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Coronavirus disease 2019 (COVID-19) threatens public health all over the world. It is well-accepted that the immune cells in peripheral blood are widely involved in the pathological process of COVID-19. However, hematopoietic stem and progenitor cells (HSPCs), as the main source of peripheral immune cells, have not been well studied during COVID-19 infection. We comprehensively revealed the transcriptome changes of peripheral blood HSPCs after COVID-19 infection and vaccination by single-cell RNA-seq. Compared with healthy individuals, the proportion of HSPCs in COVID-19 patients significantly increased. The increase in the proportion of HSPCs might be partly attributed to the enhancement of the HSPCs proliferation upon COVID-19 infection. However, the stemness damage of HSPCs is reflected by the decrease of differentiation signal, which can be used as a potential specific indicator of the severity and duration of COVID-19 infection. Type I interferon (IFN-I) and translation signals in HSPCs were mostly activated and inhibited after COVID-19 infection, respectively. In addition, the response of COVID-19 vaccination to the body is mild, while the secondary vaccination strengthens the immune response of primary vaccination. In conclusion, our study provides new insights into understanding the immune mechanism of COVID-19 infection.
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COVID-19 , Transcriptoma , Humanos , Vacinas contra COVID-19 , Análise da Expressão Gênica de Célula Única , Células-Tronco HematopoéticasRESUMO
Intestinal stem cells (ISCs) play a crucial role in maintaining intestinal homeostasis upon chemotherapy and radiotherapy. It has been documented that prostaglandin E2 (PGE2) treatment improved hematopoietic stem cell function in vitro and in vivo, while the relationship between PGE2 and intestinal stem cells remains unclear. Presently, mice were exposed to PGE1, dmPGE2 and indomethacin. Numbers and function of ISCs were assessed by analyzing Olfm4+ ISCs. Intestinal protection of dmPGE2 was investigated on a 5-fluorouracil (5FU)-induced intestinal damage mouse model. The results showed that dmPGE2 treatment, but not PGE1, increased numbers of Olfm4+ ISCs in dose- and time-dependent manners. Indomethacin treatment decreased numbers of Olfm4+ ISCs. The beneficial effects of short-term dmPGE2 treatment on intestine were supported in a 5FU-induced intestinal damage model. Our data showed that 5FU treatment significantly decreased numbers of Olfm4+ ISCs and goblet cells in intestine, which could be ameliorated by dmPGE2 treatment. dmPGE2 treatment accelerated the recovery of 5FU-induced ISC injury via increasing expression of cyclin D1 and D2 in intestine. Furthermore, dmPGE2 treatment-induced expression of cyclin D1 and D2 might be mediated by up-regulation of FOXM1 expression in intestine. These findings feature PGE2 as an effective protector against chemotherapy-induced intestinal damage.
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Ciclina D/metabolismo , Dinoprostona/farmacologia , Fluoruracila/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Ciclina D/genética , Humanos , Mucosa Intestinal/lesões , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocitócicos/farmacologia , Células-Tronco/metabolismo , Células-Tronco/patologia , Células Tumorais CultivadasRESUMO
It is well known that exposure of double-stranded RNA (dsRNA) to intestine immediately induces villus damage with severe diarrhea, which is mediated by toll-like receptor 3 signaling activation. However, the role of intestinal stem cells (ISCs) remains obscure during the pathology. In the present study, polyinosinic-polycytidylic acid (poly[I:C]), mimicking viral dsRNA, was used to establish intestinal damage model. Mice were acutely and chronically exposed to poly(I:C), and ISCs in jejunum were analyzed. The results showed that the height of villus was shorter 48 hr after acute poly(I:C) exposure compared with that of controls, while chronic poly(I:C) treatment increased both villus height and crypt depth in jejunum compared with control animals. The numbers of ISCs in jejunum were significantly increased after acute and chronic poly(I:C) exposure. Poly (I:C)-stimulated ISCs have stronger capacities to differentiate into intestine endocrine cells. Mechanistically, poly(I:C) treatment increased expression of Stat1 and Axin2 in the intestinal crypt, which was along with increased expression of Myc, Bcl2, and ISC proliferation. These findings suggest that dsRNA exposure could induce ISC proliferation to ameliorate dsRNA-induced intestinal injury.
