The Complex Roles of DNA Repair Pathways, Inhibitors, Hyperthermia, and Contact Inhibition in Cell Cycle Halts.

The cell cycle has the capacity to safeguard the cell's DNA from damage. Thus, cell cycle arrest can allow tumor cells to investigate their own DNA repair processes. Cancer cells become extremely reliant on G1-phase cyclin-dependent kinases due to mutated oncogenes and deactivated tumor suppressors, producing replication stress and DNA damage during the S phase and destroying checkpoints that facilitate progression through the S/G2/M phase. DNA damage checkpoints activate DNA repair pathways to prevent cell proliferation, which occurs when the genome is damaged. However, research on how cells recommence division after a DNA lesion-induced arrest is insufficient which is merely the result of cancer cells' susceptibility to cell cycle arrest. For example, defects in the G1 arrest checkpoint may cause a cancer cell to proliferate more aggressively, and attempts to fix these complications may cause the cell to grow more slowly and eventually die. Defects in the G2-M arrest checkpoint may enable a damaged cell to enter mitosis and suffer apoptosis, and attempts to boost the effectiveness of chemotherapy may increase its cytotoxicity. Alternatively, attempts to promote G2-M arrest have also been linked to increased apoptosis in the laboratory. Furthermore, variables, such as hyperthermia, contact inhibition, nucleotide shortage, mitotic spindle damage, and resting phase effects, and DNA replication inhibitors add together to halt the cell cycle. In this review, we look at how nucleotide excision repair, MMR, and other variables, such as DNA replication inhibitors, hyperthermia, and contact inhibition, contribute to the outlined processes and functional capacities that cause cell cycle arrest.

Gastroprotective potential and mechanisms of action of Hedera nepalensis

Abstract Hedera nepalensis (H. nepalensis) , belonging to the family Araliaceae, is a medicinal plant traditionally used to treat stomach problems. The current study investigated the gastroprotective potential and the mechanism of action of H. nepalensis in diclofenac-and ethanol-induced ulcer models. Anti-oxidant and lipid peroxidation inhibitory prospects of H. nepalensis were checked out by free radical scavenging assay and UV spectrophotometer respectively. Effect of H. nepalensis on the pH, gastric total acidity of gastric juice and protective effects of H. nepalensis against ulcer models have been examined. Histopathological studies have been carried out. The aqueous methanol extract of H. nepalensis (100 µg/mL) showed anti-oxidant (83.55%) and lipid peroxidation inhibitory (70.88%) potential at 1000 µg/mL; the extract had no buffer potential. The extract (400 mg/kg) significantly (81.12% and 63.46%) showed gastroprotective effect in diclofenac and ethanol-induced rat ulcer models respectively. Histopathological studies confirmed the biochemical findings. FTIR analysis showed the presence of carboxylic acid, alkanes, conjugated alkanes, aldehydes and alkyl-aryl ethers. Gallic acid, M-coumaric acid and quercetin were found by HPLC analysis. H. nepalensis exhibited significant protection against diclofenac and ethanol induced gastric damage by anti-oxidant and lipid peroxidation suppression effects suggesting potential broad utility in treatment of diseases characterized with gastric damage.

Phytochemicals as Chemo-Preventive Agents and Signaling Molecule Modulators: Current Role in Cancer Therapeutics and Inflammation.

Cancer is one of the deadliest non communicable diseases. Numerous anticancer medications have been developed to target the molecular pathways driving cancer. However, there has been no discernible increase in the overall survival rate in cancer patients. Therefore, innovative chemo-preventive techniques and agents are required to supplement standard cancer treatments and boost their efficacy. Fruits and vegetables should be tapped into as a source of compounds that can serve as cancer therapy. Phytochemicals play an important role as sources of new medication in cancer treatment. Some synthetic and natural chemicals are effective for cancer chemoprevention, i.e., the use of exogenous medicine to inhibit or impede tumor development. They help regulate molecular pathways linked to the development and spread of cancer. They can enhance antioxidant status, inactivating carcinogens, suppressing proliferation, inducing cell cycle arrest and death, and regulating the immune system. While focusing on four main categories of plant-based anticancer agents, i.e., epipodophyllotoxin, camptothecin derivatives, taxane diterpenoids, and vinca alkaloids and their mode of action, we review the anticancer effects of phytochemicals, like quercetin, curcumin, piperine, epigallocatechin gallate (EGCG), and gingerol. We examine the different signaling pathways associated with cancer and how inflammation as a key mechanism is linked to cancer growth.

