Evolving spectrum of diabetic wound: Mechanistic insights and therapeutic targets.

Diabetes mellitus is a chronic metabolic disorder resulting in an increased blood glucose level and prolonged hyperglycemia, causes long term health conse-quences. Chronic wound is frequently occurring in diabetes patients due to compromised wound healing capability. Management of wounds in diabetic patients remains a clinical challenge despite many advancements in the field of science and technology. Increasing evidence indicates that alteration of the biochemical milieu resulting from alteration in inflammatory cytokines and matrix metalloproteinase, decrease in fibroblast and keratinocyte functioning, neuropathy, altered leukocyte functioning, infection, etc., plays a significant role in impaired wound healing in diabetic people. Apart from the current pharmacotherapy, different other approaches like the use of conventional drugs, antidiabetic medication, antibiotics, debridement, offloading, platelet-rich plasma, growth factor, oxygen therapy, negative pressure wound therapy, low-level laser, extracorporeal shock wave bioengineered substitute can be considered in the management of diabetic wounds. Drugs/therapeutic strategy that induce angiogenesis and collagen synthesis, inhibition of MMPs, reduction of oxidative stress, controlling hyperglycemia, increase growth factors, regulate inflammatory cytokines, cause NO induction, induce fibroblast and keratinocyte proliferation, control microbial infections are considered important in controlling diabetic wound. Further, medicinal plants and/or phytoconstituents also offer a viable alternative in the treatment of diabetic wound. The focus of the present review is to highlight the molecular and cellular mechanisms, and discuss the drug targets and treatment strategies involved in the diabetic wound.

TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.

BACKGROUND: Coronary allograft vasculopathy (CAV) is a devastating sequela of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown. METHODS: We assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle-specific Tet2 knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNγ (interferon γ), a cytokine elaborated by T cells that drives CAV progression. RESULTS: In the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner. CONCLUSIONS: TET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.

Revival, modernization and integration of Indian traditional herbal medicine in clinical practice: Importance, challenges and future.

In spite of incredible advances in modern science, technology and allopathic medicine a large we are unable to provide quality healthcare to all. Traditional medicine particularly herbal medicine considered as a major healthcare provider around the globe particularly in rural and remote areas. A large section of people depends on such medicine for their primary healthcare mainly in underdeveloped or developing countries. Indian traditional medicinal system like Ayurveda, Siddha and Unani has a very rich history of their effectiveness; modern research also acknowledged the importance of such medicine. Indian traditional medicine or medicinal plants are also considered as a vital source of new drug. Mainstreaming of such medicine is important for the people. Several steps have been taken in India to promote such medicine and to integrate them into clinical practice. Evidence based incorporation of Indian traditional medicine in clinical practice will help to provide quality healthcare to all.

SPORTS PREFERENCE AND DIGIT RATIO (2D:4D) AMONG FEMALE STUDENTS IN WROCLAW, POLAND.

Humans exhibit sex differences in competitiveness, sensation seeking and risk-taking attitude, which are required in sports. These attributes are often linked to prenatal testosterone (PT) exposure. The second-to-fourth digit length ratio (2D:4D) is an indicator of PT exposure. A lower 2D:4D indicates higher PT exposure and vice versa. Males generally have a lower 2D:4D than females. Sensation- and/or thrill-seeking behaviours have also been found to be negatively associated with 2D:4D. Boxing and judo are considered to be high-risk sports. Voluntary participation in judo/boxing in contrast to aerobics can be guided by such behaviours and thus have an association with lower 2D:4D. This cross-sectional study included 167 female students from a military academy in Wroclaw, Poland. Of them, 119 had voluntarily chosen aerobic exercise, and 48 opted for judo/boxing. Height, weight and second and fourth digit lengths were measured. Physical fitness was assessed using Eurofit tests. The two groups showed similar physical fitness and body size. However, the judo/boxing group had significantly lower mean 2D:4D values than the aerobics group. It is proposed that voluntary choice of participation in a sport discipline by women could be linked to the 'organizational' effect of intrauterine testosterone exposure during prenatal growth.

Hepatoprotective and antioxidant activity of Karisalai Karpam, a polyherbal Siddha formulation against acetaminophen-induced hepatic damage in rats.

