Tomato agamous-like6 parthenocarpy is facilitated by ovule integument reprogramming involving the growth regulator KLUH.

Fruit set is established during and soon after fertilization of the ovules inside the quiescent ovary, but the signaling pathways involved remain obscure. The tomato (Solanum lycopersicum) CRISPR loss-of-function mutant of the transcription factor gene AGAMOUS-like6 (SlAGL6; slagl6CR-sg1) is capable of fertilization-independent setting of normal, yet seedless (parthenocarpic), fruit. To gain insight into the mechanism of fleshy fruit set, in this study, we investigated how slagl6CR-sg1 uncouples fruit set from fertilization. We found that mutant ovules were enlarged due to integument over-proliferation and failed to differentiate an endothelium, the integument's innermost layer, upon maturation. A causal relationship between slagl6 loss-of-function and these abnormal phenotypes is inferred from the observation that SlAGL6 is predominantly expressed in the immature ovule integument, and upon ovule maturation, its expression shifts to the endothelium. The transcriptome of unfertilized mutant ovules profoundly differs from that of wild-type and exhibits substantial overlap with the transcriptomes of fertilized ovules sporophytic tissues. One prominent upregulated gene was the fertilization-induced cytochrome P450 cell proliferation regulator SlKLUH. Indeed, ectopic overexpression of SlKLUH stimulated both integument growth in unfertilized ovules and parthenocarpy, suggesting that its suppression by SlAGL6 is paramount for preventing fertilization-independent fruit set. Taken together, our study informs on the transcriptional programs that are regulated by SlAGL6 and demonstrates that it acts from within the ovule integument to inhibit ovary growth beyond anthesis. That by suppressing components of the fertilization-induced ovule reprogramming underlying fruit set.

CRISPR/Cas9 mutants of tomato MICRORNA164 genes uncover their functional specialization in development.

Plant MICRORNA164 (miR164) plays diverse regulatory functions by post-transcriptional repression of certain NAM/ATAF/CUC-domain transcription factors. However, the involvement of miR164 in fleshy fruit development and ripening remains poorly understood. Here, de novo prediction of tomato (Solanum lycopersicum) MIR164 genes identified four genes (SlMIR164a-d), of which SlMIR164d has an atypically long pre-miRNA. The roles of the fruit expressed SlMIR164a, b, and d were studied by analysis of their Clustered Regularly Interspaced Short Palindromic Repeats mutants. The slmir164bCR mutant plants exhibited shoot and flower abnormalities characteristic of ectopic boundary specification, whereas the shoot and flower development of slmir164aCR and slmir164dCR mutants were indistinguishable from wild-type. Strikingly, the knockout of SlMIR164a practically eliminated sly-miR164 from the developing and ripening fruit pericarp. The sly-miR164-deficient slmir164aCR fruits were smaller than the wild-type, due to reduced pericarp cell division and expansion, and displayed intense red color and matte, instead of glossy appearance, upon ripening. We found that the fruit skin phenotypes were associated with morphologically abnormal outer epidermis and thicker cuticle. Quantitation of sly-miR164 target transcripts in slmir164aCR ripening fruits demonstrated the upregulation of SlNAM3 and SlNAM2. Specific expression of their miR164-resistant versions in the pericarp resulted in the formation of extremely small fruits with abnormal epidermis, highlighting the importance of their negative regulation by sly-miR164a. Taken together, our results demonstrate that SlMIR164a and SlMIR164b play specialized roles in development: SlMIR164b is required for shoot and flower boundary specification, and SlMIR164a is required for fruit growth including the expansion of its outer epidermis, which determines the properties of the fruit skin.

MIR172d Is Required for Floral Organ Identity and Number in Tomato.