Evaluation of Hepatoprotective and Gastroprotective Activities of Paspalidium flavidum Leaves Extract in Experimental Animal Models.

Paspalidium flavidum (watercrown grass), a medicinal plant, is traditionally used in liver ailments and stomach problems. The hepatoprotective and gastroprotective activities of the aqueous methanol extract of Paspalidium flavidum (AMEPF) were studied in experimental animal models. Paracetamol and aspirin were used to induce hepatotoxicity and gastric ulcer in rats, respectively. Biochemical hepatic parameters, gastric pH, total acidity, ulcer index, percentage protection, nitric oxide and TNF-α were measured in AMEPF-treated groups. Moreover, GC-MS analysis of AMEPF was performed. Pretreatment with AMEPF improved the blood lipid profile and restored liver function tests in paracetamol-induced hepatotoxicity. While in aspirin-induced gastric ulcer, oral administration of AMEPF significantly reduced (P<0.05) the gastric lesions, total acidity and ulcer scoring index, TNF-α with upregulation of nitric oxide when compared with the Diseased group. AMEPF exhibited anti-lipid peroxidation activity. Histopathological studies were in good agreement with the biochemical findings. GC-MS analysis revealed the presence of anti-oxidant phyto-constituents, including oleic acid and 1,2-benzenedicarboxylic acid, mono(2-ethylhexyl) in AMEPF. This study suggested that aqueous methanol extract from the leaves of P. flavidum has beneficial hepatoprotective and gastroprotective activities related to its anti-oxidant phytochemicals.

Therapeutic appraisal of ephedrine against rheumatoid arthritis: A new indication.

Ephedra, natural flora has been used traditionally to treat rheumatism since decades. The scientific evidence of anti-rheumatic effect of this plant has also been reported. But the anti-rheumatic activity of major constituent of this plant (ephedrine) has not been evaluated. Based on this, the current study was aimed to assess anti-arthritic activity of ephedrine by using in vitro and in vivo approaches. Correspondingly, enzyme linked immunosorbent assay was performed for the estimation of prostaglandins E2 (PGE2) and tumor necrosis factor-α (TNF-α) in serum of formaldehyde-induced arthritic animals. The results elaborated significant reduction in albumin denaturation and remarkable progress on stabilization of red blood cells outer membrane at higher concentration during in vitro experiments. The ephedrine (40mg/kg) revealed noteworthy (p<0.001) inhibition in paw swelling in animals intoxicated with albumin as well as formaldehyde as compared to animals of control group by in vivo results. In this assay, ephedrine (20 & 40 mg/kg orally) significantly suppressed the level of these inflammatory markers (PGE2 & TNF-α). Ephedrine exhibited anti-arthritic effect by decreasing pro-inflammatory cytokines (PGE2 & TNF-α). This experimental work pharmacologically supports the use of ephedrine as anti-rheumatic drug but limited to evaluate in immunological arthritic model.

Understanding oxidants and antioxidants: Classical team with new players.

The free radical oxidants such as reactive oxygen species, reactive nitrogen species, and reactive sulfur species are produced inside cells through various metabolic processes. The body is equipped with an antioxidant defense system that guards against oxidative damage caused by these reactive oxidants and plays a major role in protecting cells from oxidative stress and damage. Antioxidants such as glutathione (GSH), thioredoxin, ascorbic acid and enzymes, for example, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) counter the oxidative stress and protect lipids, proteins, and DNA. Antioxidants such as tocopherols, ascorbic acid, carotenoids, flavonoids, amino acids are also natural antioxidants present in foods. There is increasing demand and availability of designer foods fortified with antioxidants and probiotics that may be important in human health. The review article presents a brief overview of oxidants and antioxidant systems inside the human body including the role of probiotics and inflammation. PRACTICAL APPLICATIONS: Antioxidants such as GSH, thioredoxin, ascorbic acid, etc. and protective enzymes, for example, SOD, GPx, CAT, etc. counter oxidative stress and protect cellular biomolecules. Antioxidants such as tocopherols, ascorbic acid, carotenoids, flavonoids, amino acids, phospholipids, and sterols are natural antioxidants found in consumed foods. They play a major role in scavenging free radical and non-radical oxidants, and protect cells from oxidative stress and damage. The importance of antioxidants can be understood from the fact that oxidative damage is now associated with a variety of diseases including cancer, neurodegeneration, diabetes, etc. Several approaches to improve human health and achieve longevity use dietary antioxidants as formulation in diet and fortified foods. Antioxidants also maintain freshness and prolonging the shelf life of food products. The fortified or designer foods that are added with antioxidant nutrients and the use of microorganisms as probiotics are increasingly available in the market as health foods and supplements.

