gingerol and Sepsis

Sepsis is characterized by an overactive inflammatory response. Acute lung injury (ALI) is the most common type of organ injury in sepsis, with high morbidity and mortality. 6-Gingerol is the main bioactive compound of ginger, and it possesses anti-inflammatory bioactivity in different diseases. This study is aimed to explore the specific function of 6-Gingerol in sepsis-induced ALI.. Lipopolysaccharide (LPS) was intraperitoneally injected into Sprague-Dawley rats for establishing the ALI models in vivo. The ALI rats were intraperitoneally injected with 20 mg/kg 6-Gingerol. The contents of oxidative stress markers malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were detected in the lung tissues of ALI rats. The concentrations of inflammatory factors [Tumor Necrosis Factor alpha (TNF-α), interleukin (IL)-6, and IL-1β] were measured by ELISA. Inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) of rats was tested. Western blot was utilized to test the protein levels of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1) in lung tissues. Furthermore, immunohistochemical staining was applied for testing the expression of NLRP3 inflammasome in lung tissues.. The pathological changes in ALI rats were characterized by increased accumulation of inflammatory cells, alveolar hemorrhage, and pulmonary interstitial edema. However, the degree of pathological injury of lung tissues was significantly improved after 6-Gingerol treatment. Additionally, 6-Gingerol significantly attenuated the lung wet/dry ratio and protein permeability index (PPI) of LPS-induced rats. Furthermore, 6-Gingerol repressed oxidative stress and inflammatory reaction in LPS-induced rats by reducing the contents of MDA, GSH, SOD, TNF-α, IL-6, and IL-1β in the lung. LPS-induced infiltration of eosinophils, macrophages, neutrophils, and lymphocytes into lung was suppressed by 6-Gingerol administration. Moreover, 6-Gingerol activated Nrf2/HO-1 signaling and repressed LPS-induced‑NLRP3 inflammasome expression in lung tissues of LPS-induced rats. Intraperitoneal injection of ML385 (Nrf2 inhibitor) treatment into rats reversed the effects of 6-Gingerol on lung injury, inflammation, and oxidative stress in LPS-subjected rats.. 6-Gingerol attenuates sepsis-induced ALI by suppressing NLRP3 inflammasome activation via stimulation of Nrf2.

Topics: Acute Lung Injury; Animals; Inflammasomes; Inflammation; Interleukin-6; Lipopolysaccharides; Lung; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Sprague-Dawley; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Topics: Animals; Apoptosis; Catechols; Cytokines; Fatty Alcohols; Humans; Immune System Diseases; Lymphocytes; Male; Mice; Sepsis

Sepsis is a major cause of death for ICU patients. Sepsis development depends heavily on the presence of mature IL-1β cytokine. This study evaluates the potential therapeutic properties of a bioactive compound known as 6-gingerol on sepsis. This compound has previously been demonstrated to possess anti-inflammatory properties both in vivo and in vitro.. C57BL/6 mice was used to establish models of sepsis by means of cecal ligation and puncture (CLP). Upon treatment with 6-gingerol, we assessed the survival rate of mice and measured the levels of key pro-inflammatory cytokines in serum and colon tissues. Sepsis pathogenesis was further explored using the RAW264.7 cell line and bone marrow-derived macrophages (BMDMs) treated with ATP and lipopolysaccharide (LPS). The impact of 6-gingerol on pyroptosis was also examined. In addition, we assessed the role of MAPK signaling in 6-gingerol-induced effects in BMDMs and RAW264.7 cells.. In CLP mice, 6-gingerol significantly ameliorated sepsis development, which was associated with the reduction of serum IL-1β. In BMDMs and RAW264.7 cells, 6-gingerol strongly attenuated pyroptosis as well as the release of caspase-1p20, HMGB1, mature IL-1β, IL-18 in response to ATP and LPS treatment. 6-Gingerol conferred these effects by blocking MAPK activation. Exposure to an ERK agonist (EGF) reversed effects of 6-gingerol, causing pyroptosis, LDH and caspase-1p20 release.. By targeting MAPK signaling, 6-gingerol significantly suppressed secretion of pro-inflammatory cytokines and inhibited macrophage cells pyroptosis resulting in overall inhibition of sepsis development.

Topics: Adenosine Triphosphate; Animals; Caspase 1; Catechols; Cytokines; Disease Models, Animal; Epidermal Growth Factor; Fatty Alcohols; HMGB1 Protein; Interleukin-18; Interleukin-1beta; Lipopolysaccharides; Macrophages; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Prognosis; Pyroptosis; RAW 264.7 Cells; Sepsis

Sepsis-induced liver injury is very common in intensive care units. Here, we investigated the effects of 6-gingerol on sepsis-induced liver injury and the role of the Nrf2 pathway in this process. 6-Gingerol is the principal ingredient of ginger that exerts anti-inflammatory and antioxidant effects. Using cecal ligation and puncture (CLP) to induce polymicrobial sepsis and related liver injury, we found that mice pre-treated with 6-Gingerol showed less incidences of severe liver inflammation and death than untreated CLP groups. 6-Gingerol administration also inhibited the expression of pyroptosis-related proteins, including NOD-like receptor protein 3 (NLRP3), IL-1β, and caspase-1. Consistent with these findings, 6-gingerol reduced the effects of pyroptosis induced by lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP) in RAW 264.7 cells, as evidenced by IL-1β and caspase-1 protein levels in the supernatant and propidium iodide (PI) staining. 6-Gingerol was shown to activate the Nrf2 pathway in vivo and in vitro. Notably, Nrf2 siRNA transfection nullified the inhibitory effects of 6-gingerol on pyroptosis in vitro. In summary, these findings suggested that 6-gingerol alleviated sepsis-induced liver injury by inhibiting pyroptosis through the Nrf2 pathway.

Topics: Animals; Catechols; Disease Models, Animal; Fatty Alcohols; Gene Knockdown Techniques; Humans; Liver; Liver Failure, Acute; Male; Mice; NF-E2-Related Factor 2; Pyroptosis; RAW 264.7 Cells; RNA, Small Interfering; Sepsis; Signal Transduction

Acute kidney injury (AKI) and metabolic dysfunction are critical complications in sepsis syndrome; however, their pathophysiological mechanisms remain poorly understood. Therefore, we evaluated whether the pharmacological properties of 6-gingerol (6G) and 10-gingerol (10G) could modulate AKI and metabolic disruption in a rat model of sepsis (faecal peritonitis). Animals from the sham and AKI groups were intraperitoneally injected with 6G or 10G (25 mg/kg). Septic AKI decreased creatinine clearance and renal antioxidant activity, but enhanced oxidative stress and the renal mRNA levels of tumour necrosis factor-α, interleukin-1β, and transforming growth factor-β. Both phenol compounds repaired kidney function through antioxidant activity related to decreased oxidative/nitrosative stress and proinflammatory cytokines. Metabolomics analysis indicated different metabolic profiles for the sham surgery group, caecal ligation and puncture model alone group, and sepsis groups treated with gingerols.

Topics: Acute Kidney Injury; Animals; Catechols; Dimethyl Sulfoxide; Dimethylamines; Disease Models, Animal; Fatty Alcohols; Feces; Humans; Injections, Intraperitoneal; Male; Metabolome; Metabolomics; Oxidative Stress; Peritonitis; Rats; Rats, Wistar; Sepsis; Sulfones; Survival Analysis; Treatment Outcome