S1P1 Regulates M1/M2 Polarization toward Brain Injury after Transient Focal Cerebral Ischemia

( Bhakta Prasad Gaire ),( Young Joo Bae ),( Ji Woong Choi ) 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.6

M1/M2 polarization of immune cells including microglia has been well characterized. It mediates detrimental or beneficial roles in neuroinflammatory disorders including cerebral ischemia. We have previously found that sphingosine 1-phospate receptor subtype 1 (S1P₁) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between S1P₁ and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of S1P₁ is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether S1P₁ was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing S1P₁ activity with its functional antagonist, AUY954 (5 mg/kg, p.o.), attenuated mRNA upregulation of M1 polarization markers in post-ischemic brain at 1 day and 3 days after tMCAO challenge. Similarly, suppressing S1P₁ activity with AUY954 administration inhibited M1-polarizatioin-relevant NF-κB activation in post-ischemic brain. Particularly, NF-κB activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through S1P₁ in post-ischemic brain mainly occurred in activated microglia. Suppressing S1P₁ activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that S1P₁ could also influence M2 polarization in post-ischemic brain. Finally, suppressing S1P₁ activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevant Akt, all of which were downstream pathways following S1P₁ activation. Overall, these results revealed S1P₁-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.

Peripartum Cardiomyopathy: Review of the Literature

Pradipta Bhakta,Binay K Biswas,Basudeb Banerjee 연세대학교의과대학 2007 Yonsei medical journal Vol.48 No.5

Peripartum cardiomyopathy (PPCM) is a rare but serious form of cardiac failure affecting women in the last months of pregnancy or early puerperium. Clinical presentation of PPCM is similar to that of systolic heart failure from any cause, and it can sometimes be complicated by a high incidence of thromboembolism. Prior to the availability of echocardiography, diagnosis was based only on clinical findings. Recently, inclusion of echocardiography has made diagnosis of PPCM easier and more accurate. Its etiopathogenesis is still poorly understood, but recent evidence supports inflammation, viral infection and autoimmunity as the leading causative hypotheses. Prompt recognition with institution of intensive treatment by a multidisciplinary team is a prerequisite for improved outcome. Conventional treatment consists of diuretics, β blockers, vasodilators, and sometimes digoxin and anticoagulants, usually in combination. In resistant cases, newer therapeutic modalities such as immunomodulation, immunoglobulin and immunosuppression may be considered. Cardiac transplantation may be necessary in patients not responding to conventional and newer therapeutic strategies. The role of the anesthesiologist is important in perioperative and intensive care management. Prognosis is highly related to reversal of ventricular dysfunction. Compared to historically higher mortality rates, recent reports describe better outcome, probably because of advances in medical care. Based on current information, future pregnancy is usually not recommended in patients who fail to recover heart function. This article aims to provide a comprehensive updated review of PPCM covering etiopathogeneses, clinical presentation and diagnosis, as well as pharmacological, perioperative and intensive care management and prognosis, while stressing areas that require further research.

Sternal Fracture Fixation with a Steel Wire: The New “Timala” Technique

( Rabindra Bhakta Timala ),( Nirmal Panthee ) 대한외상학회 2021 大韓外傷學會誌 Vol.34 No.3

Purpose: Traumatic sternal fractures are rare but quite disabling injuries. Timely fixation of sternal fractures reduces pain and prevents respiratory complications. However, the fixation technique should be simple, effective, and readily available in local circumstances. Methods: From January 2014 to March 2020, seven patients with sternal fracture/ dislocation underwent steel wire fixation with the new “Timala” technique. In this technique, adjacent ribs are anchored with two steel wires to form an “X” in front of the fractured segment of the sternum. Patients were followed up clinically and radiologically. Results: Six of the patients were men and one was a female. Five of them had injuries due to falls and two were injured in road traffic accidents. Their age ranged from 18 years to 76 years, with a median age of 41 years. All seven patients experienced immediate recovery from pain and showed evidence of fracture healing on postoperative chest X-rays and clinical examinations. Conclusions: Anchoring ribs to fix the sternum with steel wire is a safe, effective, easily available, and reproducible method to fix sternal fractures or dislocations.