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Mucosa Intestinal/crescimento & desenvolvimento , Poli I-C/farmacologia , Proteínas Proto-Oncogênicas c-myc/genética , Células-Tronco/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteína Axina/genética , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Jejuno/efeitos dos fármacos , Jejuno/crescimento & desenvolvimento , Camundongos , RNA de Cadeia Dupla/efeitos dos fármacos , Fator de Transcrição STAT1/genética , Transdução de Sinais , Receptor 3 Toll-Like/genéticaRESUMO
Upregulation of histone acetylation plays a critical role in the dysregulation of transcription. It alters the structure of chromatin, which leads to the onset of cancer. Histone deacetylase inhibitors may therefore be a promising way to limit cancer progression. In this study, we examined the effects of droxinostat on the growth of HT-29 colon cancer cells. Our results show that droxinostat effectively inhibited cell growth and colony-forming ability by inducing cellular apoptosis and ROS production in HT-29 cells. Notably, the apoptotic inhibitor Z-VAD-FMK significantly decreased the levels of cellular apoptosis and the antioxidant γ-tocotrienol (GT3) significantly decreased ROS production induced by droxinostat treatment. Z-VAD-FMK and GT3 also partially reversed the negative growth effects of droxinstat on HT-29 cells. GT3 treatment decreased cellular apoptosis and increased colony-forming ability upon droxinostat administration. Z-VAD-FMK treatment also partially decreased droxinostat-induced ROS production. Our findings suggest that the effects of droxinostat on colon cancer cells are mediated by the induction of oxidative stress and apoptotic cell death.
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Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Clorometilcetonas de Aminoácidos/farmacologia , Neoplasias do Colo/metabolismo , Células HT29 , Humanos , Espécies Reativas de Oxigênio/metabolismoRESUMO
With the continuous development of nuclear technology, the radiation exposure caused by radiation therapy is a serious health hazard. It is of great significance to further develop effective radiation countermeasures. B cells easily succumb to irradiation exposure along with immunosuppressive response. The approach to ameliorate radiation-induced B cell damage is rarely studied, implying that the underlying mechanisms of B cell damage after exposure are eager to be revealed. Recent studies suggest that Notch signaling plays an important role in B cell-mediated immune response. Notch signaling is a critical regulator for B cells to maintain immune function. Although accumulating studies reported that Notch signaling contributes to the functionality of hematopoietic stem cells and T cells, its role in B cells is scarcely appreciated. Presently, we discussed the regulation of Notch signaling on B cells under radiation exposure to provide a scientific basis to prevent radiation-induced B cell damage.
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Fenômenos Biológicos , Exposição à Radiação , Diferenciação Celular/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Physical, chemical, and biological factors in the environment constantly influence in vivo and in vitro biological processes, including diverse histone modifications involved in cancer and metabolism. However, the intricate mechanisms of acetylation regulation remain poorly elucidated. In mammalian spermatogenesis, acetylation plays a crucial role in repairing double-strand DNA breaks, regulating gene transcription, and modulating various signaling pathways. RESULTS: This review summarizes the histone acetylation sites in the mouse testis and provides a comprehensive overview of how histone acetylation is involved in different stages of spermatogenesis under the regulation by histone deacetylases. The regulatory functions of various class histone deacetylases during spermatogenesis and the crossroad between histone acetylation and other histone modifications are highlighted. It is imperative to understand the mechanisms of histone acetylation regulated by histone deacetylases in spermatogenesis, which facilitates to prevent and treat infertility-related diseases.
