Inhibition of homodimerization of Toll-like receptor 4 by curcumin

Toll-like receptors play a key role in sensing microbial components and inducing innate immune responses. Ligand-induced dimerization of TLR4 is required for the activation of downstream signaling pathways. Thus, the receptor dimerization may be one of the first lines of regulation in activating TLR-mediated signaling pathways and induction of subsequent immune responses. LPS induces the activation of NF-kappaB and IRF3 through MyD88- or TRIF-dependent pathways. Curcumin, a polyphenol found in the plant Curcuma longa, has been shown to suppress the activation of NF-kappaB induced by various pro-inflammatory stimuli by inhibiting IKKbeta kinase activity in MyD88-dependent pathway. Curcumin also inhibited LPS-induced IRF3 activation. These results imply that curcumin inhibits both MyD88- and TRIF-dependent pathways in LPS-induced TLR4 signaling. However, in TRIF-dependent pathway, curcumin did not inhibit IRF3 activation induced by overexpression of TRIF in 293T cells. These results suggest that TLR4 receptor complex is the molecular target of curcumin in addition to IKKbeta. Here, we report biochemical evidence that phytochemicals (curcumin and sesquiterpene lactone) inhibit both ligand-induced and ligand-independent dimerization of TLR4. Furthermore, these results demonstrate that small molecules with non-microbial origin can directly inhibit TLRs-mediated signaling pathways at the receptor level. These results imply that the activation of TLRs and subsequent immune/inflammatory responses induced by endogenous molecules or chronic infection can be modulated by certain dietary phytochemicals we consume daily.     

Prevalence and risk of colorectal polyps among the Korean population under 50 years

Colorectal cancer is a common cancer; generally, adults aged ≥ 50 years are screened using stool occult blood tests and colonoscopy. However, colorectal adenoma and cancer have been found in patients under the aged of 50, and studies on characteristics and risk factors in young patients are lacking. We evaluated the prevalence and risk factors of colorectal adenoma and cancer in young adults aged under 50 years.We retrospectively analyzed 570 individuals aged under 50 years who underwent colonoscopy at the Haeundae Paik Hospital, Korea, from January to June 2018. Logistic regression model was used to identify the risk factors for colorectal adenoma and colorectal cancer.The prevalence of colorectal adenoma in group of 19–29 years was 3.2% (1 of 31), 30–39 years was 13.8% (30 of 217) and in the group of 40–49 years was 21.1% (68 of 322) (P = .009). In multivariable analysis, age over 45 years (adjusted odds ratio [OR], 1.941; 95% confidence interval [CI], 1.187–3.172; P = .008) and male sex (adjusted OR, 1.711; 95% CI, 1.044–2.806; P = .033) were independent risk factors for colorectal neoplasia including cancer.The prevalence of colorectal adenoma increases as the age increased in young adults under 50 years of age, especially after the age of 45 years, the risk of colorectal neoplasia increases; hence, early screening should be considered before the age of 50 years.     

Spontaneous reduction of transvaginal small bowel evisceration after abdominal hysterectomy for cervical cancer: A case report

Rationale:Transvaginal evisceration of the small bowel is an extremely rare condition after hysterectomy, which requires urgent surgical intervention to prevent serious bowel morbidity and mortality.Patient concerns:A 65-year-old woman presented with sudden-onset severe abdominal pain and a mass protruding through the vagina. The past surgical history was significant, with an abdominal hysterectomy for cervical cancer performed 11 weeks prior to presentation.Diagnosis:Pelvic examination revealed prolapsed small-bowel loops (18-20 cm in length). Pelvic computed tomography scan confirmed the presence of transvaginal evisceration of the small bowel.Interventions:Bowel reduction and urgent laparotomy were the selected treatment approaches for a detailed inspection and thorough washing of the intrα-abdominal cavity. A Foley catheter was inserted in the emergency room, with the subject in the lithotomy position. The prolapsed bowel loops spontaneously reduced without manual reduction, and the vault defect was repaired transvaginally.Outcomes:The patient experienced no postoperative complications and remained disease-free for 9months postoperatively.Lessons:Transvaginal evisceration of the small bowel should be considered a surgical emergency. A multidisciplinary approach to prompt case management involving clinicians in gynecology, general surgery, and emergency medicine is vital for preventing serious consequences. Hysterectomy is the most frequently performed gynecological surgical procedure, and evisceration occurs most often after hysterectomy. Therefore, patients should be informed about this rare but possible hysterectomy complication.     

Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neu^hi), but low levels of CD8⁺ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neu^hi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.     

Puerarin activates endothelial nitric oxide synthase through estrogen receptor-dependent PI3-kinase and calcium-dependent AMP-activated protein kinase

The cardioprotective properties of puerarin, a natural product, have been attributed to the endothelial nitric oxide synthase (eNOS)-mediated production of nitric oxide (NO) in EA.hy926 endothelial cells. However, the mechanism by which puerarin activates eNOS remains unclear. In this study, we sought to identify the intracellular pathways underlying eNOS activation by puerarin. Puerarin induced the activating phosphorylation of eNOS on Ser1177 and the production of NO in EA.hy926 cells. Puerarin-induced eNOS phosphorylation required estrogen receptor (ER)-mediated phosphatidylinositol 3-kinase (PI3K)/Akt signaling and was reversed by AMP-activated protein kinase (AMPK) and calcium/calmodulin-dependent kinase II (CaMKII) inhibition. Importantly, puerarin inhibited the adhesion of tumor necrosis factor (TNF)-α-stimulated monocytes to endothelial cells and suppressed the TNF-α induced expression of intercellular cell adhesion molecule-1. Puerarin also inhibited the TNF-α-induced nuclear factor-κB activation, which was attenuated by pretreatment with N^G-nitro-l-arginine methyl ester, a NOS inhibitor. These results indicate that puerarin stimulates eNOS phosphorylation and NO production via activation of an estrogen receptor-mediated PI3K/Akt- and CaMKII/AMPK-dependent pathway. Puerarin may be useful for the treatment or prevention of endothelial dysfunction associated with diabetes and cardiovascular disease.     

Comparison between anisometropic and strabismic amblyopia using functional magnetic resonance imaging

AIMS: To assess calcarine activation with functional magnetic resonance imaging (fMRI) in patients with anisometropic and strabismic amblyopia. METHODS: 14 amblyopes (eight anisometropic and six strabismic) were studied with fMRI using stimuli of checkerboards of various checker sizes and temporal frequencies. While T2* weighted MRI were obtained every 3 seconds for 6 minutes, patients viewed the stimuli monocularly with either the amblyopic or sound eye. RESULTS: Amblyopic eyes showed reduced calcarine activation compared with contralateral sound eyes in fMRI in all subjects. The calcarine activation from amblyopic eyes in anisometropic amblyopes was more suppressed at higher spatial frequencies, while that from amblyopic eyes in strabismic amblyopes was more suppressed at lower spatial frequencies. CONCLUSION: These results suggest that fMRI is a useful tool for the study of amblyopia in humans. The calcarine activation via amblyopic eyes because of anisometropia or strabismus has different temporospatial characteristics, which suggests differences in the neurophysiological mechanisms between two types of amblyopia.     

Influencing factors of pressure pain hypersensitivity of the upper trapezius in food service workers with nonspecific neck/shoulder myofascial pain: A cross-sectional study

It is unclear which factors contribute to the developing pressure pain hypersensitivity of the upper trapezius, a type of neurophysiological hyperexcitability. The present study investigated the relationship between physical and psychological factors and pressure pain hypersensitivity of the upper trapezius for each sex. In total, 154 individuals with neck/shoulder myofascial pain participated, among 372 food service workers. Participants completed a questionnaire (Beck Depression Inventory, and Borg Rating of Perceived Exertion scale) and were photographed to measure posture. Pressure pain sensitivity, 2 range of motions (cervical lateral bending and rotation), and 4 muscle strengths (serratus anterior, lower trapezius [LT], biceps, and glenohumeral external rotator) were measured by a pressure algometer, iPhone application, and handheld dynamometer, respectively. For each sex, forward multivariate logistic regression was used to test our a priori hypothesis among selected variables that a combination of psychosocial and physical factors contributed to the risk for pressure pain hypersensitivity. In multivariate analyses, LT strength (odds ratio = 0.94, 95% confidence interval = 0.91–0.97, P = .001) was the only significant influencing factor for pressure pain hypersensitivity in men. Dominant painful ipsilateral cervical rotation range of motion (odds ratio = 0.96, 95% confidence interval = 0.92–0.99, P = .037) was the only influencing factor for pressure pain hypersensitivity in women. LT strength and dominant painful ipsilateral cervical rotation range of motion could serve as guidelines for preventing and managing pressure pain hypersensitivity of the upper trapezius in food service workers with nonspecific neck/shoulder myofascial pain.