bims-stacyt 2022-03-13 papers

Mini Rev Med Chem. 2022 Mar 09.

The Role of IL-6 Released During Exercise to Insulin Sensitivity and Muscle Hypertrophy.

Álvaro Nóbrega de Melo Madureira, João Ricardhis Saturnino de Oliveira, Vera Lúcia de Menezes Lima.

Interleukin-6 (IL-6) influences both inflammatory response and anti-inflammatory processes. This cytokine can be released by the exercising skeletal muscle, which characterizes it as a myokine. Unlike what is observed in inflammation, IL-6 produced by skeletal muscle is not preceded by the release of other pro-inflammatory cytokines, but is seems to be dependent on the lactate produced during exercise, thus causing different effects from those of seen in inflammatory state. After binding to its receptor, myokine IL-6 activates the PI3K-Akt pathway. One consequence of this upregulation is the potentiation of insulin signaling, which enhances insulin sensitivity. IL-6 increases GLUT-4 vesicle mobilization to muscle cell periphery, increasing the glucose transport into the cell, and also glycogen synthesis. Muscle glycogen provides energy for the ATP resynthesis, and regulates Ca2+ release by the sarcoplasmic reticulum, influencing muscle contraction, and, hence, muscle function by multiple pathways. Another implication for the upregulation of PI3K-Akt pathway is the activation of mTORC1, which regulates mRNA translational efficiency by regulating translation machinery, and translational capacity by inducing ribosomal biogenesis. Thus, IL-6 may contribute for skeletal muscle hypertrophy and function by increasing contractile protein synthesis.

Keywords: Cytokine; TNF-α; diabetes; glucose; glycogen.; hypertrophy

DOI: https://doi.org/10.2174/1389557522666220309161245

Front Immunol. 2022 ;13 821816

Role of Hypoxia in the Interferon Response.

Esther Arnaiz, Adrian L Harris.

In solid tumors, as the tumor grows and the disease progresses, hypoxic regions are often generated, but in contrast to most normal cells which cannot survive under these conditions, tumour cells adapt to hypoxia by HIF-driven mechanisms. Hypoxia can further promote cancer development by generating an immunosuppressive environment within the tumour mass, which allows tumour cells to escape the immune system recognition. This is achieved by recruiting immunosuppressive cells and by upregulating molecules which block immune cell activation. Hypoxia can also confer resistance to antitumor therapies by inducing the expression of membrane proteins that increase drug efflux or by inhibiting the apoptosis of treated cells. In addition, tumor cells require an active interferon (IFN) signalling pathway for the success of many anticancer therapies, such as radiotherapy or chemotherapy. Therefore, hypoxic effects on this pathway needs to be addressed for a successful treatment.

Keywords: IFN; cancer; hypoxia; therapy; type I IFN

DOI: https://doi.org/10.3389/fimmu.2022.821816

Semin Cancer Biol. 2022 Mar 05. pii: S1044-579X(22)00060-8. [Epub ahead of print]

Emerging perspectives on growth factor metabolic relationships in the ovarian cancer ascites environment.

Mehri Monavarian, Amal Elhaw, Priscilla Tang, Zaineb Javed, Zainab Shonibare, Carly Bess Scalise, Rebecca Arend, Mohit Kumar Jolly, Mary Kathryn Sewell-Loftin, Nadine Hempel, Karthikeyan Mythreye.

The ascites ecosystem in ovarian cancer is inhabited by complex cell types and is bathed in an environment rich in cytokines, chemokines, and growth factors that directly and indirectly impact metabolism of cancer cells and tumor associated cells. This milieu of malignant ascites, provides a 'rich' environment for the disease to thrive, contributing to every aspect of advanced ovarian cancer, a devastating gynecological cancer with a significant gap in targeted therapeutics. In this perspective we focus our discussions on the 'acellular' constituents of this liquid malignant tumor microenvironment, and how they influence metabolic pathways. Growth factors, chemokines and cytokines are known modulators of metabolism and have been shown to impact nutrient uptake and metabolic flexibility of tumors, yet few studies have explored how their enrichment in malignant ascites of ovarian cancer patients contributes to the metabolic requirements of ascites-resident cells. We focus here on TGF-βs, VEGF and ILs, which are frequently elevated in ovarian cancer ascites and have all been described to have direct or indirect effects on metabolism, often through gene regulation of metabolic enzymes. We summarize what is known, describe gaps in knowledge, and provide examples from other tumor types to infer potential unexplored roles and mechanisms for ovarian cancer. The distribution and variation in acellular ascites components between patients poses both a challenge and opportunity to further understand how the ascites may contribute to disease heterogeneity. The review also highlights opportunities for studies on ascites-derived factors in regulating the ascites metabolic environment that could act as a unique signature in aiding clinical decisions in the future.

