Anti-Inflammatory Mechanism of An Alkaloid Rutaecarpine in LTA-Stimulated RAW 264.7 Cells: Pivotal Role on NF-κB and ERK/p38 Signaling Molecules.

Lipoteichoic acid (LTA) is a key cell wall component and virulence factor of Gram-positive bacteria. LTA contributes a major role in infection and it mediates inflammatory responses in the host. Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from Evodia rutaecarpa, has shown a variety of fascinating biological properties such as anti-thrombotic, anticancer, anti-obesity and thermoregulatory, vasorelaxing activity. It has also potent effects on the cardiovascular and endocrine systems. Herein, we investigated rutaecarpine's (Rut) anti-inflammatory effects in LTA-stimulated RAW macrophage cells. The Western blot and spectrophotometric results revealed that Rut inhibited the production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin (IL)-1ß in the LTA-induced macrophage cells. Successively, our mechanistic studies publicized that Rut inhibited LTA-induced phosphorylation of mitogen-activated protein kinase (MAPK) including the extracellular signal-regulated kinase (ERK), and p38, but not c-Jun NH2-terminal kinase (JNK). In addition, the respective Western blot and confocal image analyses exhibited that Rut reserved nuclear transcription factor kappa-B (NF-κB) by hindering inhibitor of nuclear factor κB-α (IκBα) and NF-κB p65 phosphorylation and p65 nuclear translocation. These results indicate that Rut exhibits its anti-inflammatory effects mainly through attenuating NF-κB and ERK/p38 signaling pathways. Overall, this result suggests that Rut could be a potential therapeutic agent for the treatment of Gram-positive bacteria induced inflammatory diseases.

Possible Molecular Targets of Novel Ruthenium Complexes in Antiplatelet Therapy.

In oncotherapy, ruthenium (Ru) complexes are reflected as potential alternatives for platinum compounds and have been proved as encouraging anticancer drugs with high efficacy and low side effects. Cardiovascular diseases (CVDs) are mutually considered as the number one killer globally, and thrombosis is liable for the majority of CVD-related deaths. Platelets, an anuclear and small circulating blood cell, play key roles in hemostasis by inhibiting unnecessary blood loss of vascular damage by making blood clot. Platelet activation also plays a role in cancer metastasis and progression. Nevertheless, abnormal activation of platelets results in thrombosis under pathological settings such as the rupture of atherosclerotic plaques. Thrombosis diminishes the blood supply to the heart and brain resulting in heart attacks and strokes, respectively. While currently used anti-platelet drugs such as aspirin and clopidogrel demonstrate efficacy in many patients, they exert undesirable side effects. Therefore, the development of effective therapeutic strategies for the prevention and treatment of thrombotic diseases is a demanding priority. Recently, precious metal drugs have conquered the subject of metal-based drugs, and several investigators have motivated their attention on the synthesis of various ruthenium (Ru) complexes due to their prospective therapeutic values. Similarly, our recent studies established that novel ruthenium-based compounds suppressed platelet aggregation via inhibiting several signaling cascades. Our study also described the structure antiplatelet-activity relationship (SAR) of three newly synthesized ruthenium-based compounds. This review summarizes the antiplatelet activity of newly synthesized ruthenium-based compounds with their potential molecular mechanisms.

Novel Therapeutic Agent against Platelet Activation In Vitro and Arterial Thrombosis In Vivo by Morin Hydrate.

Morin hydrate, a bioactive flavonoid, has been proven to prevent inflammation and apoptosis of cells. Flavonoids can reduce the risk of cardiovascular diseases, in which platelet activation plays a major role. This study investigated the effect of morin hydrate on platelet activation in vitro and in vivo. Morin hydrate markedly inhibited platelet aggregation stimulated by collagen in human platelets but not that stimulated by other agonists. In collagen-activated platelets, morin hydrate inhibited adenosine triphosphate (ATP) release; intracellular Ca2+ mobilization; P-selectin expression; and phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), and Akt. In mitogen-activated protein kinase (MAPK) activation, morin hydrate evidently diminished ERK2 or JNK1 activation, except for p38 MAPK. Additionally, morin hydrate markedly reduced the OH· signals in platelet suspensions but not in the cell-free system (Fenton reaction solution). Moreover, morin hydrate substantially increased the occlusion time of thrombotic platelet plug formation but had no effect on bleeding time in mice. In conclusion, morin hydrate crucially inhibits platelet activation through inhibition of the PLCγ2⁻PKC cascade and subsequent suppression of Akt and MAPK activation, thereby ultimately inhibiting platelet aggregation. Therefore, this paper suggests that morin hydrate constitutes a novel and potential natural therapeutic product for preventing or treating thromboembolic disorders.

Multi-Targeting Andrographolide, a Novel NF-κB Inhibitor, as a Potential Therapeutic Agent for Stroke.