MicroRNA172 (miR172) functions as a central regulator of flowering time and flower development by post-transcriptional repression of APETALA2-LIKE transcription factors. In the model crop Solanum lycopersicum (tomato), the miR172 family is still poorly annotated and information about the functions of specific members is lacking. Here, de-novo prediction of tomato miR172 coding loci identified seven genes (SlMIR172a-g), that code for four unique species of miR172 (sly-miR172). During reproductive development, sly-miR172s are differentially expressed, with sly-miR172c and sly-miR172d being the most abundant members in developing flowers, and are predicted to guide the cleavage of eight APETALA2-LIKE transcription factors. By CRISPR-Cas9 co-targeting of SlMIR172c and SlMIR172d we have generated a battery of loss-of-function and hypomorphic mutants (slmir172c-dCR). The slmir172c-dCR plants developed normal shoot but their flowers displayed graded floral organ abnormalities. Whereas slmir172cCR loss-of-function caused only a slight greening of petals and stamens, hypomorphic and loss-of-function slmir172dCR alleles were associated with the conversion of petals and stamens to sepaloids, which were produced in excess. Interestingly, the degrees of floral organ identity alteration and proliferation were directly correlated with the reduction in sly-miR172d activity. These results suggest that sly-miR172d regulates in a dose-dependent manner floral organ identity and number, likely by negatively regulating its APETALA2-like targets.

Effect of rutin on retinal VEGF, TNF-α, aldose reductase, and total antioxidant capacity in diabetic rats: molecular mechanism and ocular pharmacokinetics.

PURPOSE: The current study was conducted to explore the potential of rutin in preventing sight-threatening diabetic retinopathy. METHODS: Wistar albino rats (either sex) weighing 200-225 g were intraperitoneally injected with 45 mg/kg streptozotocin (pH 4.5). Rats having blood glucose ≥ 300 mg/dL were divided into two groups (n = 8; each group). Group I served as diabetic control and received normal saline p.o. Group II received rutin 50 mg/kg p.o. for 24 weeks. At the end of 24 weeks, retinal fundus and fluorescein imaging were done, rats were killed, and retinal biochemical assessments were conducted. Moreover, ocular pharmacokinetics of rutin was assessed in the normal rats after a single oral dose of 50 mg/kg. RESULTS: Rutin treatment significantly (p < 0.001) lowered retinal vascular endothelial growth factor, tumor necrosis factor-α, and aldose reductase. Rutin treatment significantly (p < 0.001) elevated the levels of total antioxidant capacity of the retinas. Fundus examination of rutin-treated group showed significantly lower tortuosity index and normal fluorescein angiography. Rutin was detected in the retina as well as in aqueous humor of normal rats. CONCLUSION: Rutin treatment significantly arrested the biochemical disturbances of diabetic retinopathy. The distribution of orally ingested rutin in ocular tissues further substantiate its site-specific action.

Tuning of SlARF10A dosage by sly-miR160a is critical for auxin-mediated compound leaf and flower development.

miR160 adjusts auxin-mediated development by post-transcriptional regulation of the auxin response factors ARF10/16/17. In tomato, knockdown of miR160 (sly-miR160) suggested that it is required for auxin-driven leaf blade outgrowth, but whether additional developmental events are adjusted by sly-miR160 is not clear. Here, the SlMIR160 genes and the genes of its SlARFs targets were edited by CRISPR/Cas9 resulting in the isolation of loss-of-function mutants. In addition, hypomorphic mutants that accumulate variable reduced levels of sly-miR160a were isolated. We found that the loss-of-function mutants in SlMIR160a (CR-slmir160a-6/7) produced only four wiry leaves, whereas the hypomorphic mutants developed leaves and flowers with graded developmental abnormalities. Phenotypic severity correlated with the upregulation of SlARF10A. Consistent with that, double mutants in SlMIR160a and SlARF10A restored leaf and flower development indicating that over-accumulation of SlARF10A underlay the developmental abnormalities exhibited in the CR-slmir160a mutants. Phenotype severity also correlated with the upregulation of the SHOOT MERISTEMLESS homolog Tomato Knotted 2, which in turn activated the transcription of the cytokinin biosynthesis genes SlIPT2 and SlIPT4. However, no change in Tomato Knotted 2 was detected in the absence of SlARF10A, suggesting that it is upregulated due to auxin signaling suppression by SlARF10A. Knockout of sly-miR160a-targeted SlARFs showed that whereas SlARF10A is indispensable for leaf blade outgrowth and floral organ patterning, the functions of SlARF16A and SlARF17 are redundant. Taken together our results suggest that sly-miR160a promotes blade outgrowth as well as leaf and leaflet initiation and floral organ development through the quantitative regulation of its major target SlARF10A.

