Topical Neck Cooling Prolongs Survival of Rats with Intra-Abdominal Feculent Sepsis by Activation of the Vagus Nerve

Global hypothermia prolongs survival in rats with intraabdominal feculent sepsis by inhibiting inflammatory responses. We hypothesized that topical neck cooling (TNC) has similar benefits. Septic shock was induced by cecal ligation and incision (CLI) in Sprague Dawley rats. Rats were randomized to sham laparotomy, control with CLI, CLI with TNC, or vagotomy at the gastroesophageal junction before CLI and TNC. Two more groups underwent peritoneal washout with and without TNC two hours after CLI. TNC significantly lowered neck skin temperature (16.7 ± 1.4 vs. 30.5 ± 0.6 °C, p < 0.05) while maintaining core body normothermia. TNC rats recovered from anesthesia 70 min earlier than the control (p < 0.05). Three hours following CLI, the control and vagotomy with TNC groups had significantly more splenic contraction, fewer circulating leukocytes and higher plasma IL-1β, IL-10 and TNF-α levels than TNC rats (p < 0.05). TNC prolonged survival duration after CLI by a median of four hours vs. control (p < 0.05), but no benefit was seen if vagotomy preceded TNC. Peritoneal washout alone increased survival by 3 h (9.2 (7.8–10.5) h). Survival duration increased dramatically with TNC preceding washout, to a 56% survival rate (>10 days). TNC significantly prolonged the survival of rats with severe intraabdominal sepsis by inhibiting systemic proinflammatory responses by activating vagal anti-inflammatory pathways.

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THERAPEUTIC PROFILING OF NANO ENCAPSULATED DIOSGENIN VIA ATTENUATING HORMONAL STATUS, CELL PROLIFERATION, INFLAMMATORY RESPONSES, AND APOPTOSIS IN AN ANIMAL MODEL OF MAMMARY ONCOGENESIS

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2021v13i6.42777 ◽

2021 ◽

pp. 126-132

Author(s):

MANOBHARATHI VENGAIMARAN ◽

KALAIYARASI DHAMODHARAN ◽

MIRUNALINI SANKARAN

Keyword(s):

Cell Proliferation ◽

Molecular Docking ◽

Cyclin D1 ◽

Inflammatory Responses ◽

Chitosan Nanoparticles ◽

Hormonal Status ◽

Sprague Dawley ◽

Therapeutic Impact ◽

Sprague Dawley Rats ◽

Tnf Α

Objective: The central motive of this study is to explore the therapeutic impact of Diosgenin encapsulated Chitosan nanoparticles (DG@CS-NP) on mammary carcinogenesis in female Sprague Dawley rats via modulating hormonal status, cell proliferation, inflammatory responses, and Apoptosis. Methods: 7,12-dimethylbenz(a)anthracene (DMBA) was administered subcutaneously near the mammary gland (25 mg/kg b. wt) to provoke mammary tumor in female Sprague Dawley rats. Following the progress of a tumor, DMBA-induced tumor-bearing rats were medicated orally with 5 mg/kg b. wt of DG@CS-NP. Consequently, the expression of ER, PR, PCNA, Cyclin D1, NF-κB, TNF-α, Bcl-2, Caspases-3, and p53 in experimental rats were revealed via architectural immunohistochemistry. Further, Diosgenin interactions with these proteins were evidently confirmed by molecular docking analysis. Results: As a result, we noticed diminished levels of ER, PR, PCNA, Cyclin D1, NF-κB, TNF-α, and Bcl-2 expressions in DG@CS-NP medicated rats as well as with elevated levels of Caspases-3 and p53 expressions. In DMBA rats, the expressions were vice versa. Additionally, molecular docking analyses support these outcomes by highlighting the strong interaction between Diosgenin and breast cancer targets. Conclusion: These reports prove that DG@CS-NP imposes its therapeutic impact by hormonal adjustments, downregulating proteins involved in inflammation and cellular proliferation, and thereby promotes apoptosis by impeding apoptotic inhibitors.

