Anti-apoptotic Agent Research Articles

Apoptosis Cellular Models in Cancer Therapeutics

Apoptosis, one of the major regulated cell death pathways, is a highly regulated suicide mechanism used for the elimination of damaged and unwanted cells in multicellular organisms. Derailed apoptosis has been observed in two extremes of the disease spectrum, for example, cancer (too little apoptosis) and acute myocardial infarction (AMI; too much apoptosis). Using human cellular models and patient samples, we have previously shown that human apolipoprotein L6 (ApoL6), when overexpressed intracellularly, induces mitochondria- and reactive oxygen species (ROS)-mediated apoptosis. ApoL6 also blocks Beclin 1-initiated autophagy in both human colorectal cancer cells (DLD-1) and atherosclerotic lesion-derived cells. We speculated that small compounds enhancing ApoL6-induced apoptosis are candidate drugs to treat cancer. In the present study, we use our established human cellular models, high throughput and targeted screening strategies, and well-defined assays to identify nifedipine, L-proline, L-tryptophan, and picolinic acid as antiapoptotic agents, which would be candidate drugs for treating diseases such as AMI. We also identified fulvestrant and L-lysine, two compounds that can further enhance ApoL6-induced apoptosis in cancer cells.

Cooling and immunomodulation for treating hypoxic-ischemic brain injury.

Therapeutic hypothermia is now well established to partially reduce disability in term and near-term infants with moderate-severe hypoxic-ischemic encephalopathy. Preclinical and clinical studies have confirmed that current protocols for therapeutic hypothermia are near optimal. The challenge is now to identify complementary therapies that can further improve outcomes, in combination with therapeutic hypothermia. Overall, anti-excitatory and anti-apoptotic agents have shown variable or even no benefit in combination with hypothermia, suggesting overlapping mechanisms of neuroprotection. Inflammation appears to play a critical role in the pathogenesis of injury in the neonatal brain, and thus, there is potential for drugs with immunomodulatory properties that target inflammation to be used as a therapy in neonates. In this review, we examine the evidence for neuroprotection with immunomodulation after hypoxia-ischemia. For example, stemcell therapy can reduce inflammation, increase cell survival, and promote cell maturation and repair. There are also encouraging preclinical data from small animals suggesting that stemcell therapy can augment hypothermic neuroprotection. However, there is conflicting evidence, and rigorous testing in translational animal models is now needed.

Exposing Mouse Oocytes to MitoQ During In Vitro Maturation Improves Maturation and Developmental Competence.

Background and Purpose: Mitochondrion is the main indicator of oocyte quality and one of the components of oocyte, which is sensitive to oxidative damage during the maturation process. Mitoquinone mesylate (MitoQ) is a strong antioxidant targeting mitochondria as well as anti-apoptotic agent. However, the effect of MitoQ on the quality of oocytes during in vitro maturation (IVM) is still unknown.Objectives: This study investigated the possible effects of MitoQ on maturation and developmental competency in mice oocytes.Materials and Methods: The oocytes were collected at germinal vesicle stage from 6-8-week old female NMRI mice and then cultured in TCM-199 medium supplemented with 0, 0.01, 0.02 and 0.04 µM MitoQ. The sham group was treated with DMSO (0.01% v.v). Then intracellular Glutathione (GSH), reactive oxygen species (ROS) levels, mitochondria membrane potential (ΔΨm), as well as in vitro fertilization (IVF) rate in the 18-20 h matured oocytes and metaphase II (MII) oocytes (in vivo-control), were assessed.Results: The results showed that between three dose of MitoQ, the 0.02 µM significantly increased nuclear maturation rate, GSH level, fertilization rate and blastulation (92.6, 231.7, 90.19 and 81.66%, respectively) than the in vitro-control (71.14, 152, 78.84 and 73.50%, respectively) and more comparable to that of the in vivo matured oocytes (100, 243.5, 92.10 and 83%, respectively). Also, the mitochondria membrane potential in the 0.02 µM MitoQ was significantly higher compared with those in the other groups (4.4). However, the intracellular ROS level in 0.02 µM MitoQ was significantly decreased (38.72%) compared to in vitro-control (82.2%) and was similar to the in vivo-control (33.5%).Conclusion: The results indicated that supplementation of IVM medium with MitoQ (specially 0.02 µM) enhance maturation and fertilization rate. In conclusion, MitoQ might be considered as a novel component that could be added to IVM media.

