Activation of endoplasmic reticulum stress response following trauma-hemorrhage

Jian, Bixi; Hsieh, Chieh; Chen, Jianguo; Choudhry, Mashkoor A.; Bland, Kirby I.; Chaudry, Irshad H.; Raju, Raghavan

doi:10.1016/j.bbadis.2008.08.007

Cited by 53 publications

(55 citation statements)

References 53 publications

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“…These functional correlates might explain age-dependent effect of T-H on contractility and relaxation. Additionally, our experiments demonstrated enhanced endoplasmic reticulum (ER) stress in metabolically active organs following T-H (20,42). Previous studies have successfully demonstrated the usefulness of focused microarrays in profiling mitochondrial gene expression (11,43,44).…”

Section: Discussionmentioning

confidence: 93%

“…The upregulation of c-Myc was consistent with the observed decreased expression of genes negatively regulated by c-Myc (Cpt1 [-2.3-fold] and Gpam [-2.1-fold]). The critical function of c-Myc in regulating cardiac energy metabolism during stress and its marked upregulation after T-H in both age groups give substantial credence to its significance in energy balance in response to T-H injury and ensuing cell death (20).…”

Section: Discussionmentioning

confidence: 99%

“…Protein expression of c-myc, Bnip3 and Pgc1-α were analyzed by Western blot as described (20). Briefly, total proteins in tissue lysates were resolved using 4% to 12% Nupage gel (Invitrogen, Carlsbad, CA, USA) and transferred to PVDF membranes.…”

Section: Western Blotmentioning

confidence: 99%

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Aging Influences Cardiac Mitochondrial Gene Expression and Cardiovascular Function following Hemorrhage Injury

Jian

Yang

Chen

et al. 2010

Mol Med

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Cardiac dysfunction and mortality associated with trauma and sepsis increase with age. Mitochondria play a critical role in the energy demand of cardiac muscles, and thereby on the function of the heart. Specific molecular pathways responsible for mitochondrial functional alterations after injury in relation to aging are largely unknown. To further investigate this, 6-and 22-monthold rats were subjected to trauma-hemorrhage (T-H) or sham operation and euthanized following resuscitation. Left ventricular tissue was profiled using our custom rodent mitochondrial gene chip (RoMitochip). Our experiments demonstrated a declined left ventricular performance and decreased alteration in mitochondrial gene expression with age following T-H and we have identified c-Myc, a pleotropic transcription factor, to be the most upregulated gene in 6-and 22-month-old rats after T-H. Following T-H, while 142 probe sets were altered significantly (39 up and 103 down) in 6-month-old rats, only 66 were altered (30 up and 36 down) in 22-month-old rats; 36 probe sets (11 up and 25 down) showed the same trend in both groups. The expression of c-Myc and cardiac death promoting gene Bnip3 were increased, and Pgc1-α and Ppar-α a decreased following T-H. Eleven tRNA transcripts on mtDNA were upregulated following T-H in the aged animals, compared with the sham group. Our observations suggest a cmyc-regulated mitochondrial dysfunction following T-H injury and marked decrease in age-dependent changes in the transcriptional profile of mitochondrial genes following T-H, possibly indicating cellular senescence. To our knowledge, this is the first report on mitochondrial gene expression profile following T-H in relation to aging.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Aging Influences Cardiac Mitochondrial Gene Expression and Cardiovascular Function following Hemorrhage Injury

Jian

Yang

Chen

et al. 2010

Mol Med

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“…Severe hemorrhage is known to cause whole body hypoxia, and reoxygenation induces oxidative injury. In the animal model of T-H, activation of endoplasmic reticulum stress, mitochondrial dysfunction and a proinflammatory response have been reported (9,29,30,(34)(35)(36)(37). Severe hemorrhage can result in systemic inflammatory response and multiple organ dysfunction leading to death (8).…”

Section: Discussionmentioning

confidence: 99%

“…Western Blot was carried out as described (30). Briefly, total proteins from tissue lysates, nuclear extracts or cytosolic fractions were resolved using 4%-12% Nupage gel (Invitrogen, Carlsbad, CA, USA) and transferred to polyvinylidene difluoride membranes.…”

Section: Western Blotmentioning

confidence: 99%

Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1

Jian

Yang

Chaudry

et al. 2011

Mol Med

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Mitochondria play a critical role in metabolic homeostasis of a cell. Our recent studies, based on the reported interrelationship between c-Myc and Sirt1 (mammalian orthologue of yeast sir2 [silent information regulator 2]) expression and their role in mitochondrial biogenesis and function, demonstrated a significant downregulation of Sirt1 protein expression and an upregulation of c-Myc following trauma-hemorrhage (T-H). Activators of Sirt1 are known to improve mitochondrial function and the naturally occurring polyphenol resveratrol (RSV) has been shown to significantly increase Sirt1 activity by increasing its affinity to both NAD+ and the acetylated substrate. In this study we tested the salutary effect of RSV following T-H and its influence on Sirt1 expression. Rats were subjected to T-H or sham operation. RSV (8 mg/kg body weight, intravenously) or vehicle was administered 10 min after the onset of resuscitation, and the rats were killed 2 h following resuscitation. Sirtinol, a Sirt1 inhibitor, was administered 5 min prior to RSV administration. Cardiac contractility (±dP/dt) was measured and heart tissue was tested for Sirt1, Pgc-1α, c-Myc, cytosolic cytochrome C expression and ATP level. Left ventricular function, after T-H, was improved (P < 0.05) following RSV treatment, with significantly elevated expression of Sirt1 (P < 0.05) and Pgc-1α (P < 0.05), and decreased c-Myc (P < 0.05). We also observed significantly higher cardiac ATP content, declined cytosolic cytochrome C and decreased plasma tumor necrosis factor-α in the T-H-RSV group. The salutary effect due to RSV was abolished by sirtinol, indicating a Sirt1-mediated effect. We conclude that RSV may be a useful adjunct to resuscitation fluid following T-H.

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The pathogenesis and potential therapeutic targets in sepsis

Zhang,

Jiang,

et al. 2023

MedComm

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Sepsis is defined as “a life‐threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection.” At present, sepsis continues to pose a grave healthcare concern worldwide. Despite the use of supportive measures in treating traditional sepsis, such as intravenous fluids, vasoactive substances, and oxygen plus antibiotics to eradicate harmful pathogens, there is an ongoing increase in both the morbidity and mortality associated with sepsis during clinical interventions. Therefore, it is urgent to design specific pharmacologic agents for the treatment of sepsis and convert them into a novel targeted treatment strategy. Herein, we provide an overview of the molecular mechanisms that may be involved in sepsis, such as the inflammatory response, immune dysfunction, complement deactivation, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we highlight important targets involved in sepsis‐related regulatory mechanisms, including GSDMD, HMGB1, STING, and SQSTM1, among others. We summarize the latest advancements in potential therapeutic drugs that specifically target these signaling pathways and paramount targets, covering both preclinical studies and clinical trials. In addition, this review provides a detailed description of the crosstalk and function between signaling pathways and vital targets, which provides more opportunities for the clinical development of new treatments for sepsis.

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Activation of endoplasmic reticulum stress response following trauma-hemorrhage

Cited by 53 publications

References 53 publications

Aging Influences Cardiac Mitochondrial Gene Expression and Cardiovascular Function following Hemorrhage Injury

Aging Influences Cardiac Mitochondrial Gene Expression and Cardiovascular Function following Hemorrhage Injury

Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1

The pathogenesis and potential therapeutic targets in sepsis

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