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BACKGROUND AND PURPOSE: Damage to the testis following exposure to ionizing radiation has become an urgent problem to be solved. Here we have investigated if inhibition of p38 mitogen-activated protein kinase (p38MAPK) signalling could alleviate radiation-induced testicular damage. EXPERIMENTAL APPROACH: In mice exposed to whole body radiation (2-6 Gy), morphological changes of the epididymis and testis was measured by histochemical staining. immunohistochemical and immunofluorescence procedures and western blotting were used to monitor expression and cellular location of proteins. Expression of genes was assessed by qPCR and RNA-Seq was used to profile gene expression. KEY RESULTS: Exposure to ionizing radiation induced dose-dependent damage to mouse testis. The sperm quality decreased at 6 and 8 weeks after 6 Gy X-ray radiation. Radiation decreased PLZF+ cells and increased SOX9+ cells, and affected the expression of 969 genes, compared with data from non-irradiated mice. Expression of genes related to p38MAPK were enriched by GO analysis and were increased in the irradiated testis, and confirmed by qPCR. Levels of phospho-p38MAPK protein increased at 28 days after irradiation. In irradiated mice, SB203580 treatment increased spermatozoa, SOX9+ cells, the area and diameter of seminiferous tubules, sperm movement rate and density. Furthermore, SB203580 treatment increased SCP3+ cells, accelerating the process of spermatogenesis. CONCLUSION AND IMPLICATIONS: Exposure to ionizing radiation clearly changed gene expression in mouse testis, involving activation of p38MAPK signalling pathways. Inhibition of p38MAPK by SB203580 partly alleviated the testicular damage caused by radiation and accelerated the recovery of sperms through promoting spermatogenesis.
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Sêmen , Testículo , Masculino , Camundongos , Animais , Testículo/anatomia & histologia , Testículo/metabolismo , Espermatogênese/efeitos da radiação , Espermatozoides/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Leptin, an adipocytokine produced mainly by white adipose tissue, has a broad role in the regulation of neuronal functions. Accumulating evidence has revealed that leptin plays an important role in influencing neuropathic pain, shown recently by the finding that chronic administration of leptin induced thermal hyperalgesia and mechanical allodynia in naïve rats. Chronic constriction sciatic nerve injury (CCI) is a well characterized model used for studying neuropathic pain. The present study was designed to investigate whether leptin plays a role in neuropathic pain in rats induced by CCI by examining particular pain behaviors. RESULTS: After sciatic nerve injury in rats, endogenous levels of leptin and leptin receptor (OB-Rb) were increased in a time dependent manner within the ipsilateral dorsal root ganglion (DRG). Intrathecal administration of leptin once daily for 6 days, beginning 7 days after CCI, alleviated neuropathic pain and decreased the expression of IL-6, TNFα, and the P2X2 and P2X3 receptors. Attenuation of endogenous OB-Rb in the DRG by intrathecal administration of OB-Rb antisense oligonucleotides did not change thermal hyperalgesia or mechanical allodynia induced by CCI. CONCLUSIONS: Our findings suggest that exogenous leptin can alleviate the chronic neuropathic pain caused by CCI. The leptin effect may be mediated by attenuated expression of IL-6, TNFα, and the P2X2 and P2X3 receptors in the DRG of CCI rats.
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Leptina/farmacologia , Leptina/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/metabolismo , Receptores Purinérgicos P2X2/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X2/genética , Receptores Purinérgicos P2X3/genéticaRESUMO
Energy is becoming more and more important in the process of development. Through cluster analysis, 30 provinces chosen from the Chinese mainland are divided into high, medium, and low energy consumption regions, and the Theil index is used to analyze the characteristics of total energy consumption and other characteristics of regional differences. Based on this, an enhanced Panel-STIRPAT model is constructed. Through data and model inspection, panel models suitable for each region are selected for comprehensive analysis. The results show that: there are regional differences in energy consumption in China, and the total regional differences mainly come from within each region. The factors affecting energy consumption in different regions are the same, but due to differences in geographical environment and stress levels, the influence of these factors on energy consumption in different regions is different. Based on this, reasonable measurements to control energy consumption in different regions are presented.