Bioactive peptides attenuate cardiac hypertrophy and fibrosis in spontaneously hypertensive rat hearts

The incidence of neurodegeneration leading to the conditions such as Alzheimer's and Parkinson's diseases are on the increase, they require the approaches that focus on protection prevention rather than treatment. Plants are rich sources of many compounds which possess medicinal properties. We sought to investigate the neuroprotective effects of Uncaria hirsuta and its compounds on D-galactose-induced stress in BALB/c mice as well as 6-hydroxydopamine (6-OHDA)-induced stress in mouse nerve growth factor (mNGF)-differentiated PC12 cells. Our results demonstrate that the 95% ethanol extract of U. hirsuta reversed the D-galactose-induced learning and memory dysfunctions and decreased the malodialdehyde levels. Furthermore, the isolated compounds, 5β-carboxystrictosidine (1) and chlorogenic acid (2), protected mNGF-differentiated PC12 cells against toxicity induced by 6-OHDA by acting as antiapoptotic agents. The 50% inhibitory concentration (IC50) for intracellular reactive oxygen species (ROS) scavenging was found to be 24.5 (for 1) and 19.7 μM (for 2), and both 1 and 2 reduced intracellular calcium levels with respective IC50 values of 46.9 and 27 μM. Interestingly, both compounds inhibited caspase 3 and 9 activities with respective IC50 values of 25.6 and 24.5 μM for 1 and 19.4 and 16.3 μM for 2. Our results identify U. hirsuta and its active compounds as potential neuroprotective agents and deserve further evaluation for drug development for neuroprotection in the future. © 2019

Overview of biological effects of Quercetin on ovary.

Over the last few decades, using natural products has been increased to treat different diseases. Today, great attention has been pointed toward the usage of natural products such as flavonoids, especially Quercetin (QUR), in the treatment of diseases. QUR as a natural antioxidant has been traditionally used to prevent or treat a variety of diseases such as cancer, cardiovascular disease, polycystic ovary syndrome (PCOS), obesity, chronic inflammation, and reproductive system dysfunction. Several studies demonstrated that QUR acts as an anti-inflammatory, anti-apoptotic, antioxidant, and anticancer agent. With this in view, in this study, we intended to describe an overview of the biological effects of QUR on the ovary. QUR improves the quality of oocytes and embryos. It affects the proliferation and apoptosis and decreases the oxidative stress in granulosa cells (GCs). Furthermore, QUR can be used as a complementary and alternative therapy in ovarian cancer and it has beneficial effects in the treatment of PCOS patients. It seems that QUR as a supplementary factor has different activities for the treatment of different disorders and it also has bidirectional activities. However, further investigations are needed for understanding the efficacy of QUR in the treatment and improvement of gynecological patients.

Role and Therapeutic Potential of Melatonin in the Central Nervous System and Cancers