Influence of Ascorbic Acid on the Structure and Function of Alpha-2- macroglobulin: Investigations using Spectroscopic and Thermodynamic Techniques.

BACKGROUND: Ascorbic acid is a classic dietary antioxidant which plays an important role in the body of human beings. It is commonly found in various foods as well as taken as dietary supplement. OBJECTIVE: The plasma ascorbic acid concentration may range from low, as in chronic or acute oxidative stress to high if delivered intravenously during cancer treatment. Sheep alpha-2- macroglobulin (α2M), a human α2M homologue is a large tetrameric glycoprotein of 630 kDa with antiproteinase activity, found in sheep's blood. METHODS: In the present study, the interaction of ascorbic acid with alpha-2-macroglobulin was explored in the presence of visible light by utilizing various spectroscopic techniques and isothermal titration calorimetry (ITC). RESULTS: UV-vis and fluorescence spectroscopy suggests the formation of a complex between ascorbic acid and α2M apparent by increased absorbance and decreased fluorescence. Secondary structural changes in the α2M were investigated by CD and FT-IR spectroscopy. Our findings suggest the induction of subtle conformational changes in α2M induced by ascorbic acid. Thermodynamics signatures of ascorbic acid and α2M interaction indicate that the binding is an enthalpy-driven process. CONCLUSION: It is possible that ascorbic acid binds and compromises antiproteinase activity of α2M by inducing changes in the secondary structure of the protein.

Appraisal of anti-arthritic and nephroprotective potential of Cuscuta reflexa.

CONTEXT: Cuscuta reflexa Roxb. (Cuscutaceae) has been used traditionally for treating sore knees and kidney problems, but its efficacy has not been scientifically examined in treating arthritis and nephrotoxicity. OBJECTIVE: Present study determines antiarthritic and nephroprotective potential of the aqueous methanolic extract of Cuscuta reflexa (AMECR). MATERIALS AND METHODS: Antiarthritic activity of Cuscuta reflexa in formaldehyde and turpentine oil-induced rat arthritis models was appraised at 200, 400 and 600 mg/kg doses for 10 days and 6 h period, respectively, and in vitro protein denaturation (bovine serum albumin, egg albumin) inhibition was studied at 25-800 µg/mL concentration. The nephroprotective effect involved gentamicin-induced nephrotoxicity in rats at 200, 400 and 600 mg/kg doses. RESULTS: Plant extract at 600 mg/kg significantly reduced paw oedema and joint swelling with maximal inhibition of 71.22% at the 6th hour for turpentine oil and 76.74% on 10th day for formaldehyde. Likewise, in vitro results corroborated significant concentration-dependent increase in percentage protection at 800 µg/mL against both bovine serum albumin (89.30%) and egg albumin (93.51%) denaturation. Similarly, 600 mg/kg dose showed maximum nephroprotection by reducing serum urea (41.400 ± 0.510 mg/dL), uric acid (0.740 ± 0.032 mg/dL), blood urea nitrogen (18.370 ± 0.328), creatinine (3.267 ± 0.076) and minimizing kidney weight gain (0.586 ± 0.005) and histopathological alterations on 8th day. Furthermore, phytochemical and HPLC analysis revealed the presence of important phytoconstituents. DISCUSSION AND CONCLUSIONS: These results suggest that AMECR provides protection against arthritis and nephrotoxicity that might be due to the existence of phytoconstituents, thus supporting folkloric claim.