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Conservação de Recursos Energéticos , ChinaRESUMO
OBJECTIVE: To explore the chronic injury and its possible mechanism of ionizing radiation on multipotent hematopoietic progenitor cells (MPPs) by determining the related indicators of MPPs in bone marrow of mice post-radiation. METHODS: Sixteen C57BL/6 adult mice were randomly divided into normal control and irradiation groups, 8 mice in each group. The mice in irradiation group were exposed to 6 Gy X-ray. The proportion of bone marrow MPPs, their apoptosis and proliferation 2 months after irradiation were detected by flow cytometry. Mitochondrial activity and levels of reactive oxygen species (ROS) in each MPPs population were detected by Mitotracker Red and DCFDA probes, and the senescent state of MPPs in the bone marrow was analyzed. RESULTS: Ionizing radiation could reduce the proportion of MPPs in mouse bone marrow. The proportions and numbers of MPP1, MPP3 and MPP4 in the bone marrow were significantly decreased after whole-body irradiation with 6 Gy X-ray (P<0.05). In addition, radiation significantly reduced the colony-forming capacity of MPPs in bone marrow (P<0.05), the proportions of apoptotic cells in the MPP1 and MPP4 cell populations increased significantly in the bone marrow (P<0.05). The activity of mitochondria was significantly reduced in the bone marrow MPP2, MPP3 and MPP4 cell populations compared with that of the control group (P<0.05). It was also found that the radiation could significantly increase the ROS levels of MPPs in bone marrow, and the content of ROS in the MPP2, MPP3 and MPP4 cell population of the bone marrow was significantly increased(P<0.05). The senescent cells ratios of MPP1, MPP3 and MPP4 cells in the bone marrow after irradiation were significantly higher than those in the control group (P<0.05). CONCLUSION: Ionizing radiation can cause chronic MPPs damage in mice, which is closely associated with persistent oxidative stress, cells apoptosis, and cellular senescence.
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Medula Óssea , Células-Tronco Hematopoéticas , Camundongos , Animais , Espécies Reativas de Oxigênio , Camundongos Endogâmicos C57BL , Irradiação Corporal Total , Radiação Ionizante , Células da Medula ÓsseaRESUMO
Male infertility is an important problem in human and animal reproduction. The testis is the core of male reproduction, which is very sensitive to radiation. The decline of male reproductive ability is a common trend in the world. Radiation is a physical factor leading to abnormal male reproductive function. To investigate the potential mechanisms of testicular damage induced by radiation and explore effective strategies to alleviate radiation-induced testis injury, C57BL/6 mice were irradiated with 8.0 Gy of X-ray irradiation. Testis and epididymis were collected at days 1, 3, and 7 after radiation exposure to analyze spermatogonia and sperm function. The results showed that radiation significantly destroyed testicular structure and reduced the numbers of spermatogonia. These were associated with mTORC1 signaling activation, decreased cellular proliferation and increased apoptotic cells in the irradiated testis. Rapamycin significantly blocked mTORC1 signaling pathway in the irradiated testis. Inhibition of mTORC1 signaling pathway by rapamycin treatment after radiation could significantly improve cell proliferation in testis and alleviate radiation-induced testicular injury after radiation exposure. Rapamycin treatment benefited cell survival in testis to maintain spermatogenesis cycle at 35 days after irradiation. These findings imply that rapamycin treatment can accelerate testis recovery under radiation condition through inhibiting mTORC1 signaling pathway.
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Pseudotrophic muscular dystrophy is a common clinical skeletal muscle necrotic disease, among which Duchenne muscular dystrophy (DMD) is the predominant. For such diseases, there is no clinically effective treatment, which is only symptomatic or palliative treatment. Oxidative stress and chronic inflammation are common pathological features of DMD. In recent years, it has been found that the pathophysiological changes of skeletal muscle in DMD mice are related to muscle stem cell failure. In the present study, we established a DMD mice model and provided tocotrienol (γ-tocotrienol, GT3), an antioxidant compound, to explore the relationship between the physiological state of muscle stem cells and oxidative stress. The results showed that the application of GT3 can reduce ROS production and cellular proliferation in the muscle stem cells of DMD mice, which is beneficial to promote the recovery of muscle stem cell function in DMD mice. GT3 treatment improved the differentiation ability of muscle stem cells in DMD mice with increasing numbers of MyoD+ cells. GT3 application significantly decreased percentages of CD45+ cells and PDGFRα+ fibro-adipogenic progenitors in the tibialis anterior of DMD mice, indicating that the increased inflammation and fibro-adipogenic progenitors were attenuated in GT3-treated DMD mice. These data suggest that increased ROS production causes dysfunctional muscle stem cell in DMD mice, which might provide a new avenue to treat DMD patients in the clinic.
