Oxidative Stress-Induced Platelet Apoptosis/Activation: Alleviation by Purified Curcumin via ASK1-JNK/p-38 Pathway.

Platelets are known for their indispensable role in hemostasis and thrombosis. However, alteration in platelet function due to oxidative stress is known to mediate various health complications, including cardiovascular diseases and other health complications. To date, several synthetic molecules have displayed antiplatelet activity; however, their uses are associated with bleeding and other adverse effects. The commercially available curcumin is generally a mixture of three curcuminoids: curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Although crude curcumin is known to inhibit platelet aggregation, the effect of purified curcumin on platelet apoptosis, activation, and aggregation remains unclear. Therefore, in this study, curcumin was purified from a crude curcumin mixture and the effects of this preparation on the oxidative stress-induced platelet apoptosis and activation was evaluated. 2,2'-Azobis(2-methylpropionamidine) dihydrochloride (AAPH) compound was used as an inducer of oxidative stress. Purified curcumin restored AAPH-induced platelet apoptotic markers like reactive oxygen species, intracellular calcium level, mitochondrial membrane potential, cardiolipin peroxidation, cytochrome c release from mitochondria to the cytosol, and phosphatidyl serine externalization. Further, it inhibited the agonist-induced platelet activation and aggregation, demonstrating its antiplatelet activity. Western blot analysis confirms protective effect of the purified curcumin against oxidative stress-induced platelet apoptosis and activation via downregulation of MAPKs protein activation, including ASK1, JNK, and p-38. Together, these results suggest that the purified curcumin could be a potential therapeutic bioactive molecule to treat the oxidative stress-induced platelet activation, apoptosis, and associated complications.

Povidone Iodine Sclerotherapy for the Treatment of Persistent Seromas after Breast Cancer Surgery.

Persistent seroma following breast cancer surgery causes morbidity and delays adjuvant treatment. Sclerotherapy helps in managing recalcitrant seromas. We evaluated efficacy of 10% povidone iodine sclerotherapy treatment for persistent seromas after breast cancer surgery. Persistent drainage of > 100 mL/day 15 days following surgery, and seromas that required aspiration > 100 mL/week 2 weeks after drain removal, was considered for 10% povidone sclerotherapy in a non-randomized observational study. Resolution (drain output < 20 mL/day), treatment days, recurrence, and complications were assessed as measures of efficacy. Descriptive measures of central tendency and dispersion were reported. The relationship of the seroma quantity with risk factors (age, body mass index, levels and number of axillary lymph nodes dissected, neoadjuvant chemotherapy) and efficacy was analysed. We examined the correlation using Pearson and Spearman' signed rank, Student's t, and Mann-Whitney U-tests, to compare the means. Of 14/312 (4.5%) patients with persistent seroma, 13 (92.8%) had complete resolution after sclerotherapy within 6.71 days (range: 6-8). AC (p = 0.04), neoadjuvant chemotherapy (NACT) (p = 0.005), and number of nodes harvested without NACT (p = 0.025) were significantly associated with the quantity of discharge, while age (p = 0.072), body mass index (p = 0.432), type of surgery (breast conservation surgery vs. modified radical mastectomy) (p = 0.28), and total number of axillary lymph nodes (p = 0.679) were not. When used in this unique innovative manner, 10% povidone iodine sclerotherapy was found to be very effective (93%), minimally invasive, and safe in our study, and therefore appears to be an ideal sclerosing agent. Supplementary Information: The online version contains supplementary material available at 10.1007/s13193-022-01629-0.

Bisdemethoxycurcumin promotes apoptosis in human platelets via activation of ERK signaling pathway.

Curcumin, a major bioactive component of turmeric (Curcuma longa), is known for its multiple health benefits. Curcumin as such is a mixture of its analogs: bisdemethoxycurcumin (BDMC)-3%, and demethoxycurcumin (DMC)-17%. Although the effect of curcumin on platelets is documented, the effect of BDMC and DMC on platelets is less studied. Considering the indispensable role played by platelets in hemostasis, thrombosis, inflammation, and immunity, the present study evaluates the effect of curcumin, DMC and BDMC on platelet apoptosis. The components of curcumin were purified by silica-gel column chromatography. The purity and mass analysis of the purified curcuminoids was determined by RP-HPLC and LC-MS respectively. When analyzed for platelet apoptotic markers, only BDMC demonstrated increased incidence of platelet apoptotic markers including increase in intracellular Ca2+, decrease in ∆ψm, alteration in BCl-2 family proteins, the release of cytochrome c, caspase activation, and PS externalization via activation of ERK activation. ERK inhibitor PD98059 significantly alleviated BDMC induced decrease in ∆ψm, alteration in BCl-2, caspase-8 activation and PS externalization. Our results demonstrate that curcumin, DMC and BDMC differentially act on platelet in inducing apoptosis and the study highlights that the toxicity associated with curcumin therapy might be attributed to BDMC in the mammalian system.