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Comparison of direct and indirect models of early induced acute lung injury

Intensive Care Medicine Experimental ◽

10.1186/s40635-020-00350-y ◽

2020 ◽

Vol 8 (S1) ◽

Author(s):

Laura Chimenti ◽

Luis Morales-Quinteros ◽

Ferranda Puig ◽

Marta Camprubi-Rimblas ◽

Raquel Guillamat-Prats ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Acute Phase ◽

Cecal Ligation ◽

Sprague Dawley ◽

Acid Aspiration ◽

Sprague Dawley Rats ◽

Tnf Α ◽

Gastric Contents ◽

Bacterial Superinfection

Abstract Background The animal experimental counterpart of human acute respiratory distress syndrome (ARDS) is acute lung injury (ALI). Most models of ALI involve reproducing the clinical risk factors associated with human ARDS, such as sepsis or acid aspiration; however, none of these models fully replicates human ARDS. Aim To compare different experimental animal models of ALI, based on direct or indirect mechanisms of lung injury, to characterize a model which more closely could reproduce the acute phase of human ARDS. Materials and methods Adult male Sprague-Dawley rats were subjected to intratracheal instillations of (1) HCl to mimic aspiration of gastric contents; (2) lipopolysaccharide (LPS) to mimic bacterial infection; (3) HCl followed by LPS to mimic aspiration of gastric contents with bacterial superinfection; or (4) cecal ligation and puncture (CLP) to induce peritonitis and mimic sepsis. Rats were sacrificed 24 h after instillations or 24 h after CLP. Results At 24 h, rats instilled with LPS or HCl-LPS had increased lung permeability, alveolar neutrophilic recruitment and inflammatory markers (GRO/KC, TNF-α, MCP-1, IL-1β, IL-6). Rats receiving only HCl or subjected to CLP had no evidence of lung injury. Conclusions Rat models of ALI induced directly by LPS or HCl-LPS more closely reproduced the acute phase of human ARDS than the CLP model of indirectly induced ALI.

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TNF-α-Mediated RIPK1 Pathway Participates in the Development of Trigeminal Neuropathic Pain in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms23010506 ◽

2022 ◽

Vol 23 (1) ◽

pp. 506

Author(s):

Jo Young Son ◽

Jin Sook Ju ◽

Yu Mi Kim ◽

Dong Kuk Ahn

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Mechanical Allodynia ◽

Inflammatory Responses ◽

Inferior Alveolar Nerve ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Tnf Α ◽

Factor Α ◽

Inferior Alveolar Nerve Injury

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) participates in the regulation of cellular stress and inflammatory responses, but its function in neuropathic pain remains poorly understood. This study evaluated the role of RIPK1 in neuropathic pain following inferior alveolar nerve injury. We developed a model using malpositioned dental implants in male Sprague Dawley rats. This model resulted in significant mechanical allodynia and upregulated RIPK1 expression in the trigeminal subnucleus caudalis (TSC). The intracisternal administration of Necrosatin-1 (Nec-1), an RIPK1 inhibitor, blocked the mechanical allodynia produced by inferior alveolar nerve injury The intracisternal administration of recombinant rat tumor necrosis factor-α (rrTNF-α) protein in naive rats produced mechanical allodynia and upregulated RIPK1 expression in the TSC. Moreover, an intracisternal pretreatment with Nec-1 inhibited the mechanical allodynia produced by rrTNF-α protein. Nerve injury caused elevated TNF-α concentration in the TSC and a TNF-α block had anti-allodynic effects, thereby attenuating RIPK1 expression in the TSC. Finally, double immunofluorescence analyses revealed the colocalization of TNF receptor and RIPK1 with astrocytes. Hence, we have identified that astroglial RIPK1, activated by the TNF-α pathway, is a central driver of neuropathic pain and that the TNF-α-mediated RIPK1 pathway is a potential therapeutic target for reducing neuropathic pain following nerve injury.

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Pyrogenic and neuroinflammatory properties of zymosan and its potential as an alternative to live yeast in antipyretic drug testing

FACETS ◽

10.1139/facets-2018-0045 ◽

2019 ◽

Vol 4 (1) ◽

pp. 162-182 ◽

Cited By ~ 1

Author(s):

Rachael Dangarembizi ◽

Christoph D. Rummel ◽

Joachim Roth ◽

Kennedy H. Erlwanger ◽

Michael T. Madziva ◽

...