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Intestine is composed of various types of cells including absorptive epithelial cells, goblet cells, endocrine cells, Paneth cells, immunological cells, and so on, which play digestion, absorption, neuroendocrine, immunological function. Intestine is innervated with extrinsic autonomic nerves and intrinsic enteric nerves. The neurotransmitters and counterpart receptors are widely distributed in the different intestinal cells. Intestinal autonomic nerve system includes sympathetic and parasympathetic nervous systems, which regulate cellular proliferation and function in intestine under physiological and pathophysiological conditions. Presently, distribution and functional characteristics of autonomic nervous system in intestine were reviewed. How autonomic nervous system regulates intestinal cell proliferation was discussed. Function of autonomic nervous system on intestinal diseases was extensively reviewed. It might be helpful to properly manipulate autonomic nervous system during treating different intestinal diseases.
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Senescent cells with replicative arrest can be generated during genotoxic, oxidative, and oncogenic stress. Long-term retention of senescent cells in the body, which is attributed to highly expressed BCL-family proteins, chronically damages tissues mainly through a senescence-associated secretory phenotype (SASP). It has been documented that accumulation of senescent cells contributes to chronic diseases and aging-related diseases. Despite the fact that no unique marker is available to identify senescent cells, increased p16INK4a expression has long been used as an in vitro and in vivo marker of senescent cells. We reviewed five existing p16INK4a reporter mouse models to detect, isolate, and deplete senescent cells. Senescent cells express high levels of anti-apoptotic and pro-apoptotic genes compared to normal cells. Thus, disrupting the balance between anti-apoptotic and pro-apoptotic gene expression, such as ABT-263 and ABT-737, can activate the apoptotic signaling pathway and remove senescent cells. Mitochondrial abnormalities in senescent cells were also discussed, for example mitochondrial DNA mutation accumulation, dysfunctional mitophagy, and mitochondrial unfolded protein response (mtUPR). The mitochondrial-targeted tamoxifen, MitoTam, can efficiently remove senescent cells due to its inhibition of respiratory complex I and low expression of adenine nucleotide translocase-2 (ANT2) in senescent cells. Therefore, senescent cells can be removed by various strategies, which delays chronic and aging-related diseases and enhances lifespan and healthy conditions in the body.
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Development of hematopoietic stem cells is a complex process, which has been extensively investigated. Hematopoietic stem cells (HSCs) in mouse fetal liver are highly expanded to prepare for mobilization of HSCs into the fetal bone marrow. It is not completely known how the fetal liver niche regulates HSC expansion without loss of self-renewal ability. We reviewed current progress about the effects of fetal liver niche, chemokine, cytokine, and signaling pathways on HSC self-renewal, proliferation, and expansion. We discussed the molecular regulations of fetal HSC expansion in mouse and zebrafish. It is also unknown how HSCs from the fetal liver mobilize, circulate, and reside into the fetal bone marrow niche. We reviewed how extrinsic and intrinsic factors regulate mobilization of fetal liver HSCs into the fetal bone marrow, which provides tools to improve HSC engraftment efficiency during HSC transplantation. Understanding the regulation of fetal liver HSC mobilization into the fetal bone marrow will help us to design proper clinical therapeutic protocol for disease treatment like leukemia during pregnancy. We prospect that fetal cells, including hepatocytes and endothelial and hematopoietic cells, might regulate fetal liver HSC expansion. Components from vascular endothelial cells and bones might also modulate the lodging of fetal liver HSCs into the bone marrow. The current review holds great potential to deeply understand the molecular regulations of HSCs in the fetal liver and bone marrow in mammals, which will be helpful to efficiently expand HSCs in vitro.
