be used as growth-inhibiting agents for Mycobacterium tuberculosis [1]. In this particular study, the ant-microbial impact of selenium nanoparticles against Mycobacterium tuberculosis was evaluated as being reported to have lesser toxicity [9]. ...
One of the cardinal causes of global deaths from a single-point infectious agent has been reported to be tuberculosis (or TB). At present times, the incidence of TB cases occurs mostly due to multi-drug resistance, which is expected to boost further in the upcoming times. Accordingly, the development of alternative treatment methodologies has received significant research interest. In this regard, the application of nanoparticles has notable cognizance. The literature suggested that nanoparticles have substantial potential to be used as the delivery medium for drug injection as well as they also serve as a potential bactericidal agent. In this present study, the efficacy of the selenium nanoparticles against the inhibition of growth of Mycobacterium tuberculosis was evaluated. The obtained results indicated that the synthesized selenium nanoparticles have notable cognizance towards the inhibition of growth of Mycobacterium tuberculosis by disrupting the integrity of their cell envelope. This study thus proposes a novel approach and opens new dimensional avenues in the field of nanoparticle-induced cell disruption strategies.
... Genes HSPA5, ATF6, ERN1, EIF2A from the ER stress panel ; BCL2, CASP3 from the apoptosis panel (Gu et al., 2018); MAPLC3B, BECN1 from the autophagy panel (Q. Zhang et al., 2017); HIF1A, MMP9, VEGFA, FOXM1 from hypoxia panel (Highet et al., 2015); MMP2, CDC42, ACTB, RDX from cytoskeleton panel (Liu et al., 2018); CDH1, ITGA1, ITGAV, ADAMTS12, ITGB1 from cell adhesion molecules panel (Lin et al., 2017) were examined in the control and Tg treatment groups determined. RNA samples were isolated with an RNA isolation kit (Roche Product No: 11828665001). ...
Endoplasmic reticulum (ER) stress has been reported to play a role in the pathogenesis of intrauterine growth retardation and preeclampsia, especially implantation failure. Although in vitro ER stress studies in human trophoblast cell line have been conducted in recent years, the influence of Thapsigargin on intracellular dynamics on calcium homeostasis has not been proven. Here, the effects of ER stress and impaired calcium homeostasis on apoptosis, autophagy, cytoskeleton, hypoxia, and adhesion molecules in 2D and spheroid cultures of human trophectoderm cells were investigated at gene expression and protein levels. Thapsigargin caused ER stress by increasing GRP78 gene expression and protein levels. Human trophectoderm cells displayed different characterization properties in 2D and spheroids. While it moves in the pathway of EIF2A and IRE1A mechanisms in 2D, it proceeds in the pathway of EIF2A and ATF6 mechanisms in spheroids and triggers different responses in survival and programmed cell death mechanisms such as apoptosis and autophagy. This led to changes in the cytoskeleton, cell adhesion molecules and cell-cell interactions by affecting the hypoxia mechanism.
... Likewise, Autophagy-related proteins were also significantly up-regulated by BA treatment in macrophages [60]. And this autophagy activation effect was partially mediated by regulating PI3K-AKT-mTOR pathway [61]. It has been reported that autophagy could promote ABCA1-dependent cholesterol efflux via increasing the free cholesterol availability. ...
Atherosclerosis (AS) is the most common causes of cardiovascular disease characterized by the formation of atherosclerotic plaques in the arterial wall, and it has become a dominant public health problem that seriously threaten people worldwide. Autophagy is a cellular self-catabolism process, which is critical to protect cellular homeostasis against harmful conditions. Emerging evidence suggest that dysregulated autophagy is involved in the development of AS. Therefore, pharmacological interventions have been developed to inhibit the AS via autophagy induction. Among various AS treating methods, herbal medicines and natural products have been applied as effective complementary and alternative medicines to ameliorate AS and its associated cardiovascular disease. Recently, mounting evidence revealed that natural bioactive compounds from herbs and natural products could induce autophagy to suppress the occurrence and development of AS, by promoting cholesterol efflux, reducing plaque inflammation, and inhibiting apoptosis or senescence. In the present review, we highlight recent findings regarding possible effects and molecular mechanism of natural compounds in autophagy-targeted mitigation of atherosclerosis, aiming to provide new potential therapeutic strategies for the atherosclerosis treatment preclinically and clinically.