Keyword(s):

Drug Testing ◽

Core Body Temperature ◽

Subcutaneous Administration ◽

Circumventricular Organs ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Tnf Α ◽

Cell Wall Extract ◽

Inflammatory Drugs ◽

Core Body

Zymosan, an immunogenic cell wall extract of Saccharomyces cerevisiae has potential for use as an experimental pyrogen. However, the short-lived sickness responses noted with intraperitoneal and intra-articular administration of zymosan limits investigations on the long-term effectiveness of antipyretic drugs. Thus, there remains a need to establish an alternative route of zymosan administration that could induce long-lived fevers and inflammation. We injected male Sprague Dawley rats (250–300 g) subcutaneously with zymosan (30 or 300 mg/kg) or saline; n = 7–8. We measured core body temperature, cage activity, food intake and body mass for 24 h after injection. Blood and brain samples were collected at 2, 8, and 18 h after injection. Zymosan (300 mg/kg) induced fever, lethargy, and anorexia, which lasted for 24 h. Zymosan-induced sickness responses were accompanied by increased blood plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α; activation of inflammatory transcription factors (nuclear factor (NF) for IL-6, signal transducer and activator of transcription (STAT)-3, and NF-κB) in the hypothalamus and circumventricular organs; and increased hypothalamic mRNA expression of TNF-α, IL-1β, and IL-6 and rate-limiting enzymes for prostaglandin synthesis. Our results confirm the suitability of subcutaneous administration of zymosan for screening antipyretic and anti-inflammatory drugs in rats.

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Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00414.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. F1034-F1043 ◽

Cited By ~ 103

Author(s):

Tarek M. El-Achkar ◽

Xiaoping Huang ◽

Zoya Plotkin ◽

Ruben M. Sandoval ◽

Georges J. Rhodes ◽

...

Keyword(s):

Rat Kidney ◽

Expression Patterns ◽

Cecal Ligation ◽

Proximal Tubules ◽

Microbial Pathogens ◽

Sprague Dawley ◽

Renal Vasculature ◽

Two Photon Microscopy ◽

Sprague Dawley Rats ◽

Cellular Signal

Toll-like receptors (TLRs) are now recognized as the major receptors for microbial pathogens on cells of the innate immune system. Recently, TLRs were also identified in many organs including the kidney. However, the cellular distribution and role of these renal TLRs remain largely unknown. In this paper, we investigated the expression of TLR4 in a cecal ligation and puncture (CLP) model of sepsis in Sprague-Dawley rats utilizing fluorescence microscopy. In sham animals, TLR4 was expressed predominantly in Tamm-Horsfall protein (THP)-positive tubules. In CLP animals, TLR4 expression increased markedly in all tubules (proximal and distal), glomeruli, and the renal vasculature. The staining showed a strong apical distribution in all tubules. A moderately less intense cellular signal colocalized partially with the Golgi apparatus. In addition, kidneys from septic rats showed increased expression of CD14 and THP. They each colocalized strongly with TLR4, albeit in different tubular segments. We also imaged the kidneys of live septic animals with two-photon microscopy after fluorescent lipopolysaccharide (LPS) injection. Within 10 min, LPS was seen at the brush border of some proximal tubules. Within 60 min, LPS was fully cytoplasmic in proximal tubules. Conversely, distal tubules showed no LPS uptake. We conclude that TLR4, CD14, and THP have specific renal cellular and tubular expression patterns that are markedly affected by sepsis. Systemic endotoxin can freely access the tubular and cellular sites where these proteins are present. Therefore, locally expressed TLRs and other interacting proteins could potentially modulate the renal response to systemic sepsis.

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Proinflammatory responses in SARS-CoV-2 infected and soluble spike glycoprotein S1 subunit activated human macrophages

10.1101/2021.06.14.448426 ◽

2021 ◽

Author(s):

Kim Chiok ◽

Kevin Hutchison ◽

Lindsay Grace Miller ◽

Santanu Bose ◽

Tanya A Miura

Keyword(s):

Virus Infection ◽

Inflammatory Response ◽

Virus Replication ◽

Inflammatory Mediators ◽

Inflammatory Responses ◽

Activated Macrophages ◽

Human Macrophages ◽

Tnf Α ◽

Proinflammatory Responses

Critically ill COVID-19 patients infected with SARS-CoV-2 display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We used SARS-CoV-2 infected and glycosylated soluble SARS-CoV-2 Spike S1 subunit (S1) treated THP-1 human-derived macrophage-like cell line to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication, virus infection resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that S1 is a key viral component inducing inflammatory response in macrophages, independently of virus replication. Thus, virus-infected or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

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Senkyunolide I Protects against Sepsis-Associated Encephalopathy by Attenuating Sleep Deprivation in a Murine Model of Cecal Ligation and Puncture

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6647258 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Jian Xie ◽

Zhen-zhen Zhao ◽

Peng Li ◽

Cheng-long Zhu ◽

Yu Guo ◽

...