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BACKGROUND AND PURPOSE: Damage to intestinal epithelial cells and mucosa limits the effectiveness of several anti-cancer chemotherapeutic agents but the underlying mechanism (s) remain unknown. Little is known of how enteric nervous system regulates proliferation, differentiation, impairment, and regeneration of intestinal stem cells. Here we have investigated the effects of isoprenaline on the damaged intestinal stem cells induced by chemotherapeutic treatments in mice. EXPERIMENTAL APPROACH: The effects of inhibiting sympathetic and parasympathetic nerves on intestinal stem cells were examined in male C57BL/6J mice. Protection by isoprenaline of intestinal stem cells was assessed in the presence or absence of 5-fluorouracil (5FU) or cisplatin. Cellular apoptosis, cell cycle, PI3K/Akt signalling, and NF-κB signalling in intestinal stem cells were mechanistically evaluated. KEY RESULTS: The sympathetic nerve inhibitor 6-OHDA decreased the number and function of intestinal stem cells. 5FU or cisplatin treatment damaged both intestinal stem cells and sympathetic nerves. Notably, isoprenaline accelerated the recovery of intestinal stem cells after 5FU or cisplatin treatment. This protective effect of isoprenaline on damaged intestinal stem cells was mediated by ß2 -adrenoceptors. The benefits of isoprenaline were mainly mediated by inhibiting cellular apoptosis induced by 5FU treatment, which might contribute to fine-tuning regulating NF-κB signalling pathway by isoprenaline administration. CONCLUSIONS AND IMPLICATIONS: Treatment with isoprenaline is a new approach to ameliorate the damage to intestinal stem cells following exposure to cancer chemotherapeutic agents.
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Antineoplásicos , Fosfatidilinositol 3-Quinases , Animais , Antineoplásicos/toxicidade , Apoptose , Mucosa Intestinal , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células-TroncoRESUMO
Recurrent liver cancer after surgery is often treated with radiotherapy, which induces liver damage. It has been documented that activation of the TGF-ß and NF-κB signaling pathways plays important roles in irradiation-induced liver pathologies. However, the significance of mTOR signaling remains undefined after irradiation exposure. In the present study, we investigated the effects of inhibiting mTORC1 signaling on irradiated livers. Male C57BL/6J mice were acutely exposed to 8.0 Gy of X-ray total body irradiation and subsequently treated with rapamycin. The effects of rapamycin treatment on irradiated livers were examined at days 1, 3, and 7 after exposure. The results showed that 8.0 Gy of irradiation resulted in hepatocyte edema, hemorrhage, and sinusoidal congestion along with a decrease of ALB expression. Exposure of mice to irradiation significantly activated the mTORC1 signaling pathway determined by pS6 and p-mTOR expression via western blot and immunostaining. Transient inhibition of mTORC1 signaling by rapamycin treatment consistently accelerated liver recovery from irradiation, which was evidenced by decreasing sinusoidal congestion and increasing ALB expression after irradiation. The protective role of rapamycin on irradiated livers might be mediated by decreasing cellular apoptosis and increasing autophagy. These data suggest that transient inhibition of mTORC1 signaling by rapamycin protects livers against irradiation-induced damage.
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Background: The mechanisms underlying low intensity ultrasound (LIUS) mediated suppression of inflammation and tumorigenesis remain poorly determined. Methods: We used microarray datasets from NCBI GEO Dataset databases and conducted a comprehensive data mining analyses, where we studied the gene expression of 299 cell death regulators that regulate 13 different cell death types (cell death regulatome) in cells treated with LIUS. Results: We made the following findings: (1) LIUS exerts a profound effect on the expression of cell death regulatome in cancer cells and non-cancer cells. Of note, LIUS has the tendency to downregulate the gene expression of cell death regulators in non-cancer cells. Most of the cell death regulator genes downregulated by LIUS in non-cancer cells are responsible for mediating inflammatory signaling pathways; (2) LIUS activates different cell death transcription factors in cancer and non-cancer cells. Transcription factors TP-53 and SRF- were induced by LIUS exposure in cancer cells and non-cancer cells, respectively; (3) As two well-accepted mechanisms of LIUS, mild hyperthermia and oscillatory shear stress induce changes in the expression of cell death regulators, therefore, may be responsible for inducing LIUS mediated changes in gene expression patterns of cell death regulators in cells; (4) LIUS exposure may change the redox status of the cells. LIUS may induce more of antioxidant effects in non-cancer cells compared to cancer cells; and (5) The genes modulated by LIUS in cancer cells have distinct chromatin long range interaction (CLRI) patterns to that of non-cancer cells. Conclusions: Our analysis suggests novel molecular mechanisms that may be utilized by LIUS to induce tumor suppression and inflammation inhibition. Our findings may lead to development of new treatment protocols for cancers and chronic inflammation.