Case Report and Mini Literature Review: Anesthetic Management for Severe Peripartum Cardiomyopathy Complicated with Preeclampsia Using Sufetanil in Combined Spinal Epidural Anesthesia

Pradipta Bhakta,Pragnyadipta Mishra,Anamika Bakshi,Vijay Langer 연세대학교의과대학 2011 Yonsei medical journal Vol.52 No.1

Peripartum cardiomyopathy (PPCM) is a rare entity, and anesthetic management for cesarean section of a patient with this condition can be challenging. We hereby present the anesthetic management of a patient with PPCM complicated with preeclampsia scheduled for cesarean section, along with a mini review of literature. A 24 year-old primigravida with twin gestation was admitted to our hospital with severe PPCM and preeclampsia for peripartum care, which finally required a cesarean section. Preoperative optimization was done according to the goal of managing left ventricular failure. Combined spinal epidural (CSE) anaesthesia with bupivacaine and sufentanil was used for cesarean section under optimal monitoring. The surgery was completed without event or complication. Postoperative pain relief was adequate and patient required only one epidural top up with sufentanil 6 hours after operation. To the best of our knowledge there is no report in literature of the use of sufentanil as a neuraxial opioid in the anesthetic management of cesarean section in a patient with PPCM. CSE with sufentanil may be a safer and more effective alternative in such cases.

Aseptic subcutaneous inflammation presenting as late onset back pain after uneventful epidural anesthesia

Pradipta Bhakta,Brian O’Brien,Richard McNamara 대한마취통증의학회 2019 Korean Journal of Anesthesiology Vol.72 No.5

.

Studies on in vivo Wound Healing Activity of Cassia fistula Linn . Leaves (Leguminosae) in Rats

T. Bhakta,Pulok K. Mukherjee,Kakali Mukherjee,M. Pal,B. p. Saha 한국생약학회 1998 Natural Product Sciences Vol.4 No.2

Cassia fistula commonly known as Sundali was selected to evaluate its wound healing potentials based on traditional use and literature references. Methanol extract of C. fistula leaves were examined for its wound healing property in the form of an ointment in two types of wound models in rats : i) Excision wound model and ii) Incision wound model. The ointment of the leaf extract of two different concentrations (5% and 10% w/w ointment of leaves extract in simple ointment base) responded significantly in both models of wounds tested. The results were also comparable to that of standard drug, nitrofurazone in terms of wound contraction ability, epithelisation period, tensile strength and regeneration of tissue at wound area.

Identification of Sphingosine 1-Phosphate Receptor Subtype 1 (S1P1) as a Pathogenic Factor in Transient Focal Cerebral Ischemia

Gaire, Bhakta Prasad,Lee, Chi-Ho,Sapkota, Arjun,Lee, Sang Yeul,Chun, Jerold,Cho, Hee Jun,Nam, Tae-gyu,Choi, Ji Woong Springer-Verlag 2018 Molecular neurobiology Vol.55 No.3

<P>Medically relevant roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling have become a successful or promising target for multiple sclerosis or cerebral ischemia. Animal-based proof-of-concept validation for the latter is particularly through the neuroprotective efficacy of FTY720, a non-selective S1P receptor modulator, presumably via activation of S1P(1). In spite of a clear link between S1P signaling and cerebral ischemia, it remains unknown whether the role of S1P(1) is pathogenic or neuroprotective. Here, we investigated the involvement of S1P(1) along with its role in cerebral ischemia using a transient middle cerebral artery occlusion ('tMCAO') model. Brain damage following tMCAO, as assessed by brain infarction, neurological deficit score, and neural cell death, was reduced by oral administration of AUY954, a selective S1P(1) modulator as a functional antagonist, in a therapeutic paradigm, indicating that S1P(1) is a pathogenic mediator rather than a neuroprotective mediator. This pathogenic role of S1P(1) in cerebral ischemia was reaffirmed because tMCAO-induced brain damage was reduced by genetic knockdown with an intracerebroventricular microinjection of S1P(1) shRNA lentivirus into the brain. Genetic knockdown of S1P(1) or AUY954 exposure reduced microglial activation, as assessed by reduction in the number of activated microglia and reversed morphology from amoeboid to ramified, and microglial proliferation in ischemic brain. Its role in microglial activation was recapitulated in lipopolysaccharide-stimulated primary mouse microglia, in which the mRNA expression level of TNF-alpha and IL-1 beta, well-known markers for microglial activation, was reduced in microglia transfected with S1P(1) siRNA. These data suggest that the pathogenic role of S1P(1) is associated with microglial activation in ischemic brain. Additionally, the pathogenic role of S1P(1) in cerebral ischemia appears to be associated with the blood-brain barrier disruption and brain-derived neurotrophic factor (BDNF) downregulation. Overall, findings from the current study clearly identify S1P(1) signaling as a pathogenic factor in transient focal cerebral ischemia, further implicating S1P(1) antagonists including functional antagonists as plausible therapeutic agents for human stroke.</P>

Current Insights on Cholangiocarcinoma Research: a Brief Review

Mathema, Vivek Bhakta,Na-Bangchang, Kesara Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.4

