Inhibiting cell survival and inducing cell death are the main approaches of tumor therapy. Autophagy plays an important role on intracellular metabolic homeostasis by eliminating dysfunctional or unnecessary proteins and damaged or aged cellular organelles to recycle their constituent metabolites that enable the maintenance of cell survival and genetic stability and even promotes the drug resistance, which severely limits the efficacy of chemotherapeutic drugs. Currently, targeting autophagy has a seemingly contradictory effect to suppress and promote tumor survival, which makes the effect of targeting autophagy on drug resistance more confusing and fuzzier. In the review, we summarize the regulation of autophagy by emerging ways, the action of targeting autophagy on drug resistance and some of the new therapeutic approaches to treat tumor drug resistance by interfering with autophagy-related pathways. The full-scale understanding of the tumor-associated signaling pathways and physiological functions of autophagy will hopefully open new possibilities for the treatment of tumor drug resistance and the improvement in clinical outcomes.

/pdf/targeting-autophagy-to-overcome-drug-resistance-further-34yrrbxm2m.pdf

Targeting autophagy to overcome drug resistance: further developments.

Long-term exposure to crystalline silica particles leads to silicosis characterized by persistent inflammation and progressive fibrosis in the lung. So far, there is no specific treatment to cure the disease other than supportive care. In this study, we examined the effects of metformin, a prescribed drug for type || diabetes on silicosis and explored the possible mechanisms in an established rat silicosis model in vivo, and an in vitro co-cultured model containing human macrophages cells (THP-1) and human bronchial epithelial cells (HBEC). Our results showed that metformin significantly alleviated the inflammation and fibrosis of lung tissues of rats exposed to silica particles. Metformin significantly reduced silica particle-induced inflammatory cytokines including transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in rat lung tissue and HBEC culture supernatant. The protein levels of Vimentin and α-smooth muscle actin (α-SMA) were significantly decreased by metfomin while expression level of E-cadherin (E-Cad) increased. Besides, metformin increased the expression levels of phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase (p-AMPK), microtubule-associated protein (MAP) light chain 3B (LC3B) and Beclin1 proteins, and reduced levels of phosphorylated mammalian target of rapamycin (p-mTOR) and p62 proteins in vivo and in vitro. These results suggest that metformin could inhibit silica-induced pulmonary fibrosis by activating autophagy through the AMPK-mTOR pathway.

/pdf/metformin-attenuates-silica-induced-pulmonary-fibrosis-by-k8cpvdt5k6.pdf

Metformin Attenuates Silica-Induced Pulmonary Fibrosis by Activating Autophagy via the AMPK-mTOR Signaling Pathway.

Silicosis remains one of the most severe pulmonary fibrotic diseases worldwide, caused by chronic exposure to silica dust. In this review, we have proposed that programmed cell death (PCD), including autophagy, apoptosis, and pyroptosis, is closely associated with silicosis progression. Furthermore, some autophagy, apoptosis, or pyroptosis-related signaling pathways or regulatory proteins have also been summarized to contribute greatly to the formation and development of silicosis. In addition, silicosis pathogenesis depends on the crosstalk among these three ways of PCD to a certain extent. In summary, more profound research on these mechanisms and effects may be expected to become promising targets for intervention or therapeutic methods of silicosis in the future.

https://www.mdpi.com/1422-0067/22/15/8110/pdf

The Mechanism and Effect of Autophagy, Apoptosis, and Pyroptosis on the Progression of Silicosis.

Humans are regularly exposed to silica nanoparticles in environmental and occupational contexts, and these exposures have been implicated in the onset of adverse health effects. Existing reviews on silica nanoparticle toxicity are few and not comprehensive. There are natural and synthetic sources by which crystalline and amorphous silica nanoparticles are produced. These processes influence physiochemical properties, which are factors that can dictate toxicological effects. Toxicological assessment includes exposure scenario (e.g. environmental, occupational), route of exposure, toxicokinetics, and toxicodynamics. Broader considerations include pathology, risk assessment, regulation, and treatment after injury. This review aims to consolidate the most relevant and up-to-date research in these areas to provide an exhaustive toxicological profile of silica nanoparticles.

