Phloretin-induced suppression of oxidative and nitrosative stress attenuates doxorubicin-induced cardiotoxicity in rats

Objective:To compare the cardioprotective efficacy of equimolar doses(50 mM/kg,p.o.)of phloretin and genistein against doxorubicin-induced cardiotoxicity in rats.Methods:Cardiotoxicity was induced in rats by intraperitoneal injection of 6 mg/kg doxorubicin on alternative days till the cumulative dose reached 30 mg/kg.This study included four treatment groups of rats(n=6):the control group(0.5%carboxymethyl cellulose solution-treated),the doxorubicin-treated group(0.5%carboxymethyl cellulose solution along with doxorubicin),the genistein-treated group(50 mM/kg/day;p.o.along with doxorubicin)and phloretin-treated group(50 mM/kg/day;p.o.along with doxorubicin).On the 10th day of dosing,rats were anesthetized for recording ECG,mean arterial pressure,and left ventricular function.Oxidative stress,nitric oxide levels,and inflammatory cytokines were estimated in the cardiac tissue.Cardiac function parameters(creatine kinase MB,lactate dehydrogenase,aspartate aminotransferase,and alanine transaminase)were estimated in the serum samples.Results:Phloretin treatment inhibited doxorubicin-induced oxidative stress and also reduced nitric oxide levels in cardiac tissues of rats.Phloretin administration attenuated doxorubicin-induced alterations in hemodynamic parameters(heart rate,mean arterial blood pressure,and left ventricular function)and suppressed the expression of pro-inflammatory cytokines.The cardiac injury markers like creatine kinase MB,lactate dehydrogenase,aspartate aminotransferase,and alanine transaminase were reduced by both genistein and phloretin.All these effects of phloretin were more prominent than genistein.Conclusions:Phloretin offers cardioprotection that is comparable to genistein,a clinically validated cardioprotectant against doxorubicin-induced cardiotoxicity.Further studies are needed to confirm and establish the therapeutic utility of phloretin as a chemopreventive adjuvant to doxorubicin chemotherapy.

Synthesis and Evaluation of Glyceride Prodrugs of Naproxen

The glyceride ester derivatives 6a and 6b were prepared by reacting 1,2,3-trihydroxy propane 1,3-dipalmitate/stearate with (S)-naproxen as potential prodrugs. The synthesis was achieved successfully with the aid of N,N’-dicyclohexyl- carbodiimide. These prodrugs were evaluated for anti inflammatory, analgesic and gastroprotective activity. It was found that prodrugs 6a and 6b showed less irritation to gastric mucosa as indicated by ulcer index. The synthesized glyceride esters were found to possess good pharmacological profile as shown by results of anti inflammatory and analgesic activity. The aqueous studies were performed in order to ensure the release of prodrugs. Both prodrugs were found to stable at acidic pH while undergoes hydrolysis at pH 7.4. These findings suggest that the glyceride prodrugs 6a and 6b might be used as potential biolabile derivatives.

Aloin attenuates chronic constriction injury-induced neuropathic pain in rats by inhibiting inflammatory cytokines and oxidative stress

Objective:To investigate the effect of aloin against chronic constriction injury(CCI)-induced neuropathic pain in rats.Methods:Rats were randomly divided into 7 groups:GroupⅠ(normal control),GroupⅡ(sham-operated),GroupⅢ(CCI control)and GroupⅣ,Ⅴ,Ⅵ,andⅦ,which underwent CCI surgery and then were administered with aloin(5 mg/kg,p.o.;25 mg/kg,p.o.;125 mg/kg,p.o.)and gabapentin(50 mg/kg,p.o.),respectively for 14 days.Peripheral neuropathy was induced by silk ligatures(4-0)loosely placed around the sciatic nerve.Nociceptive thresholds against mechanical stimuli(Von-Frey filaments)and thermal stimuli(12℃and 40℃)were measured at midplantar paw region ipsilateral to the compressed nerve on day-3,7,11,and 14.The concentration of cytokines including tumor necrosis factor-α(TNF-α),interleukin-6,and interleukin-1βwas estimated at day-7.At day 14,motor nerve conduction velocity was determined under urethane anesthesia(1.25 g/kg).Oxidative stress parameters(malondiadehyde,glutathione,catalase,and superoxide dismutase)were estimated in sciatic nerve homogenates at day 14.Representative nerve samples were processed for histological investigations.Results:Aloin significantly reduced CCI-induced mechanical and thermal allodynia.It also improved motor nerve conduction velocity and decreased oxidative stress in nerve tissues.In addition,it decreased pro-inflammatory cytokine levels and restored the histoarchitecture of compressed sciatic nerve.Conclusions:Aloin mitigates CCI-induced neuropathic pain in rats by inhibiting oxidative stress and pro-inflammatory cytokines in the afflicted sciatic nerve.