Keyword(s):

Sleep Deprivation ◽

Cognitive Dysfunction ◽

Murine Model ◽

Inflammatory Responses ◽

Cecal Ligation ◽

Signaling Proteins ◽

Cecal Ligation And Puncture ◽

Inflammatory Signaling ◽

Tnf Α ◽

Senkyunolide I

Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis-associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide a sedative effect to improve sleep. However, its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP). Here, we showed that Senkyunolide I treatment improved the 7-day survival rate and reduced the excessive release of cytokines including TNF-α, IL-6, and IL-1β. A fear conditioning test was performed, and the results showed that Senkyunolide I attenuated CLP-induced cognitive dysfunction. Senkyunolide I treatment also decreased the phosphorylation levels of inflammatory signaling proteins, including p-ERK, p-JNK, p-P38, and p-P65, and the level of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, in the hippocampus homogenate. Sleep deprivation was attenuated by Senkyunolide I administration, as demonstrated by the modification of the BDNF and c-FOS expression. When sleep deprivation was induced manually, the protective effect of Senkyunolide I against inflammatory responses and cognitive dysfunction was reversed. Our data demonstrated that Senkyunolide I could protect against sepsis-associated encephalopathy in a murine model of sepsis via relieving sleep deprivation.

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IL-23 Promotes Myocardial I/R Injury by Increasing the Inflammatory Responses and Oxidative Stress Reactions

Cellular Physiology and Biochemistry ◽

10.1159/000445572 ◽

2016 ◽

Vol 38 (6) ◽

pp. 2163-2172 ◽

Cited By ~ 17

Author(s):

Xiaorong Hu ◽

Ruisong Ma ◽

Jiajia Lu ◽

Kai Zhang ◽

Weipan Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Inflammatory Responses ◽

Tunel Staining ◽

Ischemia And Reperfusion ◽

Stress Reactions ◽

Sprague Dawley ◽

Sod Activity ◽

Myocardial Ischemia And Reperfusion ◽

Tnf Α ◽

And Oxidative Stress

Background/Aims: Inflammation and oxidative stress play an important role in myocardial ischemia and reperfusion (I/R) injury. We hypothesized that IL-23, a pro-inflammatory cytokine, could promote myocardial I/R injury by increasing the inflammatory response and oxidative stress. Methods: Male Sprague-Dawley rats were randomly assigned into sham operated control (SO) group, ischemia and reperfusion (I/R) group, (IL-23 + I/R) group and (anti-IL-23 + I/R) group. At 4 h after reperfusion, the serum concentration of lactate dehydrogenase (LDH), creatine kinase (CK) and the tissue MDA concentration and SOD activity were measured. The infarcte size was measured by TTC staining. Apoptosis in heart sections were measured by TUNEL staining. The expression of HMGB1 and IL-17A were detected by Western Blotting and the expression of TNF-α and IL-6 were detected by Elisa. Results: After 4 h reperfusion, compared with the I/R group, IL-23 significantly increased the infarct size, the apoptosis of cardiomyocytes and the levels of LDH and CK (all P < 0.05). Meanwhile, IL-23 significantly increased the expression of eIL-17A, TNF-α and IL-6 and enhanced both the increase of the MDA level and the decrease of the SOD level induced by I/R (all P<0.05). IL-23 had no effect on the expression of HMGB1 (p > 0.05). All these effects were abolished by anti-IL-23 administration. Conclusion: The present study suggested that IL-23 may promote myocardial I/R injury by increasing the inflammatory responses and oxidative stress reaction.

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Ammonia reduction with ornithine phenylacetate restores brain eNOS activity via the DDAH-ADMA pathway in bile duct-ligated cirrhotic rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00097.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. G145-G152 ◽

Cited By ~ 29

Author(s):

Vairappan Balasubramaniyan ◽

Gavin Wright ◽

Vikram Sharma ◽

Nathan A. Davies ◽

Yalda Sharifi ◽

...

Keyword(s):

Bile Duct ◽

Protein Expression ◽

Ammonia Concentration ◽

Sham Operation ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Duct Ligation ◽

