Targeting SIRT1, NLRP3 inflammasome, and Nrf2 signaling with chrysin alleviates the iron-triggered hepatotoxicity in rats.

Blood transfusion-requiring diseases such as sickle cell anemia and thalassemia are characterized by an imbalance between iron intake and excretion, resulting in an iron overload (IOL) disorder. Hepatotoxicity is prevalent under the IOL disorder because of the associated hepatocellular redox and inflammatory perturbation. The current work was devoted to investigate the potential protection against the IOL-associated hepatotoxicity using chrysin, a naturally-occurring flavone. IOL model was created in male Wistar rats by intraperitoneal injection of 100 mg/kg elemental iron subdivided on five equal injections; one injection was applied every other day over ten days. Chrysin was administered in a daily dose of 50 mg/kg over the ten-day iron treatment period. On day eleven, blood and liver samples were collected and subjected to histopathological, biochemical, and molecular investigations. Chrysin suppressed the IOL-induced hepatocellular damage as revealed by decreased serum activity of the intracellular liver enzymes and improved liver histological picture. Oxidative damage biomarkers, and pro-inflammatory cytokines were significantly suppressed. Mechanistically, the levels of the redox and inflammation-controlling proteins SIRT1 and PPARγ were efficiently up-regulated. The liver iron load, NLRP3 inflammasome activation, and NF-κB acetylation and nuclear shift were significantly suppressed in the iron-intoxicated rats. Equally important, the level of the antioxidant protein Nrf2 and its target HO-1 were up-regulated. In addition, chrysin significantly ameliorated the IOL-induced apoptosis as indicated by reduction in caspase-3 activity and modulation of BAX and Bcl2 protein abundance. Together, these findings highlight the alleviating activity of chrysin against the IOL-associated hepatotoxicity and shed light on the role of SIRT1, NLRP3 inflammasome, and Nrf2 signaling as potential contributing molecular mechanisms.

Modulating SIRT1, Nrf2, and NF-κB signaling pathways by bergenin ameliorates the cadmium-induced nephrotoxicity in rats.

In light of the current industrial evolution, exposure to cadmium has become a significant public health concern. Cadmium accumulates in the renal tubular cells and causes nephrotoxicity largely through disruption of the redox homeostasis, induction of inflammation, and suppression of the histone deacetylase SIRT1 expression. The current work aimed at exploring the protective capability of bergenin, a naturally-occurring methyl gallic acid derivative, against the cadmium-evoked nephrotoxicity. Male Wistar rats were treated either with cadmium alone or with cadmium and bergenin for a 7-day experimental period followed by collection of kidney and blood specimens that were subjected to biochemical, molecular, and histological investigations. The results revealed the ability of bergenin to improve the renal functions in the cadmium-intoxicated rats as evidenced by increased glomerular filtration rate, and decreased serum creatinine and blood urea nitrogen. Equally important, bergenin reduced the renal tissue injury and enhanced its redox homeostasis as indicated by decreased protein expression of the kidney injury marker KIM-1, reduced lipid peroxidation, and improved antioxidant potential and histopathological picture of the renal tissues. Mechanistically, bergenin reduced the renal tissue cadmium content, markedly up-regulated protein expression of SIRT1 that regulates inflammation and the redox status of the renal tissues. Additionally, it improved the expression of the major antioxidant transcription factor Nrf2 and its responsive gene products heoxygenase-1 and NAD(P)H quinone dehydrogenase 1 in the cadmium-intoxicated rats. In the same context, bergenin down-regulated the acetylation and the nuclear translocation of the inflammatory transcription factor NF-κB and reduced levels of its responsive gene products TNF-α and IL-1ß, as well as the activity of the inflammatory cell infiltration biomarker myeloperoxidase. Collectively, the current study underscores the ameliorating activity of bergenin against the cadmium-evoked nephrotoxicity and highlights modulation of SIRT1, Nrf2, and NF-κB signaling as potential underlining molecular mechanisms.

An Insight into the Impact of Serum Tellurium, Thallium, Osmium and Antimony on the Antioxidant/Redox Status of PCOS Patients: A Comprehensive Study.

Humans exploit heavy metals for various industrial and economic reasons. Although some heavy metals are essential for normal physiology, others such as Tellurium (Te), Thallium (TI), antimony (Sb), and Osmium (Os) are highly toxic and can lead to Polycystic Ovarian Syndrome (PCOS), a common female factor of infertility. The current study was undertaken to determine levels of the heavy metals TI, Te, Sb and Os in serum of PCOS females (n = 50) compared to healthy non-PCOS controls (n = 56), and to relate such levels with Total Antioxidant Capacity (TAC), activity of key antioxidant enzymes, oxidative stress marker levels and redox status. PCOS serum samples demonstrated significantly higher levels of TI, Te, Sb and Os and diminished TAC compared to control (p < 0.001). Furthermore, there was significant inhibition of SOD, CAT and several glutathione-related enzyme activities in sera of PCOS patients with concurrent elevations in superoxide anions, hydrogen and lipid peroxides, and protein carbonyls, along with disrupted glutathione homeostasis compared to those of controls (p < 0.001 for all parameters). Additionally, a significant negative correlation was found between the elevated levels of heavy metals and TAC, indicative of the role of metal-induced oxidative stress as a prominent phenomenon associated with the pathophysiology of the underlying PCOS. Data obtained in the study suggest toxic metals as risk factors causing PCOS, and thus protective measures should be considered to minimize exposure to prevent such reproductive anomalies.