Melatonin (MLT) is a powerful chronobiotic hormone that controls a multitude of circadian rhythms at several levels and, in recent times, has garnered considerable attention both from academia and industry. In several studies, MLT has been discussed as a potent neuroprotectant, anti-apoptotic, anti-inflammatory, and antioxidative agent with no serious undesired side effects. These characteristics raise hopes that it could be used in humans for central nervous system (CNS)-related disorders. MLT is mainly secreted in the mammalian pineal gland during the dark phase, and it is associated with circadian rhythms. However, the production of MLT is not only restricted to the pineal gland; it also occurs in the retina, Harderian glands, gut, ovary, testes, bone marrow, and lens. Although most studies are limited to investigating the role of MLT in the CNS and related disorders, we explored a considerable amount of the existing literature. The objectives of this comprehensive review were to evaluate the impact of MLT on the CNS from the published literature, specifically to address the biological functions and potential mechanism of action of MLT in the CNS. We document the effectiveness of MLT in various animal models of brain injury and its curative effects in humans. Furthermore, this review discusses the synthesis, biology, function, and role of MLT in brain damage, and as a neuroprotective, antioxidative, anti-inflammatory, and anticancer agent through a collection of experimental evidence. Finally, it focuses on the effect of MLT on several neurological diseases, particularly CNS-related injuries.

New therapeutic strategies for combatting gastrointestinal toxicity.

An overwhelming majority of chemotherapy agents are known to cause gastrointestinal mucositis, an unwanted side effect of cancer treatment, for which no effective treatment currently exists. The pathological processes underlying the development of gastrointestinal mucositis are many and varied, with multiple pathways thought to be involved in initiation of inflammation and apoptosis. Physiological and or biochemical-based deficiencies, such as vitamin D deficiency and gut microbiome density and population, are also thought to have an impact on mucositis severity. Recent studies investigating inflammatory pathways, such as cytokines and apoptotic markers, do show that interleukin-blocking proteins alleviate symptoms of gastrointestinal mucositis. However, the effectiveness of these treatments varies depending on the type of anticancer agent administered, meaning blocking compounds may be limited in their application. Targeting the host's gut microbiome in preventing dysbiosis is also thought to be a potential avenue for exploration. The use of probiotic gut bacteria (i.e. Lactobacillus spp.), while beneficial in preventing chemotherapy radiotherapy-induced diarrhoea, does not seem to alleviate the physiological damage caused by gastrointestinal mucositis. Vitamin D has been widely shown to have a host of anti-inflammatory and immunomodulatory effects in the intestine, as well as anticancer properties and therefore, may reduce severity of gastrointestinal mucositis. While anti-inflammatory and antiapoptotic agents have shown promise in animal models of gastrointestinal mucositis, there is still no singular mechanism allowing for the development of a therapeutic drug to prevent or cure gastrointestinal injury. A greater insight into the exact mechanistic actions of both probiotics and vitamin D might reveal how to improve their use as therapeutic treatments for gastrointestinal mucositis.

Association of GRP78, HIF-1α and BAG3 Expression with the Severity of Chronic Lymphocytic Leukemia.

Parallel with the progression of Chronic Lymphocytic Leukemia (CLL), the levels of 78KDa Glucose-Regulated Protein (GRP78) and Hypoxia-Inducible Factor 1 alpha (HIF-1α) are increased as they may activate the induction of anti-apoptotic proteins such as BCL2 Associated Athanogene 3 (BAG3). Previous studies have indicated that there is a positive correlation among GRP78, HIF-1α and BAG3. This study aimed to evaluate the effect of metabolic factors involved in invasive CLL on apoptotic factors. A case-control study was conducted on 77 patients diagnosed with CLL along with 100 healthy individuals. Cell blood count was performed for all participants. According to Binet's classification, CLL patients were divided into different groups. B cells were isolated from the peripheral blood of CLL patients by binding to anti-CD19 beads. The expression of BAG3, GRP78 and HIF-1α genes was analyzed using the RT-PCR method. To confirm the results of RT-PCR, western blot analysis was carried out. The results showed that there was a strong association among the expression of BAG3, GRP78 and HIF-1α. The stage of CLL in patients was highly correlated with the expression rate of each gene (p<0.001). Accordingly, the western blot analysis indicated that the concentrations of GRP78 and HIF-1α were significantly higher than the expression of BAG3, considering the stage of CLL. It was shown that increased expression of GRP78 and HIF-1α could result in the elevation of BAG3, as well as the disease progression. Therefore, the role of these metabolic factors might be more pronounced compared with the anti-apoptotic agents to monitor disease progression in CLL patients.