BACKGROUND: The usage of Siddha medicine in Tamil Nadu and several parts of Southern India has considerably increased over the past two decades and it is steadily crossing the various geographies owing to its inexpensiveness compared to conventional medicines and has fairly high acceptance rates because of its herbal origin and therefore its nontoxic nature. AIM: This study aims to investigate the anti-hepatotoxic and antioxidant potential of the Karisalai Karpam formulation. MATERIALS AND METHODS: Karisalai Karpam tablet at 50, 100, and 200 mg/kg/day, p.o. doses were administered orally to rats for three consecutive days. Single dose of acetaminophen (3 g/kg, p.o.) was administered on the 3(rd) day. Animals were sacrificed 48 h after the administration of acetaminophen, and their serum bilirubin, different hepatic enzymes and in vivo antioxidant activity were estimated. STATISTICAL ANALYSIS: Data were evaluated using analysis of variance, followed by Tukey tests. A level of P < 0.05 was considered statistically significant. RESULTS: Pretreatment with Karisalai Karpam tablet showed dose-dependent hepatoprotective activity. Karisalai Karpam tablet (200 mg/kg) reduces serum glutamic oxaloacetate transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase and total bilirubin, direct bilirubin by 67.8%, 72.3%, 47.6%, 61.3% and 62.9% respectively compared to disease control group. A significant increase (P < 0.001) in antioxidant enzyme level was observed in Karisalai Karpam treated animals. At higher doses, Karisalai Karpam prevented the depletion of glutathione in liver tissue. CONCLUSION: Results confirmed that Karisalai Karpam tablet could protect the liver against acetaminophen-induced oxidative damage possibly by increasing the antioxidant defence mechanism in rats.

Inverse agonism of SQ 29,548 and Ramatroban on Thromboxane A2 receptor.

G protein-coupled receptors (GPCRs) show some level of basal activity even in the absence of an agonist, a phenomenon referred to as constitutive activity. Such constitutive activity in GPCRs is known to have important pathophysiological roles in human disease. The thromboxane A2 receptor (TP) is a GPCR that promotes thrombosis in response to binding of the prostanoid, thromboxane A2. TP dysfunction is widely implicated in pathophysiological conditions such as bleeding disorders, hypertension and cardiovascular disease. Recently, we reported the characterization of a few constitutively active mutants (CAMs) in TP, including a genetic variant A160T. Using these CAMs as reporters, we now test the inverse agonist properties of known antagonists of TP, SQ 29,548, Ramatroban, L-670596 and Diclofenac, in HEK293T cells. Interestingly, SQ 29,548 reduced the basal activity of both, WT-TP and the CAMs while Ramatroban was able to reduce the basal activity of only the CAMs. Diclofenac and L-670596 showed no statistically significant reduction in basal activity of WT-TP or CAMs. To investigate the role of these compounds on human platelet function, we tested their effects on human megakaryocyte based system for platelet activation. Both SQ 29,548 and Ramatroban reduced the platelet hyperactivity of the A160T genetic variant. Taken together, our results suggest that SQ 29,548 and Ramatroban are inverse agonists for TP, whereas, L-670596 and Diclofenac are neutral antagonists. Our findings have important therapeutic applications in the treatment of TP mediated pathophysiological conditions.

Cisplatin-induced nephrotoxicity in mice: protective role of Leea asiatica leaves.

Cisplatin is a popular anticancer drug, but its side effects like nephrotoxicity and hepatotoxicity due to oxidative stress limited its clinical use. In tis study, nephoprotective effect of fractions of Leea asiatica (Leeaceae) leaves was assessed against cisplatin induced toxicity in rats. Leaves of L. asiatica extracted with methanol, ethyl acetate, petroleum ether, and evaluated for in vitro and ex vivo antioxidant activity using several assay models. Methanol extract showed better antioxidant effects, and contain higher amount of phenolic (77.75 ± 0.87 mg GAE/g of dry material) and flavonoid compound (60.98 ± 0.58 mg QE/g of dry material) compared with other extracts. Hance methanol extract was selected for further investigation and fractionated with methanol, ethyl acetate, petroleum ether. Protective effect of methanol extract and its fractions was evaluated against cisplatin (20 mg/kg, i.p.) induced nephrotoxicity. Pretreatment with methanol extract (150 and 300 mg/kg), and its fractions especially methanol, ethyl acetate fraction (75 and 150 mg/kg) significantly reduced blood urea nitrogen, serum creatinine, uric acid levels, and decreased malondialdehyde level and increase total protein and albumin level (p < 0.05, 0.01). Ethyl acetate fraction produced highest nephroprotective, possibly by inhibiting lipid peroxidation process. Result suggested that ethyl acetate fraction possesses potent nephroprotective activity and can be used an adjunct therapy aiming to improve the effectiveness of several nephrotoxic drugs.