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BACKGROUND: Irradiation-induced kidney damage is inevitable during radiotherapeutic practice, which limits effective radiotherapy doses on tumor treatment. In the present study, the role of mTOR complex 1 (mTORC1) signaling was investigated in irradiation-induced renal injuries. METHODS: Mice were exposed to 8.0-Gy X-ray of total body irradiation and subsequently treated with rapamycin. Changes of renal morphology were assessed by hematoxylin and eosin staining. Expression of pS6 and CD133 was detected via immunostaining. Cellular apoptosis and proliferation were measured by TUNEL, caspase-3 and BrdU staining. Activation of mTORC1, TGF-ß and NF-κB signaling pathways was determined through western blot analysis. RESULTS: Our data displayed that irradiation disrupted the structures of renal corpuscles and tubules and decreased the density of CD133+ renal stem-like cells, which were related with increasing cellular apoptosis and decreasing cell proliferation post exposure. Activation of mTORC1, TGF-ß and NF-κB signaling pathways was determined in irradiated renal tissues, which were inhibited by rapamycin treatment. Application of rapamycin after irradiation decreased cellular apoptosis and increased autophagy and cell proliferation in renal tissues. The density of CD133+ renal stem-like cells was significantly increased in irradiated kidneys after rapamycin treatment. The morphology of irradiated renal corpuscles and tubules was gradually recovered upon rapamycin treatment. CONCLUSIONS: These findings indicate that inhibition of mTORC1 signaling by rapamycin ameliorates irradiation-induced renal toxicity mediated by decreasing cellular apoptosis and increasing CD133+ renal stem-like cells.
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Rim/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Células-Tronco/metabolismo , Animais , Apoptose , Humanos , Masculino , Camundongos , Transdução de SinaisRESUMO
Under inflammatory conditions, inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS) which cause DNA damage. If not appropriately repaired, DNA damage leads to gene mutations and genomic instability. DNA damage checkpoint factors (DDCF) and DNA damage repair factors (DDRF) play a vital role in maintaining genomic integrity. However, how DDCFs and DDRFs are modulated under physiological and pathological conditions are not fully known. We took an experimental database analysis to determine the expression of 26 DNA DDCFs and 42 DNA DDRFs in 21 human and 20 mouse tissues in physiological/pathological conditions. We made the following significant findings: (1) Few DDCFs and DDRFs are ubiquitously expressed in tissues while many are differentially regulated.; (2) the expression of DDCFs and DDRFs are modulated not only in cancers but also in sterile inflammatory disorders and metabolic diseases; (3) tissue methylation status, pro-inflammatory cytokines, hypoxia regulating factors and tissue angiogenic potential can determine the expression of DDCFs and DDRFs; (4) intracellular organelles can transmit the stress signals to the nucleus, which may modulate the cell death by regulating the DDCF and DDRF expression. Our results shows that sterile inflammatory disorders and cancers increase genomic instability, therefore can be classified as pathologies with a high genomic risk. We also propose a new concept that as parts of cellular sensor cross-talking network, DNA checkpoint and repair factors serve as nuclear sensors for intracellular organelle stresses. Further, this work would lead to identification of novel therapeutic targets and new biomarkers for diagnosis and prognosis of metabolic diseases, inflammation, tissue damage and cancers.