Cardioprotective effects of rutin via alteration in TNF-α, CRP, and BNP levels coupled with antioxidant effect in STZ-induced diabetic rats.

Diabetic cardiomyopathy (DCM) is a dreadful complication of diabetes responsible for 80 % mortality in diabetic patients, but unfortunately its pharmacotherapy is still incomplete. Rutin is a naturally occurring flavonoid having a long history of use in nutritional supplements for its action against oxidative stress, inflammation, and hyperglycemia, the key players involved in the progression of DCM, but remains unexplored for its role in DCM. This study was conducted to address this lacuna. It was performed in 4-week-old Streptozotocin-induced (45 mg/kg) diabetic rats for a period of 24 weeks to mimic the cardiotoxic effect of chronic hyperglycemia in diabetic patient's heart and to investigate the effect of rutin (50 mg/kg/day) in ameliorating these effects. Heart of the diabetic rats showed altered ECG parameters, reduced total antioxidant capacity, increased inflammatory assault, and degenerative changes. Interestingly, rutin treatment significantly ameliorated these changes with decrease in blood glucose level (p > 0.001), % HbA1c (p > 0.001) and reduced expression of TNF-α (p < 0.001), CRP (p < 0.001), and BNP (p < 0.01) compared to diabetic control rats. In addition, rutin provided significant protection against diabetes associated oxidative stress (p < 0.05), prevented degenerative changes in heart, and improved ECG parameters compared to diabetic control rats. The heart-to-body weight ratio was significantly reduced in rutin treatment group compared to diabetic control rats (p < 0.001). In conclusion, this study implicates that oxidative stress and inflammation are the central players involved in the progression of DCM and rutin ameliorates DCM through its antioxidant and anti-inflammatory actions on heart.

Complex and shifting interactions of phytochromes regulate fruit development in tomato.

Tomato fruit ripening is a complex metabolic process regulated by a genetical hierarchy. A subset of this process is also modulated by light signalling, as mutants encoding negative regulators of phytochrome signal transduction show higher accumulation of carotenoids. In tomato, phytochromes are encoded by a multi-gene family, namely PHYA, PHYB1, PHYB2, PHYE and PHYF; however, their contribution to fruit development and ripening has not been examined. Using single phytochrome mutants phyA, phyB1 and phyB2 and multiple mutants phyAB1, phyB1B2 and phyAB1B2, we compared the on-vine transitory phases of ripening until fruit abscission. The phyAB1B2 mutant showed accelerated transitions during ripening, with shortest time to fruit abscission. Comparison of transition intervals in mutants indicated a phase-specific influence of different phytochrome species either singly or in combination on the ripening process. Examination of off-vine ripened fruits indicated that ripening-specific carotenoid accumulation was not obligatorily dependent upon light and even dark-incubated fruits accumulated carotenoids. The accumulation of transcripts and carotenoids in off-vine and on-vine ripened mutant fruits indicated a complex and shifting phase-dependent modulation by phytochromes. Our results indicate that, in addition to regulating carotenoid levels in tomato fruits, phytochromes also regulate the time required for phase transitions during ripening.

Retinal neuroprotective effects of quercetin in streptozotocin-induced diabetic rats.

The aim of the present study was to evaluate the effects of Quercetin (Qctn), a plant based flavonol, on retinal oxidative stress, neuroinflammation and apoptosis in streptozotocin-induced diabetic rats. Qctn treatment (25- and 50 mg/kg body weight) was given orally for six months in diabetic rats. Retinal glutathione (GSH) and antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] were estimated using commercially available assays, and inflammatory cytokines levels [tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß)] were estimated by ELISA method. Immunofluorescence and western blot studies were performed for nuclear factor kappa B (NF-kB), caspase-3, glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) expressions. Structural changes were evaluated by light microscopy. In the present study, retinal GSH levels and antioxidant enzyme (SOD and CAT) activities were significantly decreased in diabetic group as compared to normal group. However, in Qctn-treated rats, retinal GSH levels were restored close to normal levels and positive modulation of antioxidant enzyme activities was observed. Diabetic retinas showed significantly increased expression of pro-inflammatory cytokines (TNF-α and IL-1ß) as compared to that in normal retinas, while Qctn-treated retinas showed significantly lower levels of cytokines as compared to diabetic retinas. Light microscopy showed significantly increased number of ganglion cell death and decreased retinal thickness in diabetic group compared to those in normal retina; however, protective effect of Qctn was seen. Increased apoptosis in diabetic retina is proposed to be mediated by overexpression of NF-kB and caspase-3. However, Qctn showed inhibitory effects on NF-kB and caspase-3 expression. Microglia showed upregulated GFAP expression, and inflammation of Müller cells resulted in edema in their endfeet and around perivascular space in nerve fiber layer in diabetic retina, as observed through AQP4 expression. However, Qctn treatments inhibited diabetes-induced increases in GFAP and AQP4 expression. Based on these findings, it can be concluded that bioflavonoids, such as Qctn can be effective for protection of diabetes induced retinal neurodegeneration and oxidative stress.