EVALUATION OF HEPATOPROTECTIVE ACTIVITY OF MELILOTUS OFFICINALIS L. AGAINST PARACETAMOL AND CARBON TETRACHLORIDE INDUCED HEPATIC INJURY IN MICE.

Hepatic diseases are becoming common day by day and pose serious health threats to the life of humans. In order to treat these diseases, the attention of man is diverting towards herbal drugs, which are much safer and cost effective than synthetic drugs. The aim of present study was to investigate hepatoprotective activity of methanolic extract of Melilomus officinalis against paracetamol and carbon tetrachloride induced hepatic damage. Melilotus officinalis at selected oral doses of 50 mg/kg and 100 mg/kg showed significant hepatoprotective effects by decreasing the levels of serum marker enzymes such as total bilirubin, SGOT, SGPT, ALP, albumin and total protein, when compared with standard drug (silymarin) and negative control. Similarly, histopathological studies also supported biochemical estimations. It was concluded that extract of Melilotus officinali has strong hepatoprotective activity against paracetamol and carbon tetrachloride induced hepatotoxicity, which might be due to free radical scavenging mechanisms exhibited by flavonoids and phenolics, thus affirming its traditional therapeutic role in liver injury.

ANTI-INFLAMMATORY, ANALGESIC AND ANTIPYRETIC ACTIVITIES OF THE AQUEOUS METHANOLIC EXTRACT OF BERBERIS CALLIOBOTRYS IN ALBINO MICE.

The aqueous methanolic extract of stem part of Berberis calliobotiys (AMEBC) was evaluated for anti-inflammatory, analgesic and antipyretic activities in albino mice. Anti-inflammatory activity was evaluated by using carrageenan and albumin induced paw edema, while the analgesic effect was assessed by using formalin-induced paw licking and acetic acid induced abdominal writhing in mice. The brewer's yeast-induced pyrexia model was used for antipyretic investigation. Ibuprofen (40 mg/kg) was used as a standard drug in all the three models. The aqueous methanolic extract at both (250 mg/kg and 500 mg/kg) doses, showed highly significant (p < 0.001) reduction in paw edema induced by carrageenan and albumin. Moreover, the aqueous methanolic extract also highly significantly (p < 0.001) reduced (87%) the formalin-induced paw licking at 500 mg/kg. The highly significant (p < 0.001) reductions (24.48% and 37.9%) was also observed in the number of writhings. Furthermore, aqueous methanolic extract also demonstrated significant (p < 0.001) antipyretic activity against yeast induced pyrexia. The maximum effect was observed in all the three parameters at 500 mg/kg dose. The results suggest a potential benefit of the aqueous methanolic extract of Berbeis calliobotrys in treating conditions associated with inflammation, pain and fever.

EVALUATIN OF ANTIHYPERTENSIVE ACTIVITY OF SONCHUS ASPER L. IN RATS.

The present investigation was carried out to evaluate the effect of aerial parts of Sonchus asper L. in normotensive, glucose and egg feed diet induced hypertensive rats. Aqueous-methanolic extract of Sonchus asper in 250, 500 and 1000 mg/kg doses was studied in normotensive and glucose induced hypertensive rats using the non-invasive technique. The results obtained showed that the extract has significantly (p < 0.5 - p < 0.001) decreased the blood pressure and heart rate in dose dependent manner. The dose 1000 mg/kg of the extract produced the maximum antihypertensive effect and was selected for further experiments. The extract was found to prevent the rise in blood pressure of egg and glucose fed rats as compared to control group in 21 days study. The LD50 of the plant extract was 3500 mg/kg b.w. in mice and sub-chronic toxicity study showed that there was no significant alteration in the blood chemistry of the extract treated rats. It is conceivable, therefore, that the aqueous-methanolic extract of Sonchus asper has exerted considerable antihypertensive activity in rats and has duly supported traditional medicinal use of plant in hypertension.

EVALUATION OF ANTI-DIABETIC EFFECTS OF POLY-HERBAL PRODUCT "DIABETIC BAL" IN ALLOXAN-INDUCED DIABETIC RABBITS.

