Berbamine ameliorates isoproterenol-induced myocardial infarction by inhibiting mitochondrial dysfunction and apoptosis in rats

Berbamine (BBM), a bisbenzylisoquinoline alkaloid from roots, bark, and stem of Berberis plant such as Berberis aristata has a wide range of pharmacological activities. However, the evidence for the cardioprotective effect of BBM is inadequate and the molecular mechanism of BBM remains unclear. This study investigated the underlying molecular mechanism of BBM-mediated cardioprotection on isoproterenol (ISO)-induced mitochondrial dysfunction and apoptosis in rats. The assays of mitochondria antioxidant status, mitochondrial marker enzymes, and electron microscopic analysis of mitochondria revealed BBM significantly prevented the mitochondrial dysfunction induced by ISO. The ISO-induced elevation of mitochondrial oxidative stress was also curbed by BBM. Furthermore, pretreatment with BBM protected the heart tissue from ISO-induced apoptosis as evident from decreased terminal dUTP nickend-labeling positive cells and decreased expression of Bax, cytochrome c, cleaved caspase-9, and caspase-3, and poly (ADP-ribose) polymerase and increased expression of Bcl-2 in ISO-induced rats. These current findings suggest that BBM exerts a significant cardioprotective effect on ISO-induced myocardial infarction in rats.     

Attenuation of hyperglycemia-mediated oxidative stress by indole-3-carbinol and its metabolite 3, 3′- diindolylmethane in C57BL/6J mice

In this study, we have investigated the effect of the nutritive phytochemicals, indole-3-carbinol (I3C) and its metabolite, 3, 3′- diindolylmethane (DIM) on oxidative stress developed in type 2 diabetes mellitus (T2DM). This work was carried out in the genetically modified mouse (C57BL/6J mice) that closely simulated the metabolic abnormalities of the human disease after the administration of high fat diet (HFD). Glucose, insulin, hemoglobin (Hb), glycated hemoglobin (HbA1c), thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), conjugated dienes (CD), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), vitamin C, vitamin E, and reduced glutathione (GSH) levels were monitored in all the groups. Treatments positively modulate the glucose, insulin, and Hb and HbA1c levels in HFD mice. TBARS, LOOH, and CD were decreased in treatment groups when compared to the HFD group. Treatments increase SOD, CAT, GPx levels (erythrocyte, liver, kidney, and heart) and vitamin C, vitamin E, and GSH levels (plasma, liver, kidney, and heart) in diabetic mice. From the study, it was clear that the antioxidant-scavenging action were accelerated in mice treated with DIM than the I3C treatment group which was comparable with the standard drug metformin.     

Regulation of the prostaglandin pathway during development of invasive bladder cancer in mice

Prostaglandin E(2) (PGE(2)) is reported to play an important role in tumor development. We explored the differential expression of genes governing production of, and response to, PGE(2) during development of invasive bladder cancer. N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) or vehicle-treated mice (n=4-5) were euthanized after 4-8 weeks (period 1, P1), 12-16 weeks (P2), and 20-23 weeks (P3). Half of each bladder was analyzed histologically and the other half extracted for mRNA analysis by quantitative real-time PCR. Bladders from BBN-treated mice showed progression from submucosal inflammation (P1) to squamous metaplasia/focal CIS (P2) to poorly differentiated, invasive cancer (P3). mRNA levels for the inducible cyclooxygenase, COX-2, were elevated three to fourfold at all time points in BBN-treated mice compared to controls. In contrast, mRNA levels for constitutive COX-1 and cytosolic phospholipase A(2) (cPLA(2)), which releases substrate for COX, were either unchanged or decreased in BBN-treated mice relative to controls. Downstream of COX, mRNA levels of membrane-bound PGE(2) synthase (mPGES-1) were increased 1.7-fold at P1 in BBN bladders but returned to control levels at P2 and P3. mRNA levels for 15-prostaglandin dehydrogenase (PGDH), which inactivates PGE(2), were reduced 50-80% in BBN-treated bladders at all time points. mRNA levels for EP2R and EP4R, receptors for PGE(2), were two to threefold increased at P1, but returned to control levels or below at P3. Hence, increased COX-2 and decreased PDGH expression occurred throughout tumor development, while mPGES-1, EP2R and EP4R were elevated only before development of invasive cancer. We compared expression of these genes in the malignant human urothelial cell lines, HTB-5 and HT-1376, with expression in a benign urothelial cell line, UROtsa. Neither malignant cell line reproduced the complete in vivo pattern, relative to benign cells, but each showed abnormal basal expression of several of the genes downstream of COX-2, but not COX-2 itself. We conclude that components involved in PGE(2) synthesis and activity are differentially regulated during bladder tumor development and the therapeutic efficacy of targeting the various components may vary with stage of tumor development.     