Tamarind Seed (Tamarindus indica) Extract Ameliorates Adjuvant-Induced Arthritis via Regulating the Mediators of Cartilage/Bone Degeneration, Inflammation and Oxidative Stress.

Medicinal plants are employed in the treatment of human ailments from time immemorial. Several studies have validated the use of medicinal plant products in arthritis treatment. Arthritis is a joint disorder affecting subchondral bone and cartilage. Degradation of cartilage is principally mediated by enzymes like matrix metalloproteinases (MMPs), hyaluronidases (HAase), aggrecanases and exoglycosidases. These enzymes act upon collagen, hyaluronan and aggrecan of cartilage respectively, which would in turn activate bone deteriorating enzymes like cathepsins and tartrate resistant acid phosphatases (TRAP). Besides, the incessant action of reactive oxygen species and the inflammatory mediators is reported to cause further damage by immunological activation. The present study demonstrated the anti-arthritic efficacy of tamarind seed extract (TSE). TSE exhibited cartilage and bone protecting nature by inhibiting the elevated activities of MMPs, HAase, exoglycosidases, cathepsins and TRAP. It also mitigated the augmented levels of inflammatory mediators like interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, IL-23 and cyclooxygenase-2. Further, TSE administration alleviated increased levels of ROS and hydroperoxides and sustained the endogenous antioxidant homeostasis by balancing altered levels of endogenous antioxidant markers. Overall, TSE was observed as a potent agent abrogating arthritis-mediated cartilage/bone degradation, inflammation and associated stress in vivo demanding further attention.

Methotrexate Promotes Platelet Apoptosis via JNK-Mediated Mitochondrial Damage: Alleviation by N-Acetylcysteine and N-Acetylcysteine Amide.

Thrombocytopenia in methotrexate (MTX)-treated cancer and rheumatoid arthritis (RA) patients connotes the interference of MTX with platelets. Hence, it seemed appealing to appraise the effect of MTX on platelets. Thereby, the mechanism of action of MTX on platelets was dissected. MTX (10 µM) induced activation of pro-apoptotic proteins Bid, Bax and Bad through JNK phosphorylation leading to ΔΨm dissipation, cytochrome c release and caspase activation, culminating in apoptosis. The use of specific inhibitor for JNK abrogates the MTX-induced activation of pro-apoptotic proteins and downstream events confirming JNK phosphorylation by MTX as a key event. We also demonstrate that platelet mitochondria as prime sources of ROS which plays a central role in MTX-induced apoptosis. Further, MTX induces oxidative stress by altering the levels of ROS and glutathione cycle. In parallel, the clinically approved thiol antioxidant N-acetylcysteine (NAC) and its derivative N-acetylcysteine amide (NACA) proficiently alleviate MTX-induced platelet apoptosis and oxidative damage. These findings underpin the dearth of research on interference of therapeutic drugs with platelets, despite their importance in human health and disease. Therefore, the use of antioxidants as supplementary therapy seems to be a safe bet in pathologies associated with altered platelet functions.

Anti-depressive effect of polyphenols and omega-3 fatty acid from pomegranate peel and flax seed in mice exposed to chronic mild stress.

AIM: In this study polyphenols from pomegranate peel, and n-3 fatty acids with polyphenols from flax seed were evaluated for their anti depression properties in mice exposed to chronic mild stress (CMS). METHODS: A total of 40 mice initially trained to consume 2% sucrose solution for 3 weeks were then divided into five groups of eight each. The first group was the normal control, the remaining four groups were exposed to CMS but were force fed with either: 10 mL water per kg bodyweight per day; imipramine (a standard antidepressant) 15 mg kg bodyweight; 30 mg per kg bodyweight polyphenol equivalent extract from pomegranate peel; or 30 mg polyphenols per kg bodyweight with omega-3 fatty acids present, for 50 days. At the end, blood and brain were analyzed for various biomarkers of depression. RESULTS: The flax seed and imipramine groups had significantly increased sucrose consumption, decreased cortisol (blood), decreased epinephrine and norepinephrine concentration, decreased monoamine oxidase A and B activity, and decreased superoxide dismutase activity. Lipid peroxidation was completely inhibited. In contrast, pomegranate peel extract also completely inhibited lipid peroxidation in the brain, and reduced enzyme activity and hormone concentration but to a lesser extent than flax seed. CONCLUSION: Polyphenols from flax seed with omega-3 fatty acids were able to reduce all the CMS effects tested compared to polyphenols from pomegranate peel.