Total phenolic, total flavonoid content, and antioxidant capacity of the leaves of Meyna spinosa Roxb., an Indian medicinal plant.

AIM: The objective of the present study was to determine the total phenolic and total flavonoid contents, and to evaluate the antioxidant potential of different leaf extracts of Meyna spinosa Roxb. ex Link, a traditional medicinal plant of India. METHODS: Free radical scavenging and antioxidant potential of the methanol, ethyl acetate, and petroleum ether extracts of Meyna spinosa leaves were investigated using several in vitro and ex vivo assays, including the 2, 2-diphenyl-picrylhydrazyl radical scavenging, superoxide anion scavenging, hydroxyl radical scavenging, nitric oxide radical scavenging, hydrogen peroxide scavenging activity, metal chelating assay, and reducing power ability method. Total antioxidant activity of the extracts was estimated by the ferric thiocyanate method. Inhibition assay of lipid peroxidation and oxidative hemolysis were also performed to confirm the protective effect of the extracts. Total phenolic and total flavonoid contents of the extracts were estimated using standard chemical assay procedures. RESULTS: Methanol extracts showed the highest polyphenolic content and possessed the better antioxidant activity than the other two extracts. Total phenolic and total flavonoid contents in the methanol extract were (90.08 ± 0.44) mg gallic acid equivalents/g and (58.50 ± 0.09) mg quercetin equivalents/g, respectively. The IC50 of the methanol extract in the DPPH(·), superoxide anion, hydroxyl radical, nitric oxide radical, hydrogen peroxide scavenging activity and metal chelating assays were (16.4 ± 0.41), (35.9 ± 0.19), (24.1 ± 0.33), (23.7 ± 0.09), (126.8 ± 2.92), and (117.2 ± 1.01) µg·mL(-1), respectively. The methanol extract showed potent reducing power ability, total antioxidant activity, and significantly inhibit lipid peroxidation and oxidative hemolysis which was similar to that of standards. CONCLUSION: The results indicated a direct correlation between the antioxidant activity and the polyphenolic content of the extracts, which may the foremost contributors to the antioxidant activity of the plant. The present study confirmed that the methanol extract of Meyna spinosa leaves is a potential source of natural antioxidants.

Antitussive, expectorant activity of Marsilea minuta L., an Indian vegetable.

Marsilea minuta L., an aquatic or sub-aquatic fern used as a vegetable, has wide applications in traditional/folk medicine in India and Bangladesh. In our study, we evaluated the antitussive, expectorant activity of M. minuta crude extracts. The antitussive activity of M. minuta methanol, ethyl acetate, and petroleum ether extracts was evaluated using ammonia and sulfur dioxide induced mice coughing. The expectorant activity was evaluated by the volume of phenol red in mice's tracheas. Extracts significantly increased mice's cough latent period and inhibited the frequency of cough induced by ammonia and sulfur dioxide, and improved tracheal phenol red output in expectorant evaluation. Methanol extract produced the highest activity in all tested models. Methanol extract at 500 mg/kg showed 59.5% and 55.8% inhibition in the number of coughing induced by ammonium liquor and SO2, respectively, while it showed 89.3% increase in phenol red secretion at the same dose, which showed superior activity compared to other extracts. The present study provided evidence for M. minuta to be used as an antitussive and expectorant in Indian folk medicine.

Anti-inflammatory, analgesic, and antioxidant activities of Pisonia aculeata: folk medicinal use to scientific approach.