Nrf2 activator corosolic acid meliorates alloxan induced diabetic nephropathy in mice

Objective: To determine whether corosolic acid(CA) targeting nuclear protein expression of Nrf2 activation can be used to attenuate renal damage and preserve renal function in alloxan diabetic mice.Methods: A mouse model with diabetic nephropathy was established to examine the Nrf2 expression. Mice were randomly divided into control, diabetic control, and CA groups treated at 0.4 mg/kg, 2 mg/kg and 10 mg/kg p.o. for 8 weeks. Diabetes was induced in mice by single intraperitoneal injection of alloxan 200 mg/kg in all groups except the control. The mice with fasting blood glucose level over 200 mg/d L were considered as diabetic and were employed in the study. After 4 th and 8 th weeks, urine samples were collected(using metabolic cages) to measure protein and urea. Animals were euthanized, and serum samples were collected to estimate the glucose, creatinine, total protein, urea and blood urea nitrogen. Kidney was isolated at the end of experiment for histology to evaluate anti-oxidant parameters. Immunohistochemistry was performed to examine the Nrf2 expression.Results: CA treatment showed dose dependent reduction in level of biochemical parameters in serum and urine. CA group(10 mg/kg) showed significantly higher body weight and reduced kidney weight. Histopathological examination revealed reduced inflammation, collagen deposition and glomerulosclerosis in renal tissue. CA attenuated renal dysfunction, oxidative stress and inflammatory pro-cytokine levels.Conclusions: CA treatment exhibited ameliorative effect on kidney in mice with its enhanced Nrf2 expression.

QSAR,docking studies and pharmacophore identification of phenylmethyl phenoxy propyl amino propanoic acid derivatives as leukotriene A_4 hydrolase inhibitors

The enzyme leukotriene A4 (LTA4) plays an important role as precursor of slow reactive substances as LTC4, LTD4, and LTE4. It is an attractive target for molecular modeling and QSAR study. Our effort is mainly focused on exploring the SAR for inhibitors of the LTA4 hydrolase through docking study, pharmacophore modeling and molecular descriptor study. The binding of these small molecules on LTA4 hydrolase enzyme was described by the models developed on 2D molecular descriptors, with good predictive power (39 compounds, 6 descriptors, r2 0.98, SEE 0.167, F-value 268.53, q2 0.90, r2adj 0.97, P-value < 0.0001, SD of residuals 0.15). Docking studies were employed to presume the probable binding conformation of these analogues and exploring the SAR for the compounds. The novel pharmacophore represents the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The efforts are aimed to discover the SAR for the inhibitors of LTA4 hydrolase through techniques of QSAR, docking and pharmacophore.

Trigonelline mitigates bleomycin-induced idiopathic pulmonary fibrosis in mice

Objective:To evaluate the effect of trigonelline on bleomycin-induced idiopathic pulmonary fibrosis(IPF)and to explore its underlying mechanisms using network pharmacology.Methods:IPF was induced in C57BL/6 mice by a single intratracheal instillation of bleomycin(5 mg/kg).Trigonelline was administered at doses of 25,50,and 100 mg/kg/day orally from the 2nd day post-bleomycin induction up to the 14th day.In IPF-induced mice,lung coefficient,immune cell infiltration in bronchoalveolar lavage fluid,and oxidative stress were measured.Histological alterations in lung tissues were also assessed.Moreover,network pharmacology approach was conducted to reveal molecular interactions of bleomycin and trigonelline with targets of IPF.Results:Trigonelline treatment reduced bleomycin-induced oxidative stress and immune cell infiltration,and mitigated physiological changes in the lung tissues of mice.Moreover,trigonelline alleviated bleomycin-induced histological alterations in lung tissues.Network pharmacology analysis showed that bleomycin and trigonelline interacted with IPF targets,such as NFKB1,HDAC2,HIF1A,and TLR4.Conclusions:The interaction of trigonelline with key IPF targets and its ameliorative effects on lung damage and oxidative stress highlight its potential in treating IPF.It may be considered an antifibrotic agent for further clinical development.

Small interfering RNA for cancer treatment:overcoming hurdles in delivery

In many ways,cancer cells are different from healthy cells.A lot of tactical nano-based drug delivery systems are based on the difference between cancer and healthy cells.Currently,nanotechnology-based delivery systems are the most promising tool to deliver DNA-based products to cancer cells.This review aims to highlight the latest development in the lipids and polymeric nanocarrier for siRNA delivery to the cancer cells.It also provides the necessary information about siRNA development and its mechanism of action.Overall,this review gives us a clear picture of lipid and polymer-based drug delivery systems,which in the future could form the base to translate the basic siRNA biology into siRNA-based cancer therapies.