The Program Cell Death (Apoptosis) and the Therapy of Cancer

Apoptosis plays many vital roles in maintaining organ homeostasis and represents type I programmed cell death. Programmed cell death happens when the DNA damage is irremediable and has two important pathways, the intrinsic death pathway also known as the mitochondrial pathway, and the extrinsic programmed cell death pathway. Any defects in the regulation of these crucial pathways have been associated with many disorders, most importantly cancer. Therefore, understanding the molecular basis of apoptosis is essential for the treatment of incurable cancer. To date, several anti-cancer drugs have been developed by targeting anti-apoptotic proteins, which are upregulated in many cancers. Nonetheless, a disease progression often time warranted due to the deregulation of several anti or pro-apoptotic proteins which also contribute to drug resistance. Hence, it is important to understand the maintenance and counteraction of apoptosis and improve successful new pharmacological applications of cell death mechanisms for future therapies. This chapter discusses the mechanism of apoptosis and emerging principles of drug resistance in cancer

Phytocannabinoids promote viability and functional adipogenesis of bone marrow-derived mesenchymal stem cells through different molecular targets.

Abstract The cellular microenvironment plays a critical role in the maintenance of bone marrow-derived mesenchymal stem cells (BM-MSCs) and their subsequent cell lineage differentiation. Recent studies suggested that individuals with adipocyte-related metabolic disorders have altered function and adipogenic potential of adipose stem cell subpopulations, primarily BM-MSCs, increasing the risk of heart attack, stroke or diabetes. In this study, we explored the potential therapeutic effect of some of the most abundant non-euphoric compounds derived from the Cannabis sativa plant (or phytocannabinoids) including tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), by analysing their pharmacological activity on viability of endogenous BM-MSCs as well as their ability to alter BM-MSC proliferation and differentiation into mature adipocytes. We provide evidence that CBD, CBDA, CBGA and THCV (5 µM) increase the number of viable BM-MSCs; whereas only CBG (5 µM) and CBD (5 µM) alone or in combination promote BM-MSCs maturation into adipocytes via distinct molecular mechanisms. These effects were revealed both in vitro and in vivo. In addition, phytocannabinoids prevented the insulin signalling impairment induced by palmitate in adipocytes differentiated from BM-MSCs. Our study highlights phytocannabinoids as a potential novel pharmacological tool to regain control of functional adipose tissue in unregulated energy homeostasis often occurring in metabolic disorders including type 2 diabetes mellitus (T2DM), aging and lipodystrophy

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

FORMİL GRUBU İÇEREN PORFİRİN BİLEŞİKLERİNİN SENTEZİ VE TEPKİMELERİ

Porphyrin compounds such as chlorophyll and heme molecules and properties of these compounds have been an important research area in chemistry, biology, medicine and material science. Especially, highly conjugated macrocyclic hybrid compounds is a current research topic in organic synthesis and porphyrin chemistry. In this study, directly linked porphyrin-corrole hybrid compounds were synthesized by the acid catalyzed [2+1] condensation reaction of β-formylated porphyrins and meso-substituted dipyrromethanes and their structures were identified. In the scond part of the study, a new and simple synthetic procedure was described for the synthesis of porphyrin-porphyrin dyads which are connected on β- and meso- positions. β-meso Directly linked porphyrin-porphyrin dyads were synthesized by adapting a method known as “Adler-Longo method” in the literatüre to β-formylated porphyrin compounds. Reaction conditions of synthesized β-meso substituted porphyrin-corrole hybrid and porphyrin-porphyrin dyad compounds were optimized and structures of product compounds were identified by using spectroscopic techniques.TÜBİTAK- 115Z886 nolu projeKlorofil ve heme molekülleri gibi pek çok doğal bileşiğe benzerlik gösteren porfirinler ve bu bileşiklerin özellikleri, kimya, biyoloji, tıp ve malzeme bilimlerinde önemli bir araştırma alanına sahiptir. Özellikle yüksek derecede konjugasyona sahip makrohalkalı hibrit bileşiklerinin araştırmaları, organik sentez ve porfirin kimyasında güncel bir konudur. Bu çalışmada, β-konumunda formillenmiş porfirin bileşikleri ile mezo-sübstitüe dipirolmetan bileşiklerinin [2+1] asit katalizörlü kondenzasyon reaksiyonu sonucu, ilk kez β-mezo pozisyonlarından direkt bağlı porfirin-korol hibrit bileşiklerinin sentezi ve karakterizasyonu gerçekleştirilmiştir. Çalışmasının ikinci bölümünde, β-mezo konumlarından direkt bağlı ikili porfirin-porfirin bileşiklerinin sentezi için yeni ve basit bir sentetik prosedür tanımlanmıştır. Literatürde Adler-Longo metodu olarak bilinen porfirin sentezi β-formil porfirin bileşikleri için adapte edilerek β-mezo pozisyonlarından birbirine direkt bağlı porfirin-porfirin ikili bileşiklerinin sentezi gerçekleştirilmiştir β-mezo Sübstitüe porfirin-korol hibrit bileşikleri ve ikili porfirin-porfirin bileşiklerinin sentezi için tepkime koşulları optimize edilerek, elde edilen bileşiklerin yapıları spektroskopik yöntemler kullanılarak aydınlatılmıştır

Unexpected formation of β, <i>meso</i>-directly linked diporphyrins under Adler–Longo reaction conditions

<p>Unexpected formation of β, <i>meso</i>-directly linked diporphyrin products has been described in the reactions of β-formyl porphyrins with pyrrole under Adler–Longo reaction conditions. Preliminary mechanistic studies indicates that β-dipyrromethane substituted porphyrin structure is the crucial intermediate for the formation of diporphyrin product.</p

Dysfunctional endocannabinoid CB1 receptor expression and signaling contribute to skeletal muscle cell toxicity induced by simvastatin

: Statins are the most prescribed lipid-lowering agents worldwide. Their use is generally safe, although muscular toxicity occurs in about 1 in 10.000 patients. In this study, we explored the role of the endocannabinoid system (ECS) during muscle toxicity induced by simvastatin. In murine C2C12 myoblasts exposed to simvastatin, levels of the endocannabinoids AEA and 2-AG as well the expression of specific miRNAs (in particular miR-152) targeting the endocannabinoid CB1 gene were increased in a time-dependent manner. Rimonabant, a selective CB1 antagonist, exacerbated simvastatin-induced toxicity in myoblasts, while only a weak opposite effect was observed with ACEA and GAT211, selective orthosteric and allosteric agonists of CB1 receptor, respectively. In antagomiR152-transfected myoblasts, simvastatin toxicity was in part prevented together with the functional rescue of CB1. Further analyses revealed that simvastatin in C2C12 cells also suppresses PKC and ERK signaling pathways, which are instead activated downstream of CB1 receptor stimulation, thus adding more insight into the mechanism causing CB1 functional inactivation. Importantly, simvastatin induced similar alterations in skeletal muscles of C57BL/6 J mice and primary human myoblasts. In sum, we identified the dysregulated expression of the endocannabinoid CB1 receptor as well as the impairment of its downstream signaling pathways as a novel pathological mechanism involved in statin-induced myopathy

6098 sayılı Türk Borçlar Kanunu, Karşılaştırmalı, Notlu, İçtihatlı, Atıflı

6098 sayılı Türk Borçlar Kanunu</p