CONTEXT: Pisonia aculeata leaves (Nyctagenaceae), a Folk medicinal plant used in the treatment of several inflammation, pain, and oxidative stress associated diseases. OBJECTIVE: To evaluate anti-inflammatory, analgesic, and antioxidant potential of crude methanol extract of P. aculeata leaves (MEPA). MATERIALS AND METHODS: Analgesic and anti-inflammatory activities of MEPA (250 and 500 mg/kg) were evaluated using writhing, formalin, hot plate, tail flick, carrageenan-induced paw edema test, and membrane stabilizing activity. Free radical scavenging activity, total phenolic and flavonoid contents of MEPA were also determined using standard methods. RESULTS: Oral administration of MEPA showed significant (p < 0.001) inhibition of paw edema, pronounced at 4 h and 5 h after carrageenan injection, and at 200 µg/mL exerts 77.67 and 38.51% protective effect against hypotonic solution and heat induced hemolysis, respectively. MEPA (250 and 500 mg/kg) produced 35.21 and 79.14% inhibition of acetic acid-induced writhing. Furthermore, MEPA (500 mg/kg) inhibited 49.19% early and 73.14% late phase of formalin-induced hypernociception. In contrast, a lower dose of MEPA did not prevent hot plate induced nociception, while in the tail immersion method, pronounced analgesic activity was observed between 1 and 4 h postdosing. The extract possesses significant in vitro antioxidant activity and a lipid peroxidation inhibition effect. Total phenolic and total flavonoid content in MEPA were 87.99 ± 0.87 mg GAE/g and 58.98 ± 0.01 mg QE/g, respectively. DISCUSSION AND CONCLUSION: Our findings confirmed the analgesic, anti-inflammatory and antioxidant activities of Pisonia aculeata leaves. Contents of flavonoids and phenolic compounds in extract could be correlated with its observed biological activities.

Anthelmintic and in vitro antioxidant evaluation of fractions of methanol extract of Leea asiatica leaves.

Leea asiatica, a folk medicinal plant of India, is used in the treatment of worm infection and other oxidative stress-related disorders, traditionally. In the present study, the in vitro anthelmintic and in vitro antioxidant activity of different fractions of the methanol extract from the Leea asiatica leaves were evaluated. The fraction displayed significant anthelmintic activity against Indian adult earthworms (Pheretima posthuma). The ethyl acetate fraction showed a better paralysis activity (13.99 ± 0.59), while the methanol fraction showed a better death time (63.76 ± 0.73 minutes), when compared with other fractions, at a dose of 50 mg/ml concentration. The anthelmintic activity of methanol and the ethyl acetate fraction were almost similar and comparable to the standard drug, piperazine citrate. The petroleum ether fraction did not produce a potent anthelmintic effect compared to the standard. The in vitro antioxidant activity was evaluated by using the diphenyl-picrylhydrazyl (DPPH) radical scavenging assay, nitric oxide radical scavenging assay, lipid peroxidation assay, and the ferric thiocyanate method. The ethyl acetate fraction showed better antioxidant activity in all tested methods. The IC(50) value of the ethyl acetate fraction in the DPPH radical, nitric oxide radical scavenging assay, and lipid peroxidation assay were 9.5, 13.0, and 57.0 µg/ml, respectively. The fractions significantly (P < 0.05) inhibited the peroxidation of linoleic acid. The results confirmed the folk use of Leea asiatica in warm infection and the plant could be viewed as a potential source of natural anthelmintic and antioxidant compound.

Acetaminophen-induced nephrotoxicity in rats: protective role of Cardiospermum halicacabum.

CONTEXT: Nephrotoxicity induced by several synthetic drugs is a major problem of modern age. Medicinal plants and phytomedicine are the prime choice of research as they possess better activity and lesser side effects. OBJECTIVE: To investigate the protective effect of Cardiospermum halicacabum Linn. (Sapindaceae), methanol and petroleum ether extracts against acetaminophen-induced nephrotoxicity in rats. MATERIALS AND METHODS: Nephrotoxicity was induced by the administration of acetaminophen suspension (750 mg/kg, p.o.) after the pretreatment with methanol extract (MECF) and petroleum ether extract (PEECF) of Cardiospermum halicacabum for 7 days. Forty-eight h after the acetaminophen administration estimations of serum alkaline phosphate, creatinine, blood urea nitrogen, uric acid, total proteins, cholesterol, albumin level and histological analysis of kidney injuries were determined. RESULTS: In nephrotoxic animals, a significant (P < 0.01) elevation of serum alkaline phosphate, creatinine, blood urea nitrogen, uric acid, cholesterol and depletion of total proteins and albumin were observed. Pretreatment with MECF and PEECF (400 mg/kg) significantly (P < 0.01, P < 0.05) decreased serum alkaline phosphate, creatinine, blood urea nitrogen, uric acid, cholesterol level and causes elevation of total protein and albumin level, though MECF produces better effect than PEECF in rats. Histopathological studies also confirm the protective effect of extracts. The protective effect of Cardiospermum halicacabum was associated with restoration of serum alkaline phosphate, creatinine, blood urea nitrogen, uric acid, cholesterol, total protein and albumin level. DISCUSSION AND CONCLUSIONS: Methanol and petroleum ether extracts of Cardiospermum halicacabum had a significant nephroprotective activity against acetaminophen-induced nephrotoxicity in rats.