Effects of Trigonella foenum-graecum (L.) on retinal oxidative stress, and proinflammatory and angiogenic molecular biomarkers in streptozotocin-induced diabetic rats.

The aim of the present study was to investigate the protective effects of Trigonella foenum-graecum Linn. (fenugreek) in Streptozotocin-induced diabetic rat retina. Fenugreek (100 and 200 mg/kg body weights) treatment was carried out for 24 weeks and evaluated for inflammatory [tumor necrosis factor (TNF)-α and interleukin (IL)-1ß] and angiogenic [vascular endothelial growth factor (VEGF) and protein kinase C (PKC)-ß] molecular biomarkers. Retinal oxidative stress was evaluated by estimating antioxidant (Glutathione, Superoxide dismutase, and Catalase) parameters. Fluorescein angiography was performed to detect retinal vascular leakage. Electron microscopy was performed to determine basement membrane thickness. In the present study, significant rises in the expressions of retinal inflammatory (TNF-α and IL-1ß) and angiogenic (VEGF and PKC-ß) molecular biomarkers were observed in diabetic retinae compared with normal retinae. However, fenugreek-treated retinae showed marked inhibition in the expression of inflammatory and angiogenic molecular biomarkers. Moreover, results from the present study showed positive modulatory effects of fenugreek on retinal oxidative stress. Fluorescein angiograms and fundus photographs obtained from diabetic retinae showed retinal vascular leakage. On the other hand, fenugreek-treated retinae did not show vascular leakage. Further, thickened BM was recorded in diabetic retina compared with normal retinae. However, fenugreek-treated retinae showed relatively lesser thickening of capillary BM. In conclusion, it may be postulated that fenugreek has great potential in preventing diabetes-induced retinal degeneration in humans after regular consumption in the specified dosage.

Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats.

The purpose of the study was to evaluate the effects of hesperetin (Hsp) on diabetes-induced retinal oxidative stress, neuroinflammation and apoptosis in rats. The Hsp treatment (100 mg/kg body weight) was carried for twenty four weeks in STZ-induced diabetic rats and evaluated for antioxidant (Superoxide dismutase; SOD, Catalase; CAT and glutathione; GSH) enzymes, inflammatory cytokines (TNF-α, IL-1ß), caspase-3, glial fibrillary acidic protein (GFAP) and aquaporin-4(AQP4) expression. Histological changes were evaluated by light and transmission electron microscopic (LM and TEM) studies. Retinal GSH levels and anti-oxidant enzymes (SOD and CAT) activity were significantly decreased in diabetic group as compared to normal group. However, in Hsp-treated rats, retinal GSH levels were restored close to normal levels and positive modulation of anti-oxidant enzyme activity was observed. Diabetic retinae showed significantly increased expression of Pro-inflammatory cytokines (TNF-α and IL-1ß) as compared to normal retinae. While Hsp-treated retinae showed significantly lower levels of cytokines as compared to diabetic retinae. Diabetic retinae showed increased caspase-3, GFAP and AQP4 expression. However, Hsp-treated retinae showed inhibitory effect on caspase-3, GFAP and AQP4 expression. LM images showed edematous Müller cell endfeet, and also degenerated photoreceptor layer; however, protective effect of Hsp was seen on Müller cell processes and photoreceptors. TEM study showed increased basement membrane (BM) thickness in diabetic retina, while relatively thin BM was recorded in Hsp-treated retina. It can be postulated that dietary flavanoids, like Hsp, can be effective for the prevention of diabetes induced neurovascular complications such as diabetic retinopathy.