Colangiocarcinoma (CCA) is a progressively fatal disease which generally occurs due to malignant transformation of hepatic biliary cholangiocytes. The incidence of CCA has been increasing worldwide and there is an urgent requirement for effective diagnosis and treatment strategies against this devastating disease. Different factors including liver-fluke infestation, viral hepatitis, exogenous nitrosamine-mediated DNA damage, and chronic inflammation have been linked to CCA genesis. However, the risk factors and underlying complex mechanisms leading to development of CCA are not sufficiently understood to devise an effective targeted treatment therapy. In this review, we summarize currently known epidemiological and pathological aspects of the disease and briefly describe various potential biomarkers and experimental anticancer phytochemicals related to CCA research. In addition, we also sum up recent findings that link chronic inflammation of hepatic biliary cholangiocytes with CCA. The collective information concisely presented in this article would provide useful insights into the current understanding of this cancer.

Kinetics and molecular docking studies of loganin, morroniside and 7-O-galloyl-D-sedoheptulose derived from Corni fructus as cholinesterase and b-secretase 1 inhibitors

Himanshu Kumar Bhakta,Chan Hum Park,Takako Yokozawa,민병선,Hyun Ah Jung,최재수 대한약학회 2016 Archives of Pharmacal Research Vol.39 No.6

We evaluated the major active componentsisolated from Corni Fructus: loganin, morroniside, and7-O-galloyl-D-sedoheptulose as inhibitors of acetylcholinesterase(AChE), butyrylcholinesterase (BChE), andb-site amyloid precursor protein (APP) cleaving enzyme 1(BACE1) for use in Alzheimer’s disease treatment. Thesecompounds exhibited predominant cholinesterase (ChEs)inhibitory effects with IC50 values of 0.33, 3.95, and10.50 ± 1.16 lM, respectively, for AChE, and 33.02,37.78, and 87.94 ± 4.66 lM, respectively, for BChE. Kinetics studies revealed that loganin and 7-O-galloyl-Dsedoheptuloseinhibited AChE with characteristics typicalof mixed inhibitors, while morroniside was found to be anoncompetitive inhibitor against AChE and also exertedmixed BChE inhibitory activities. For BACE1, loganinshowed noncompetitive type inhibitory effects, whilemorroniside and 7-O-galloyl-D-sedoheptulose were foundto be mixed inhibitors. Furthermore, these compoundsexhibited dose-dependent inhibitory activity with ONOO--mediated protein tyrosine nitration. Molecular dockingsimulation of these compounds demonstrated negativebinding energies for ChEs, and BACE1, indicating highaffinity and tighter binding capacity for the active site ofthe enzyme. Loganin was the most potent inhibitor againstboth ChEs and BACE1. The data suggest that these compoundstogether can act as a triple inhibitor of AChE,BChE, and BACE1, providing a preventive and therapeuticstrategy for Alzheimer’s disease treatment.

Oligonol promotes glucose uptake by modulating the insulin signaling pathway in insulin-resistant HepG2 cells via inhibiting protein tyrosine phosphatase 1B

Himanshu Kumar Bhakta,Pradeep Paudel,Hajime Fujii,Atsuya Sato,박찬흠,Takako Yokozawa,정현아,최재수 대한약학회 2017 Archives of Pharmacal Research Vol.40 No.11

Insulin resistance and protein tyrosine phosphatase1B (PTP1B) overexpression are strongly associatedwith type 2 diabetes mellitus (T2DM), which is characterizedby defects in insulin signaling and glucose intolerance. In a previous study, we demonstrated oligonolinhibits PTP1B and a-glucosidase related to T2DM. In thisstudy, we examined the molecular mechanisms underlyingthe anti-diabetic effects of oligonol in insulin-resistantHepG2 cells. Glucose uptake was assessed using a fluorescentglucose tracer, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose, and the signaling pathwaywas investigated by western blotting. Oligonol significantlyincreased insulin-provoked glucose uptake and decreasedPTP1B expression, followed by modulation of ERKphosphorylation. In addition, oligonol activated insulinreceptor substrate 1 by reducing phosphorylation at serine307 and increasing that at tyrosine 895, and enhanced thephosphorylations of Akt and phosphatidylinositol 3-kinase. Interestingly, it also reduced the expression of two keyenzymes of gluconeogenesis (glucose 6-phosphatase andphosphoenolpyruvate carboxykinase), attenuated oxidativestress by scavenging/inhibiting peroxynitrite, and reactiveoxygen species (ROS) generation, and augmented theexpression of nuclear factor kappa B. These findings suggestoligonol improved the insulin sensitivity of insulinresistantHepG2 cells by attenuating the insulin signalingblockade and modulating glucose uptake and production. Furthermore, oligonol attenuated ROS-related inflammationand prevented oxidative damage in our in vitro modelof type 2 diabetes. These result indicate oligonol haspromising potential as a treatment for T2DM.