The current study was conducted to evaluate the anti-diabetic effect of polyherbal product "diabetic bal" in normal and alloxan induced diabetic rabbits. Glibenclamide was used as standard drug. Diabetes was induced by single i.v. injection of 150 mg/kg b.w. of alloxan monohydrate in rabbits. "Diabetic bal" (250 and 500 mg/kg) significantly decreased the blood glucose level both in normal and diabetic rabbits in dose dependent manner. In oral glucose tolerance test, "Diabetic bal" demonstrated a significant inhibitory effect on rise of blood glucose level compared to control. "Diabetic bal" showed synergistic anti-hyperglycemic effect with dif- ferent units of insulin in diabetic rabbits. The "diabetic bal" decreased the glucose level and prevented the weight loss of diabetic rabbits as compared to control for an extended period of one month. It caused a significant increase (p < 0.001) in the insulin level of treated diabetic rabbits in 30 days study. In addition AST, ALT, ALP, cholesterol, LDLs, VLDLs and triglyceride level were significantly reduced whereas HDLs level was sig- nificantly elevated in diabetic rabbits with 500 mg/kg dose. The herbal product did not cause any significant change in CBC as compared to normal control in diabetic rabbits for one month. It is conceivable; therefore, that "diabetic bal" is effective in diabetes and its associated complications which support its use in folklore.

A review of characterization of tocotrienols from plant oils and foods.

Tocotrienols, members of the vitamin E family, are natural compounds found in a number of vegetable oils, wheat germ, barley and certain types of nuts and grains. Vegetable oils provide the best sources of these vitamin E forms, particularly palm oil and rice bran oil contain higher amounts of tocotrienols. Other sources of tocotrienols include grape fruit seed oil, oats, hazelnuts, maize, olive oil, buckthorn berry, rye, flax seed oil, poppy seed oil and sunflower oil. Tocotrienols are of four types, viz. alpha (α), beta (ß), gamma (γ) and delta (δ). Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid side chain. A number of researchers have developed methods for the extraction, analysis, identification and quantification of different types of vitamin E compounds. This article constitutes an in-depth review of the chemistry and extraction of the unsaturated vitamin E derivatives, tocotrienols, from various sources using different methods. This review article lists the different techniques that are used in the characterization and purification of tocotrienols such as soxhlet and solid-liquid extractions, saponification method, chromatography (thin layer, column chromatography, gas chromatography, supercritical fluid, high performance), capillary electrochromatography and mass spectrometry. Some of the methods described were able to identify one form or type while others could analyse all the analogues of tocotrienol molecules. Hence, this article will be helpful in understanding the various methods used in the characterization of this lesser known vitamin E variant.

Evaluation of anti-inflammatory, analgesic and antipyretic activities of Thymus serphyllum Linn. in mice.

The present study was conducted to evaluate the analgesic, anti-inflammatory and antipyretic activities of Thymus serphyllum Linn. in mice. Anti-inflammatory activity was evaluated by carrageenan and egg albumin induced paw edema in mice, while analgesic activity was assessed using formalin induced paw licking and acetic acid induced abdominal writhing in mice. For determination of antipyretic activity, pyrexia was induced by subcutaneous injection of 20% yeast. All the extracts produced significant anti-inflammatory effect however, ether extract produced maximum effect 34% inhibition (p < 0.001) against carrageenan and 22% (p < 0.01) inhibition against egg albumin induced paw edema in mice at the end of 3 h. Ether extract produced prominent analgesic effect 77% (p < 0.001) inhibition in acetic acid induced abdominal writhing and 59% inhibition in formalin induced paw licking model in mice, respectively. Ether extract also demonstrated significant (p < 0.001) antipyretic activity against yeast induced pyrexia. The plant showed no sign of toxicity up to the dose of 2000 mg/kg in mice. This study supports the use of Thymus serphyllum in traditional medicine for inflammation accompanied by pain and fever.

Tocotrienols have a nephroprotective action against lipid-induced chronic renal dysfunction in rats.