Fulminant Orbital Cellulitis - A Rare Presentation of Endogenous Endophthalmitis.

BACKGROUND: Endogenous endophthalmitis refers to the intraocular infection resulting via haematogenous spread from the distant foci. Dengue is an important health problem in India with varied ophthalmic manifestations either due to viremia, immunologic phenomenon, or haemorrhagic tendency. CASE: We report an unusual presentation of endogenous endophthalmitis as fulminant orbital cellulitis in a young adult patient having a history of dengue fever. OBSERVATIONS: Young male having history of dengue fever presented with complaints of sudden pain, swelling, redness, and loss of vision in the left eye. His clinical features and radiographic examination were suggestive of orbital cellulitis with pan-ophthalmitis, which rapidly progressed to endophthalmitis. CONCLUSION: This case highlights the role of orbital vessels as a possible route for occurrence of endophthalmitis in a case of orbital cellulitis.

Green tea prevents hyperglycemia-induced retinal oxidative stress and inflammation in streptozotocin-induced diabetic rats.

PURPOSE: Our objective was to investigate the effect of green tea (GT) on diabetes-induced retinal oxidative stress and proinflammatory parameters in rats. METHODS: Treatment (200 mg/kg body weight) was carried out for a period of 16 weeks in streptozotocin-induced diabetic rats and was evaluated for hypoglycemic, antioxidant [reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT)] and anti-inflammatory [tumor necrosis factor (TNF) α, vascular endothelial growth factor (VEGF)] activity. Histological changes were evaluated by transmission electron microscopy. RESULTS: Retinal GSH levels were 1.5-fold lower in diabetic rats as compared to normal rats (p < 0.05). However, in GT-treated rats, retinal GSH levels were restored close to those of the normal group. The antioxidant enzymes SOD and CAT showed a more than 2-fold decrease in activity in diabetic retinae as compared to normal retinae (p < 0.05). Both SOD and CAT enzymatic activities were restored close to normal in the GT-treated group. Expression of proinflammatory parameters (TNF-α and VEGF) was significantly inhibited in GT-treated retinae as compared to diabetic retinae (p < 0.05). Moreover, GT treatment prevented retinal capillary basement membrane thickness. CONCLUSION: The beneficial effects of GT suggest its potential role in the prevention and treatment of diabetic retinopathy in human subjects.

Calotropis procera root extracts block VEGF-induced angiogenesis: quantitative analysis.

Angiogenesis is controlled by number of growth factors, including vascular endothelial growth factor (VEGF). Plant derived anti-angiogenic molecules acting via VEGF are being investigated for curtailing angiogenesis dependent diseases. In this study, methanolic (CM), n-hexane (CH), ethylacetate (CE) and water (CW) extracts of the roots of Calotropis procera were tested for anti-angiogenic activity. In the chicken egg chorioallantoic membrane (CAM) assay, CM, CH and CE but not CW inhibited VEGF-induced neovascularization in a dose-dependent manner. Of all the tested extracts, CM at the dose of 10, 5 and 2.5 ng most effectively inhibited over 83, 71 and 64%, of neovascularization induced by 10ng of VEGF, respectively. Sponge implantation assay in mice further showed that at the dose of 100ng CM, CH and CE but not CW significantly inhibited neovascularization induced by VEGF (100 ng). Taken together, this study indicates that the root extracts of C. procera may possess anti-angiogenic activity.

Risk of brain tumors from wireless phone use.

The debate regarding the health effects of low-intensity electromagnetic radiation from sources such as power lines, base stations, and cell phones has recently been reignited. Wireless communication has dramatically influenced our lifestyle; its impact on human health has not been completely assessed. Widespread concern continues in the community about the deleterious effects of radiofrequency radiations on human tissues and the subsequent potential threat of carcinogenesis. Exposure to low-frequency electromagnetic field has been linked to a variety of adverse health outcomes. This article surveys the results of early cell phone studies, where exposure duration was too short to expect tumor genesis, and 2 sets of more recent studies with longer exposure duration: the Interphone studies and the Swedish studies led by Hardell.

Intraocular pressure-lowering activity of topical application of Aegle marmelos fruit extract in experimental animal models.

