Background: Intravesical bacillus Calmette-Guérin (BCG) application is widely used in the treatment of superficial bladder carcinoma. Despite being an effective therapy, the pathogenicity and lethal side effects of BCG limits its usage. Intensive research has been carried out to find less toxic and more potent therapeutic agents for the treatment of bladder cancer. Researchers have focused on Mycobacterium phlei as an alternative. The cell wall extract of M. phlei is sufficient for antitumoral activity. Our preliminary experiments indicate that the fractions rich in cell wall proteins cause activation of tumor necrosis factor (TNF)-α and interleukin (IL)-12. This study aims to identify powerful and less harmful mycobacteria among 88 strains in terms of how they stimulate the immune system. Methods: Eighty-eight mycobacterial strains were grown in Middlebrook 7H9 medium. The bacterial cells were sonicated after heat treatment. The supernatants were incubated with the monocytic cell line THP-1, followed by measurement of TNF-α and IL-12 response. Results and Conclusion: In addition to M. phlei, the following 12 mycobacterial strains were selected as candidates for superficial bladder tumor treatment: M. agri, M. aichiense, M. aurum, M. brumae, M. chitae, M. chubuense, M. diernhoferi, M. gadium, M. murale, M. obuense, M. tokaiense and M. vaccae.
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The Hippo pathway, with its core components and the downstream transcriptional coactivators, controls the self-renewable capacity and stemness features of stem cells and serves as a stress response pathway by regulating proliferation, differentiation, and apoptosis. The Hippo pathway interaction with other signaling ways plays a vital role in response to various stress stimuli arising from energy metabolism, hypoxia, reactive oxygen species, and mechanical forces. Depending on the energy levels, the Hippo pathway is regulated by AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), which in turn determines stem cell proliferation (cell survival and growth) and differentiation. Oxidative stress-driven by ROS production also affects the Hippo pathway with transcriptional changes through MST/YAP/FoxO pathway and leads to the activation of pro-apoptotic genes and eventually cell death. HIF1alpha/YAP signaling is critical for the long-term maintenance of mesenchymal stem cells (MSCs) under hypoxia. In this review, we present an overview of stem cell response to stress, including mechanical, hypoxia, metabolic and oxidative stress through the modulation of the Hippo pathway. The biological effects such as autophagy, apoptosis and senescence were discussed in the context of the Hippo pathway in stem cells.
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