Keywords: Growth factors; TGF-β; VEGF; ascites; metabolism; ovarian cancer

DOI: https://doi.org/10.1016/j.semcancer.2022.03.004

Cells. 2022 Feb 23. pii: 782. [Epub ahead of print]11(5):

Ghrelin Regulates Expression of the Transcription Factor Pax6 in Hypoxic Brain Progenitor Cells and Neurons.

Irina I Stoyanova, Andrii Klymenko, Jeannette Willms, Thorsten R Döppner, Anton B Tonchev, David Lutz.

The nature of brain impairment after hypoxia is complex and recovery harnesses different mechanisms, including neuroprotection and neurogenesis. Experimental evidence suggests that hypoxia may trigger neurogenesis postnatally by influencing the expression of a variety of transcription factors. However, the existing data are controversial. As a proof-of-principle, we subjected cultured cerebral cortex neurons, cerebellar granule neurons and organotypic cerebral cortex slices from rat brains to hypoxia and treated these cultures with the hormone ghrelin, which is well-known for its neuroprotective functions. We found that hypoxia elevated the expression levels and stimulated nuclear translocation of ghrelin's receptor GHSR1 in the cultured neurons and the acute organotypic slices, whereas ghrelin treatment reduced the receptor expression to normoxic levels. GHSR1 expression was also increased in cerebral cortex neurons of mice with induced experimental stroke. Additional quantitative analyses of immunostainings for neuronal proliferation and differentiation markers revealed that hypoxia stimulated the proliferation of neuronal progenitors, whereas ghrelin application during the phase of recovery from hypoxia counteracted these effects. At the mechanistic level, we provide a link between the described post-ischemic phenomena and the expression of the transcription factor Pax6, an important regulator of neural progenitor cell fate. In contrast to the neurogenic niches in the brain where hypoxia is known to increase Pax6 expression, the levels of the transcription factor in cultured hypoxic cerebral cortex cells were downregulated. Moreover, the application of ghrelin to hypoxic neurons normalised the expression levels of these factors. Our findings suggest that ghrelin stimulates neurogenic factors for the protection of neurons in a GHSR1-dependent manner in non-neurogenic brain areas such as the cerebral cortex after exposure to hypoxia.

Keywords: GHSR1; ghrelin; hypoxia; neurogenesis; progenitor cells; transcription factors

DOI: https://doi.org/10.3390/cells11050782

Cell Rep. 2022 Mar 08. pii: S2211-1247(22)00223-6. [Epub ahead of print]38(10): 110490

On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm.

Arwen Conod, Marianna Silvano, Ariel Ruiz I Altaba.

How metastatic cells arise is unclear. Here, we search for the induction of recently characterized pro-metastatic states as a surrogate for the origin of metastasis. Since cell-death-inducing therapies can paradoxically promote metastasis, we ask if such treatments induce pro-metastatic states in human colon cancer cells. We find that post-near-death cells acquire pro-metastatic states (PAMEs) and form distant metastases in vivo. These PAME ("let's go" in Greek) cells exhibit a multifactorial cytokine storm as well as signs of enhanced endoplasmic reticulum (ER) stress and nuclear reprogramming, requiring CXCL8, INSL4, IL32, PERK-CHOP, and NANOG. PAMEs induce neighboring tumor cells to become PAME-induced migratory cells (PIMs): highly migratory cells that re-enact the storm and enhance PAME migration. Metastases are thus proposed to originate from the induction of pro-metastatic states through intrinsic and extrinsic cues in a pro-metastatic tumoral ecosystem, driven by an impending cell-death experience involving ER stress modulation, metastatic reprogramming, and paracrine recruitment via a cytokine storm.

Keywords: ER stress; PAME; apoptosis; colon cancer; cytokine storm; metastasis; metastasis-initiating cells; metastatic reprogramming; primary heterogeneity; regulated cell death

DOI: https://doi.org/10.1016/j.celrep.2022.110490