AIM: The present study was designed to evaluate the intraocular pressure (IOP)-lowering activity of topical application of the aqueous extract of Aegle marmelos fruit in experimental animal models. MATERIALS AND METHODS: New Zealand white rabbits with normal and experimentally elevated IOP using water loading and steroid-induced models were included in this study. The IOP-lowering effect of A. marmelos fruit extract in rabbits with experimentally elevated IOP was also compared with that of timolol 0.25%. RESULTS: In rabbits with normal IOP, the A. marmelos fruit extract at a concentration of 1% showed the maximum IOP-lowering effect with 22.81% reduction from baseline IOP. The maximum IOP reduction achieved in water loading and steroid-induced models with the same concentration of A. marmelos was 27.57 and 28.41% from baseline, respectively. The efficacy was comparable to that of timolol after 45 min of water loading in the water loading model, and during the first 2 h of treatment in the steroid-induced model. CONCLUSION: A. marmelos fruit extract showed significant IOP-lowering activity in experimental animal models.

Ocimum sanctum extracts attenuate hydrogen peroxide induced cytotoxic ultrastructural changes in human lens epithelial cells.

Hydrogen peroxide (H2O2) is the major oxidant involved in cataract formation. The present study investigated the effect of an aqueous leaf extract of Tulsi (Ocimum sanctum) against H2O2 induced cytotoxic changes in human lens epithelial cells (HLEC). Donor eyes of the age range 20-40 years were procured within 5-8 h of death. After several washings with gentamicin (50 mL/L) and betadine (10 mL/L), clear transparent lenses (n=6 in each group) were incubated in Dulbecco's modified Eagle's medium (DMEM) alone (normal) or in DMEM containing 100 microm of H2O2 (control) or in DMEM containing both H2O2 (100 microm) and 150 microg/mL of Ocimum sanctum extract (treated) for 30 min at 37 degrees C with 5% CO2 and 95% air. Following incubation, the semi-hardened epithelium of each lens was carefully removed, fixed and processed for electron microscopic studies. Thin sections (60-70 mm) were contrasted with uranyl acetate and lead citrate and viewed under a transmission electron microscope. Normal epithelial cells showed intact, euchromatic nucleus with few small vacuoles (diameter 0.58+/-0.6 microm) in well-demarcated cytoplasm. After treatment with H2O2, they showed pyknotic nuclei with clumping of chromatin and ill-defined edges. The cytoplasm was full of vacuoles (diameter 1.61+/-0.7 microm). The overall cellular morphology was typical of dying cells. Treatment of cells with Ocimum sanctum extract protected the epithelial cells from H2O2 insult and maintained their normal architecture. The mean diameter of the vacuoles was 0.66+/-0.2 microm. The results indicate that extracts of O. sanctum have an important protective role against H2O2 injury in HLEC by maintaining the normal cellular architecture. The protection could be due to its ability to reduce H2O2 through its antioxidant property and thus reinforcing the concept that the extracts can penetrate the HLEC membrane.

Oculohypotensive effects of foeniculum vulgare in experimental models of glaucoma.

PURPOSE: Evaluation of oculohypotensive activity of single drop application of aqueous extract of Foeniculum vulgare in experimental models of glaucoma. METHODS: The evaluation of oculohypotensive activity of Foeniculum vulgare was done in rabbits with normal intraocular pressure (IOP) and with experimentally elevated IOP. The experimental increase in IOP was achieved using water loading and steroid induced glaucoma models. RESULTS: The aqueous seed extract of Foeniculum vulgare exhibited 17.49, 21.16 and 22.03% reduction of intraocular pressure (IOP) in normotensive rabbits at 0.3%, 0.6% and 1.2% (w/v) concentrations respectively. The 0.6% concentration was further evaluated in acute and chronic models of glaucoma. A maximum mean difference of 31.20% was observed between vehicle treated and extract treated eyes in water loading model while a maximum mean IOP lowering of 31.29% was observed in steroid induced model of glaucoma. CONCLUSIONS: The aqueous extract of Foeniculum vulgare possesses significant oculohypotensive activity, which was found to be comparable to that of timolol. Further investigations into the mechanism of action, possible toxicity and human clinical trials are warranted before the Foeniculum vulgare finds place in the arsenal of antiglaucoma drugs prescribed by physicians.