Vitamin E is the generic term for a group of tocopherols and tocotrienols (T3). Hyperlipidemia has been known to cause progressive chronic renal dysfunction (CRD). Several investigators have reported that T3 have hypolipidemic and nephroprotective activity against free radical-related diseases. This study was conducted to determine if T3 as tocotrienol-rich fraction (TRF) from palm oil would protect against lipid-induced CRD in rats. For the induction of atherosclerosis and hyperlipidemia, Wistar male rats were fed an atherogenic diet containing 1.25% cholesterol, 0.5% cholic acid and 21% beef tallow (42.6% calories from fat). The atherogenic diet was given for 14 weeks to induce atherosclerosis. The control rats were given normal rat chow and drug control animals treated with TRF (100 mg/kg bw; orally). The first group was taken as disease control in which the animals were left untreated and given normal rat chow for six weeks, while the second group was treated with 100 mg TRF/kg bw. Atherosclerosis and renal functions were evaluated after six weeks of TRF treatment. Feeding an atherogenic diet to rats for 14 weeks resulted in dyslipidemia and impaired renal functions with decreased glomerular filtration rate. The treatment with TRF significantly reduced dyslipidemia and inhibited the development of CRD caused by atherogenic factors. These findings show that low-dose treatment of TRF may provide significant health benefits in the prevention of lipid-induced CRD. The study suggests that TRF is effective in preventing lipid-induced CRD.

Pharmacological potential of tocotrienols: a review.

Tocotrienols, members of the vitamin E family, are natural compounds found in a number of vegetable oils, wheat germ, barley, and certain types of nuts and grains. Like tocopherols, tocotrienols are also of four types viz. alpha, beta, gamma and delta. Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid side chain. Tocopherols are lipophilic in nature and are found in association with lipoproteins, fat deposits and cellular membranes and protect the polyunsaturated fatty acids from peroxidation reactions. The unsaturated chain of tocotrienol allows an efficient penetration into tissues that have saturated fatty layers such as the brain and liver. Recent mechanistic studies indicate that other forms of vitamin E, such as γ-tocopherol, δ-tocopherol, and γ-tocotrienol, have unique antioxidant and anti-inflammatory properties that are superior to those of α-tocopherol against chronic diseases. These forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids and suppress proinflammatory signalling, such as NF-κB and STAT. The animal and human studies show tocotrienols may be useful against inflammation-associated diseases. Many of the functions of tocotrienols are related to its antioxidant properties and its varied effects are due to it behaving as a signalling molecule. Tocotrienols exhibit biological activities that are also exhibited by tocopherols, such as neuroprotective, anti-cancer, anti-inflammatory and cholesterol lowering properties. Hence, effort has been made to compile the different functions and properties of tocotrienols in experimental model systems and humans. This article constitutes an in-depth review of the pharmacology, metabolism, toxicology and biosafety aspects of tocotrienols. Tocotrienols are detectable at appreciable levels in the plasma after supplementations. However, there is inadequate data on the plasma concentrations of tocotrienols that are sufficient to demonstrate significant physiological effect and biodistribution studies show their accumulation in vital organs of the body. Considering the wide range of benefits that tocotrienols possesses against some common human ailments and having a promising potential, the experimental analysis accounts for about a small fraction of all vitamin E research. The current state of knowledge deserves further investigation into this lesser known form of vitamin E.

Possible mechanism of cardiac depressant activity of Berberis orthobotrys roots in isolated rabbit heart.

Berberis orhob, otrvs Bien. ex Aitch. (B.o.) has been reported to have antihypertensive effect in different experimental models. The aim of present study was to evaluate the possible antihypertensive mechanism. Aqueous methanolic extract of B.o. roots and its various fractions namely (ethyl acetate, n-butanol or aqueous) in different concentrations (10 ng/mL, 100 ng/mL, I pg/mL, 10 pg/mL, 100 pg/mL ) were evaluated in isolated perfused rabbit heart to assess their effect on force of contraction, HR and perfusion pressure. The crude extract of B.o. and its fractions exhibited a significant decrease in heart rate, contractility and perfusion pressure of isolated rabbit heart, however, butanolic fraction produced more prominent effect and was selected for further study. The effects of butanol fraction were not blocked by atropine (10' M) in isolated perfused heart. However, butanol fraction significantly blocked the effects of adrenaline (10' M). It is therefore conceivable that cardiac depressant activity of B.o. butanol fraction might be due to the presence of certain 3-blocking agents which might be responsible for antihypertensive effect However, further experiments are required to isolate the active compound(s) and elucidate exact mechanism of action.

Pharmacological evaluation of antihypertensive effect of aerial parts of Thymus linearis benth.