A unique investigation of thallium, tellurium, osmium, and other heavy metals in recurrent pregnancy loss: A novel approach.

OBJECTIVE: To study the impact of heavy metals especially tellurium, thallium, and osmium, in recurrent pregnancy loss (RPL) and to study their association with antioxidant status and DNA damage. METHODS: This case-control study included women with RPL (n = 30) and healthy pregnant women as control (n = 30). Following blood collection, serum levels of thallium, tellurium, osmium, lead, mercury, and cadmium were estimated by inductively coupled plasma mass spectrophotometer. RESULTS: Women with RPL exhibited significantly higher levels of heavy metals (P < 0.001) when compared with control women. Intriguingly, increased levels of serum thallium, tellurium, osmium, and lead were negatively correlated with total antioxidant status (P < 0.05). Further, the RPL group demonstrated strong positive correlation between heavy metals (thallium, tellurium, osmium, lead) and DNA damage (P < 0.05). No significant correlation between other heavy metals and markers of cellular damage was noted. CONCLUSION: Enhanced levels of heavy metals in women with RPL and correlation of thallium, tellurium, osmium, and lead with markers of cellular damage reflect the role of heavy metal poisoning, especially thallium, tellurium, and osmium, as potential risk factor in the etiology underlying recurrent miscarriage.

Antioxidant status in relation to heavy metals induced oxidative stress in patients with polycystic ovarian syndrome (PCOS).

Polycystic ovary syndrome (PCOS) is a global health concern for women of reproductive age, as 6.5% of women worldwide are affected by this syndrome. PCOS is marked by hyperandrogenism, anovulation, menstrual abnormalities, and polycystic ovaries. Metals such as arsenic, cadmium, lead and mercury are considered to be systemic toxicants/human carcinogens and seem to have devastating effects on humans, even at minimal exposures. One of the probable aetiological factors for PCOS has been identified as oxidative stress. In view of the probable associations among oxidative stress, metal toxicity and PCOS, the present study examined the role of heavy metals in the generation of oxidative stress among females. This prospective study included 106 women (56 women diagnosed with PCOS and 50 women who were not diagnosed with PCOS as control women). There were no significant differences in the sociodemographic characteristics between the two groups except for the irregularity of menses and the presence of acne. The serum As, Cd, Pb, and Hg levels increased and the serum glutathione (GSH) and superoxide dismutase (SOD) levels diminished significantly in the PCOS group compared to the control group at P < 0.001. The SOD levels were negatively correlated with the As and Pb levels at P < 0.05. Additionally, the PCOS group exhibited a strong negative correlation between the GSH and As levels (P < 0.01), GSH and Pb levels (P < 0.05) and GSH and Hg levels (P < 0.01). Furthermore, the As levels were positively correlated with increased levels of Cd, Pb and Hg among PCOS women. Significant positive correlations were observed between Pb and Cd and between Cd and Hg at P < 0.001. The outcome of the study provides clear insight into the role of metal-induced oxidative stress, which plays a vital role in the pathophysiology underlying PCOS and suggests the use of these markers as prognostic tools to reduce the consequences of high-risk exposure to these metals among females.

Assessment of DNA damage in relation to heavy metal induced oxidative stress in females with recurrent pregnancy loss (RPL).

Pregnancy termination consecutively for three or more times during the first trimester is termed as Recurrent pregnancy loss (RPL). In addition to the abnormal karyotype, heavy metal induced oxidative damage may contribute as prominent etiological factor in pregnancy termination. Oxidative stress is considered crucial in etiology underlying RPL with altered antioxidant status and subsequent DNA damage. The current case controlled study investigated Total antioxidant capacity (TAC), DNA damage (8OHdG) and heavy metals in RPL group (n = 30) and the women with successful pregnancies and no cases of miscarriage as control group (30 women). Heavy metals -Antimony (Sb) and Arsenic (As) were measured by Inductively Coupled Plasma Mass spectrophotometry (ICP-MS). There was significant decrease in levels of TAC in RPL group compared to healthy pregnant women (P < 0.05). On contrary, elevated levels of As and Sb were observed in RPL group with subsequent increase in the levels of 8OHdG (P < 0.001); indicating extensive DNA damage in these patients. Furthermore, increased levels of As and Sb in RPL group were positively correlated with 8OHdG and negatively with total antioxidant capacity. The outcome of the study provides clear insight of the role of metal induced oxidative stress that plays a vital role in the pathophysiology underlying RPL.