Comparative evaluation of pharmacovigilance regulation of the United States, United Kingdom, Canada, India and the need for global harmonized practices.

The primary focus of the pharmacovigilance (PV) practice has been on the collection, assessment, and reporting of the adverse drug reactions to medicinal products. Globalization of the pharmaceutical industry has prompted efforts to toward harmonization of PV practices worldwide to enable improved knowledge of medicine's benefit-risk profile and risk communication. Even as PV has evolved over the past decade, there still exist few areas of discordance across global PV practices. This article compares the PV legislation in the United States, United Kingdom, Canada, and India with a view to understand areas of harmony in the current legislation across regions and further compare health authorities' requirements with recommendations made by international organizations. Identification of potential areas of disharmony would pave the way to design solutions and strategies toward creation of a comprehensive PV system, which can be easily implemented across the globe, thus promoting the safer use of medicines.

Pyruvate provides cardioprotection in the experimental model of myocardial ischemic reperfusion injury.

The present study was designed to evaluate the cardioprotective potential of pyruvate and to characterize the mechanism underlying the protection. Wistar albino rats were randomly divided into three groups. Two groups were administered saline orally (sham, ischemia-reperfusion (I-R) control group) and animals of third group received pyruvate (500 mg/kg) for 4 weeks. On the 29th day, animals of the I-R control and pyruvate treated groups underwent 45 min of occlusion of the left anterior descending (LAD) coronary artery and were thereafter reperfused for 60 min. In the I-R control group, a significant cardiac necrosis, depressed mean arterial pressure (MAP) and heart rate (HR), decline in myocardial antioxidant status and elevation in lipid peroxidation were observed as compared to sham control. Pyruvate treatment restored the myocardial antioxidant status and favorably modulated the altered MAP as compared to I-R control. Furthermore, I/R-induced lipid peroxidation was significantly inhibited by pyruvate treatment. These beneficial cardioprotective effects translated into significant improvement in MAP. Histopathological examination and restored specific myocardial injury marker CK-MB isoenzyme activity further confirmed protective effects of pyruvate. In conclusion, our study has demonstrated that the beneficial effect of pyruvate likely results from improved MAP and suppression of oxidative stress.

Effect of Curcuma longa and Ocimum sanctum on myocardial apoptosis in experimentally induced myocardial ischemic-reperfusion injury.

BACKGROUND: In the present investigation, the effect of Curcuma longa (Cl) and Ocimum sanctum (Os) on myocardial apoptosis and cardiac function was studied in an ischemia and reperfusion (I-R) model of myocardial injury. METHODS: Wistar albino rats were divided into four groups and orally fed saline once daily (sham, control IR) or Cl (100 mg/kg; Cl-IR) or Os (75 mg/kg; Os-IR) respectively for 1 month. On the 31st day, in the rats of the control IR, Cl-IR and Os-IR groups LAD occlusion was undertaken for 45 min, and reperfusion was allowed for 1 h. The hemodynamic parameters{mean arterial pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular peak positive (+) LVdP/dt (rate of pressure development) and negative (-) LVdP/dt (rate of pressure decline)} were monitored at pre-set points throughout the experimental duration and subsequently, the animals were sacrificed for immunohistopathological (Bax, Bcl-2 protein expression & TUNEL positivity) and histopathological studies. RESULTS: Chronic treatment with Cl significantly reduced TUNEL positivity (p < 0.05), Bax protein (p < 0.001) and upregulated Bcl-2 (p < 0.001) expression in comparison to control IR group. In addition, Cl demonstrated mitigating effects on several myocardial injury induced hemodynamic {(+)LVdP/dt, (-) LVdP/dt & LVEDP} and histopathological perturbations. Chronic Os treatment resulted in modest modulation of the hemodynamic alterations (MAP, LVEDP) but failed to demonstrate any significant antiapoptotic effects and prevent the histopathological alterations as compared to control IR group. CONCLUSION: In the present study, significant cardioprotection and functional recovery demonstrated by Cl may be attributed to its anti-apoptotic property. In contrast to Os, Cl may attenuate cell death due to apoptosis and prevent the impairment of cardiac performance.