Identification of native Bacillus thuringiensis strain from South India having specific cytocidal activity against cancer cells

Aim: To identify the parasporin‐producing, indigenous Bacillus thuringiensis strains that specifically targets human cancer cells in Madurai, Tamil Nadu, South India. Methods and Results: Alkali‐solubilized inclusion proteins from the 82 nonclonal indigenous isolates of B. thuringiensis were analysed for their cytotoxicity against two human cancer cell lines, U‐937 (human histiocytic lymphoma) and HCT‐250 (adherent human colon cancer cells). Activated inclusion protein from one of the isolates, B. thuringiensis LDC‐391, was found to be highly cytotoxic to HCT‐250 and moderately toxic to U‐937, but nontoxic to normal lymphocytes. This strain did not show any insecticidal activity against the lepidopteran and dipteran larvae tested, as well as it was nonhaemolytic on human erythrocytes. The Western‐blotting analysis showed that the putative 180 kDa cytotoxic protein from the isolate B. thuringiensis LDC‐391 cross‐reacted with the reference antisera of 81‐kDa parasporin‐1. Conclusions: Our observations imply that B. thuringiensis LDC‐391 is different from the already reported parasporin producers, as it is showing variation in the target specificity. Significance and Impact of the Study: Characterizing these proteins can pave the way to alleviate problems associated with neoplastic transformation and cancer progression.     

Niaspan Attenuates the Adverse Effects of Bone Marrow Stromal Cell Treatment of Stroke in Type One Diabetic Rats

Aims

Our previous studies have found that bone-marrow-stromal cells (BMSC) therapy improves functional recovery after stroke in non-diabetic rats while increases brain hemorrhage and induces arteriosclerosis-like changes in type-one-diabetic (T1DM) rats. Niaspan treatment of stroke increases vascular stabilization, decreases brain hemorrhage and blood-brain-barrier (BBB) leakage in T1DM rats. We therefore tested the hypothesis that combination therapy of BMSC with Niaspan attenuates the side effects of BMSC monotherapy in T1DM rats.

Methods

T1DM-rats induced by streptozotocin were subjected to 2 hours of middle-cerebral-artery occlusion (MCAo) and treated with: 1) PBS; 2) BMSC (5×10⁶); 3) Niaspan (40 mg/kg) daily for 14 days; 4) BMSC (5×10⁶) +Niaspan (40 mg/kg, daily for 14 days) combination starting at 24 hours after MCAo. All rats were monitored for 14 days.

Results

Combination BMSC+Niaspan treatment of T1DM-MCAo rats did not increase brain hemorrhage, and significantly decreased BBB leakage and vascular arteriosclerosis-like changes as well as decreased Angiogenin, matrix metalloproteinase 9 (MMP9) and ED1 expression in ischemic brain and internal-carotid-artery compared to non-treatment control and BMSC monotherapy animals.

Conclusions

Combination therapy using BMSC with Niaspan decreases BBB leakage and cerebral arteriosclerosis-like changes. These beneficial effects may be attributed to the decreased expression of Angiogenin, MMP9 and ED1.     

Synthesis,DNA/protein binding and in vitro cytotoxic studies of new palladium metallothiosemicarbazones

A series of four new thiosemicarbazone complexes of palladium have been synthesized, characterized and evaluated for their DNA/protein binding with CT-DNA and BSA, respectively. The new complexes bound to CT-DNA by intercalation mode and in protein binding studies, the complexes bound to BSA binding mechanism was found as static quenching. Among them the complex 4 had a strong binding affinity with BSA. In addition, in vitro cytotoxic studies were carried out on lung cancer (A549) and liver cancer (HepG2) cell lines and found that the complexes exhibited better activity than their parent thiosemicarbazone analogues. The complex 3 exhibited better activity than other complexes and this fact supported by the increased accumulation of the complexes in to the cancer cells which are evident from inter cellular uptake studies.     

2-Thiophenyltellurium derivatives: Alternative synthetic routes and structural characterization

Grignard reagent prepared from 2-thiophenyl bromide in THF consumes elemental tellurium readily at room temperature and provides a route to obtain bis(2-thiophenyl)ditelluride, Tpn₂Te₂ (1, Tpn = 2-C₄H₃S) in good yield. It can also thiophenylate aryltellurium(II) bromides, producing solutions of mixed aryl(heteroaryl)tellurides, which when chlorinated give crystalline aryl(heteroaryl)tellurium(IV) dichlorides, ArTpnTeCl₂ (Ar = 1-C₁₀H₇, Npl; 2,4,6-Me₃C₆H₂, Mes). Oxidative addition of α-bromo-N,N-diethylacetamide to (2-thiophenyl)tellurium(II) bromide, gave the mixed alkyl(heteroaryl)tellurium(IV) dibromide, (Et₂NCOCH₂)TpnTeBr₂. Ditelluride 1 can be detellurated by electrolytic copper to the bis(2-thiophenyl)telluride, Tpn₂Te (2). Chemical shifts, δ(¹H, ¹³C and ¹²⁵Te) for (2-thiophenyl)tellurium(IV) halides are reported. Crystal structures of Tpn₂TeBr₂ (2b), Tpn₂TeI₂ (2c) and Mes(Tpn)TeCl₂ (2e) have been determined unambiguously. In the case of 2e, steric repulsion of the mesityl ligand counters the tellurium lone pair repulsion to widen the equatorial C-Te-C angle to the extent of 108°. In the crystal lattices of 2b and 2c, the intermolecular Te?X secondary bonds give rise to an interesting tetrameric supramolecular architecture with S₂ symmetry that defies the stereochemical activity of the lone pair on the central tellurium atom.