/pdf/a-toxicological-profile-of-silica-nanoparticles-2udl1hce.pdf

A toxicological profile of silica nanoparticles.

Anti-PD-L1 antibody alleviates pulmonary fibrosis by inducing autophagy via inhibition of the PI3K/Akt/mTOR pathway.

Silicosis is a well-acknowledged occupational lung disease caused by inhalation of a large amount of free silica dust during the production period and eventually a considerable negative impact on the patients' quality of life. Autophagy exerts a critical influence on immune and inflammatory responses during the pathogenesis of pulmonary fibrosis. In this study, we sought to determine whether autophagy is involved in silicosis's pathogenesis and how it may affect pulmonary cellular physiology. In the animal experiments, we found persistent activation of autophagy in the development of pulmonary fibrosis, which was also accompanied by tumor necrosis factor and transforming growth factor expression increased. Therefore, the autophagy signaling pathway may regulate the inflammatory response and affect the progression of fibrosis. Further, in vitro experiments, we used LY294002, RAPA, and N-acetylcysteine (NAC) intervened autophagy. Our results showed that PI3K/Akt/mTOR signaling pathway is involved in the autophagy changed mediated by SiO2 exposed, and autophagy might play a protective role in the progression of pulmonary fibrosis. Additionally, NAC's effect is not apparent on SiO2 -mediated autophagy through the PI3K/Akt/mTOR signaling pathway, but it can reduce the inflammatory response on NR8383 cells mediated by SiO2-exposed. Nevertheless, it's interesting that NAC can reduce the inflammatory response on NR8383 cells mediated by SiO2 -exposed. Taken together, our data demonstrated that SiO2 -exposed can induce pulmonary fibrosis along with autophagy both in vivo and in vitro, NAC could alleviate the inflammatory response NR8383 cells by SiO2 -exposed through non PI3K/Akt/mTOR signaling pathway, and the specific mechanism of its action needs further studying.

Silica dust exposure induces pulmonary fibrosis through autophagy signaling.

Silica nanoparticle induces pulmonary fibroblast transdifferentiation via macrophage route: Potential mechanism revealed by proteomic analysis.

Increased deposition of silica dust in pulmonary interstitial tissues leads to silicosis, in which autophagy plays a defensive role in silica dust-associated stress response and cell death. Our previous studies revealed that silica dust exposure contributed to autophagy in pulmonary macrophages in vivo, while the specific regulatory mechanism is still unclear. This study aimed to figure out the regulatory mechanism as well as the role of autophagy in the pathogenesis of experimental silicosis. We used 3-methyladenine (3-MA) and ABT-737 to suppress the expression of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and B cell leukemia/lymphoma 2 (Bcl-2), two critical initiators of autophagy, and detected and evaluated the autophagy in NR8383 cells with or without silica dust exposure. We found that exposure of silica dust increased autophagy in NR8383 cells and elevated the expression of Beclin1 and PIK3C3, but it reduced the expression of Bcl-2. The relationship among Beclin1, PIK3C3, and Bcl-2 were then investigated using immunoprecipitation analysis, and we found that suppression of PIK3C3 and/or Bcl-2 using 3-MA and/or ABT-737 could alter the autophagy induced by silica dust in NR8383 cells, and the complexes of Beclin1/PIK3C3 and Beclin1/Bcl-2 were both downregulated, which may be that inhibition of PIK3C3 and Bcl-2 altered the affinity of Beclin1 with PIK3C3 and Bcl-2 and lead to the silence of PIK3C3 signaling. These findings indicate that silica dust exposure induces autophagy via changing the connectivity of Beclin1 from Bcl-2 to PIK3C3.

Silica dust exposure induces autophagy in alveolar macrophages through switching Beclin1 affinity from Bcl‐2 to PIK3C3

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Silica dust exposure induces pulmonary fibrosis through autophagy signaling.

Silica nanoparticle induces pulmonary fibroblast transdifferentiation via macrophage route: Potential mechanism revealed by proteomic analysis.

Silica dust exposure induces autophagy in alveolar macrophages through switching Beclin1 affinity from Bcl‐2 to PIK3C3