A key focus in the field of drug discovery has been motivated by the neuroprotection of natural compounds. Cerebral ischemia is a multifaceted pathological process with a series of mechanisms, and a perspective for the development of neuroprotectants from traditional herbal medicine or natural products is a promising treatment for this disease. Natural compounds with the effects of anti-oxidation, anti-inflammation, anti-apoptosis, and neurofunctional regulation exhibit therapeutic effects on experimental ischemic brain injury. Conferring to the pharmacological mechanisms underlying neuroprotection, a study found that androgapholide, a diterpene lactone compound, exhibits varying degrees of neuroprotective activities in both in vitro and in vivo experimental models of stroke. The neuroprotective mechanisms of andrographolide are suggested as: (I) increasing nuclear factor E2-related factor 2-heme oxygenase (Nrf2-HO-1) expression through p38-mitogen activated protein kinase (MAPK) regulation, (II) inducing cerebral endothelial cells (CEC) apoptosis and caspase-3 activation, (III) down regulating Bax, inducible nitric oxide synthase (iNOS), and (IV) inhibiting hydroxyl radical (OH-) formation, and activating transcription factor NF-κB signaling pathways. Recently, several researchers have also been trying to unveil the principal mechanisms involved in the neuroprotective effects of andrographolide. Therefore, this review aims to summarize an overview on the neuroprotective effects of andrographolide and exemplifies the essential mechanisms involved. This paper can provide information that andrographolide drug discovery may be a promising strategy for the development of a novel class of neuroprotective drug.

Laparoscopic versus open subtotal gastrectomy for locally advanced gastric cancer: A retrospective analysis from a single institution.

BACKGROUND: /Objective: Laparoscopic distal gastrectomy for early gastric cancer is described as a treatment option in general practice. However, the oncological efficacy and technical safety of laparoscopic gastrectomy with D2 lymphadenectomy in locally advanced gastric cancer are controversial, and clinical trials are ongoing. This study aimed to evaluate the short-term and surgical outcomes between laparoscopic and open gastrectomy procedures in locally advanced gastric cancer. METHODS: We retrospectively analyzed data from 134 patients who underwent subtotal D2 gastrectomy for locally advanced gastric cancer in our hospital between January 2011 and December 2018. Clinicopathological characteristics, surgical outcome, postoperative recovery, disease-free survival, and overall survival were compared between those who underwent laparoscopic and open gastrectomies. RESULTS: Baseline characteristics were similar between patients who underwent open and laparoscopic surgeries. Less surgical time (250.8 vs. 347.6 min in laparoscopic vs. open surgery, respectively; P < 0.05) and lower blood loss (83.7 vs. 333 mL in laparoscopic vs. open surgery, respectively; P < 0.05) were noted in patients who underwent laparoscopic surgery than in those who underwent open gastrectomy. The time of starting oral intake was earlier and the length of postoperative hospital stay was shorter in the laparoscopic group than in the open group. Surgical morbidity and mortality rates, as well as disease-free survival and overall survival rates, did not differ between the two groups. CONCLUSION: Laparoscopic gastrectomy is feasible and safe for locally advanced gastric cancer. Based on the perioperative results and short-term outcomes, laparoscopic gastrectomy is non-inferior to open gastrectomy.

Effects of a novel oral appliance on snoring in adults: A pilot study.

ABSTRACTBACKGROUND/PURPOSE: Oral appliances (OAs) have been recommended as alternatives for adult patients with obstructive sleep apnea who are intolerant of continuous positive airway pressure therapy. The aim of this study was to explore the effect on snoring rates among adult patients through use of a novel OA termed the Lin OA (LOA, airflow-interference-type nasal congestion relieving and snore-ceasing oral appliance). MATERIALS AND METHODS: The LOA consist of two parts: dental braces and a fixed tongue compressor. The compressor lengths range from 0.5 cm to 3.5 cm across versions. Patients used the LOA during sleep and the SnoreClock smartphone application recorded their snoring rates. RESULTS: A total of 4920 recordings (4239 recordings from 34 men, 681 recordings from 8 women) were used for the analysis. The recordings were sorted in accordance with the applied length of the LOA tongue compressor (0.5-3.5 cm, LOA-0.5, LOA-1 and LOA-3.5), and participants not using the LOA were denoted as the LOA-0 group. The women had higher snoring rates in the LOA-0, LOA-0.5 to LOA-2 groups, but lower snoring rates in the LOA-3 group than men by the univariate analysis. The snoring rates were significantly reduced by a mean of 5.04% with every 1 cm increase in tongue compressor length. Continuous LOA use resulted in snoring rate reductions of 0.02% per day by the random intercept model of the linear regression. CONCLUSION: Use of this novel LOA may significantly reduce snoring rates by 5.04% with each 1 cm increase in tongue compressor length.