Tnf Α ◽

No Signaling ◽

Brain Water

Ammonia is central in the pathogenesis of hepatic encephalopathy, which is associated with dysfunction of the nitric oxide (NO) signaling pathway. Ornithine phenylacetate (OP) reduces hyperammonemia and brain water in cirrhotic animals. This study aimed to determine whether endothelial NO synthase activity is altered in the brain of cirrhotic animals, whether this is associated with changes in the endogenous inhibitor, asymmetric-dimethylarginine (ADMA) and its regulating enzyme, dimethylarginine-dimethylaminohydrolase (DDAH-1), and whether these abnormalities are restored by ammonia reduction using OP. Sprague-Dawley rats were studied 4-wk after bile duct ligation (BDL) ( n = 16) or sham operation ( n = 8) and treated with placebo or OP (0.6 g/kg). Arterial ammonia, brain water, TNF-α, plasma, and brain ADMA were measured using standard techniques. NOS activity was measured radiometrically, and protein expression for NOS enzymes, ADMA, DDAH-1, 4-hydroxynonenol (4HNE), and NADPH oxidase (NOX)-1 were measured by Western blotting. BDL significantly increased arterial ammonia ( P < 0.0001), brain water ( P < 0.05), and brain TNF-α ( P < 0.01). These were reduced significantly by OP treatment. The estimated eNOS component of constitutive NOS activity was significantly lower ( P < 0.05) in BDL rat, and this was significantly attenuated in OP-treated animals. Brain ADMA levels were significantly higher and brain DDAH-1 significantly lower in BDL compared with sham ( P < 0.01) and restored toward normal following treatment with OP. Brain 4HNE and NOX-1 protein expression were significantly increased in BDL rat brain, which were significantly decreased following OP administration. We show a marked abnormality of NO regulation in cirrhotic rat brains, which can be restored by reduction in ammonia concentration using OP.

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2251

Journal of Clinical and Translational Science ◽

10.1017/cts.2017.214 ◽

2017 ◽

Vol 1 (S1) ◽

pp. 60-60

Author(s):

Andrea Lee Frump ◽

Margie Albrecht ◽

Sandra Breuils-Bonnet ◽

Bakhtiyor Yakubov ◽

Mary Beth Brown ◽

...

Keyword(s):

Western Blot ◽

Knockout Mice ◽

Sprague Dawley ◽

Protein Receptor ◽

Morphogenetic Protein ◽

Sprague Dawley Rats ◽

Tnf Α ◽

Study Population ◽

Direct Binding ◽

17Β Estradiol

OBJECTIVES/SPECIFIC AIMS: Women with pulmonary arterial hypertension (PAH) exhibit superior right ventricular (RV) function and survival compared with men, a phenomenon attributed to poorly understood cardioprotective effects of 17β-estradiol (E2). We hypothesize that E2, through ERα, attenuates PH-induced RV dysfunction by upregulating the pro-contractile and pro-angiogenic peptide apelin. This ERα-mediated increase in apelin is mediated by the myocardial remodeling effector bone morphogenetic protein receptor 2 (BMPR2). METHODS/STUDY POPULATION: ERα, BMPR2, and apelin were measured (western blot) in RVs from patients with PAH-induced RV failure and in RV homogenates from male or female Sprague-Dawley rats with sugen/hypoxia (SuHx) or monocrotaline (MCT)-induced PH. H9c2 rat cardiomyoblasts and cardiac endothelial cells were stressed with TNF-α (10 ng/mL) or staurosporine (50 nM)±E2 (100 nM; 24 h). ERα-, BMPR2-, and apelin-dependence were evaluated by siRNA (5 pM). Downstream apelin target and pro-survival factor ERK1/2 expression was measured (western blot). p<0.05 by ANOVA was considered significant. RESULTS/ANTICIPATED RESULTS: ERα correlated positively with BMPR2 and apelin expression in SuHx-RVs and human RVs. Treatment of SuHx-PH rats with E2 or ERα agonist increased RV BMPR2 and apelin, whereas RV apelin was decreased in E2-treated hypoxic ERα knockout mice (p<0.05), but not in ERβ knockout mice. In H9c2 cells, E2 or ERα agonist attenuated TNF-α- or staurosporine-induced decreases in BMPR2, apelin, and phospho-ERK1/2 (p<0.05 for all endpoints). E2 protection was lost in presence of siRNA directed against ERα, BMPR2, or apelin (p<0.05). ERα was necessary for E2-mediated increases in BMPR2, apelin, and ERK1/2, and BMPR2 was required for the E2-mediated increase in apelin (p<0.05 for siRNA vs. scramble). ERα, BMPR2, and apelin protein was increased in decompensated human RVs but downstream phospho-ERK signaling was disrupted. DISCUSSION/SIGNIFICANCE OF IMPACT: E2, via ERα, increases BMPR2 and apelin in the failing RV and in stressed rat cardiomyoblasts. The E2-mediated increase in apelin is BMPR2-dependent and likely occurs through direct binding of ERα to the BMPR2 promoter. Harnessing this E2-ERα-BMPR2-apelin axis during RV compensation may lead to novel, RV-targeted therapies for PAH patients of either sex.

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