Traditionally Thymus linearis Benth. have been used for treatment of various diseases including hypertension. The present study was conducted to evaluate the hypotensive and antihypertensive effect of aqueous methanolic extract of aerial parts of Thymus linearis Benth. in normotensive and hypertensive rats. Acute and subchronic studies were also conducted. The aqueous methanolic extract produced a significant decrease in SBP, DBP, MBP and heart rate of both normotensive and hypertensive rats. LDv, of the extract was found to be 3000 mg/kg. The extract also exhibited a reduction in serum ALT, AST, ALP, cholesterol, triglycerides and LDL levels, while a significant increase in HDL level was observed. It is conceivable therefore, that Thymus linearis Benth. contains certain active compound(s) that are possibly responsible for the observed antihypertensive activity. Moreover, these findings further authenticate the traditional use of this plant in folklore medicine.

Protective effects of tocotrienols against lipid-induced nephropathy in experimental type-2 diabetic rats by modulation in TGF-ß expression.

Dyslipidemia is common in patients with diabetes mellitus (DM) and is considered a risk factor for the progression of diabetic nephropathy (DN). Hyperlipidemia and hyperglycemia act synergistically to induce renal injury. The present study was designed to investigate the protective effects of tocotrienols as tocotrienol-rich fraction (TRF) extracted from palm (PO) and rice bran oils (RBO) against lipid induced nephropathy in type-2 diabetic rats and its probable molecular mechanism. Male Wistar rats (175-200 g) were divided into four groups. The first group served as diabetic control, while the second and third groups received PO-TRF and RBO-TRF, respectively by gavage over a period of sixteen weeks post-induction of diabetes. The fourth group comprised of age-matched rats that served as normal control. The effects of TRF on serum lipid profile, oxidative stress markers, expression of TGF-ß, fibronectin and collagen type IV were analyzed in the kidney of diabetic rats. Treatment with PO-TRF and RBO-TRF significantly improved glycemic status, serum lipid profile and renal function in type-2 diabetic rats. In addition, TRF supplementation down-regulated the expression of TGF-ß, fibronectin and collagen type IV in the kidney of diabetic rats. Transforming growth factor-ß (TGF-ß) plays a critical role in progression of DN, but its modulation by tocotrienols in DN remains unexplored. TRF ameliorated lipid induced nephropathy in type-2 diabetes by its hypoglycemic, hypolipidemic and antioxidant activities as well as by modulation of TGF-ß to prevent increased expression of collagen type IV and fibrinogen. We finally propose a mechanism for the expression of molecular markers that are significant in the events leading to diabetic nephropathy and its modulation by tocotrienols/TRF.

(-)-Epigallocatechin-3-gallate (EGCG) sensitizes melanoma cells to interferon induced growth inhibition in a mouse model of human melanoma.

Melanoma incidence has increased over the last few decades and metastatic melanoma is one of the hardest malignancies to treat. Thus, novel approaches are needed for an effective management of melanoma. Interferon-alpha2b (IFN), an immunomodulatory cytokine commonly used in melanoma treatment, has shown marginal efficacy and often results in discontinuation of therapy due to toxicity. We earlier demonstrated that epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, caused cell cycle arrest and apoptosis of human melanoma cells via modulation in cki-cyclin-cdk machinery and Bcl-2 family proteins. This study was undertaken to determine if EGCG could enhance the anti-proliferative effects of IFN. In this study, we demonstrated that EGCG and/or IFN treatments to melanoma cells resulted in a marked (1) decrease in cell proliferation and colony formation ability, and (2) induction of apoptosis. Interestingly, the combination was found to be more effective than either of the agents alone. Further, the anti-proliferative effects of EGCG and/or IFN were accompanied with an increase in Fas protein levels and a decrease in nuclear factor NFkappaB/p65 in the nucleus as well as NFkappaB promoter activity. EGCG and/or IFN also resulted in an increase in Fas-L mediated apoptosis. Further, EGCG and/or IFN treatments resulted in a decrease in melanoma tumor growth and protein levels of proliferation marker PCNA, in athymic nude mice implanted with melanoma tumors. The combination of the two modalities demonstrated a better response than either of them alone. Our data suggest that EGCG could impart therapeutic advantage if used in conjunction with IFN.