Celastrol mitigates high glucose-induced inflammation and apoptosis in rat H9c2 cardiomyocytes via miR-345-5p/growth arrest-specific 6.

Celastrol (Cel) has been corroborated as an anti-inflammatory and anti-apoptotic agent in multiple cell damage models. However, the protective effect of Cel in high glucose (HG)-induced cardiomyocyte injury is still unclear. The present study aimed to determine whether Cel can mitigate HG-stimulated cardiomyocyte injury via regulating the miR-345-5p/growth arrest-specific 6 (Gas6) signaling pathway. Cardiomyocytes were exposed to normal glucose (NG; 5 mmol/l) or HG (30 mmol/l) and then administered with Cel. Cell counting kit-8 and flow cytometry assays were used to detect cell proliferative activity and apoptosis. mRNA and protein expression were analyzed using a quantitative reverse transcriptase-polymerase chain reaction and western blotting, respectively. A bioinformatics algorithm and a luciferase reporter gene assay were used to determine whether Gas6 is a direct target of miR-345-5p. The present study confirmed the inhibitory effects of Cel in HG-induced inflammation in cardiomyocytes. Moreover, Cel exhibited the ability to antagonize HG-induced cardiomyocyte apoptosis and suppress the elevated Bax/Bcl-2 ratio elicited by HG stimulation. Intriguingly, Cel treatment revoked the HG-triggered repression of Gas6 protein expression, and Gas6 loss-of-function accelerated HG-induced cardiomyocyte apoptosis. HG-triggered up-regulation of miR-345-5p expression was depressed following Cel treatment. Importantly, we validated that Gas6 is a direct target of miR-345-5p. Transfection with miR-345-5p inhibitors restrained HG-induced release of pro-inflammatory cytokines and cell apoptosis. The findings of the present study demonstrate that Cel administration antagonized HG-induced cardiomyocyte apoptosis and inflammation through up-regulating Gas6 expression by restraining miR-345-5p.

KL1333, a derivative of β-lapachone, protects against cisplatin-induced ototoxicity in mouse cochlear cultures

Cisplatin (CP) is a chemotherapeutic drug used to treat cancerous solid tumors, but it causes serious side effects, including ototoxicity. The major cause of CP-induced ototoxicity is increased levels of mitochondrial reactive oxygen species (ROS). In this study, we examined the effect of 2-Isopropyl-3H-naphtho(1,2-d)imidazole-4,5-dione (KL1333), a β-lapachone derivative, on CP-induced ototoxicity using ex vivo organotypic culture system of cochlea. Hair cell damages in CP-treated cochlear explants with or without KL1333 were compared by immunohistochemistry. CP-induced oxidative stress and the preventive effect of KL1333 were analyzed by measuring intracellular ROS levels and depolarization of mitochondrial membrane potential. Activation of apoptosis signaling pathway was detected using TUNEL assay and immunostaining of cleaved caspase-3. As the results, it was found that KL1333 pretreatment significantly decreased stereocilia degeneration and hair cell loss, and prevented an increase in mitochondrial ROS levels in response to CP. Immunohistochemical examinations of cochlear explants revealed greater caspase-3 immunopositivity in the CP group than in controls, while the KL1333 + CP group showed significantly less immunopositivity than the CP group (P < 0.05). Thus, it appeared that KL1333 protected hair cells in the organ of Corti from CP-induced apoptosis by decreasing mitochondrial damages due to the production of mitochondrial ROS. This study is the first report showed the preventive effect of KL1333 against CP-induced ototoxicity. Although further studies should be performed to determine if KL1333 could maintain anticancer effect of CP, our data cautiously suggests that the antioxidant KL1333 can be used as an effective anti-apoptotic agent to prevent ototoxicity caused by CP-induced oxidative stress, and may prove useful in preventing hearing loss caused by CP.

Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury.

The cerebral ischemia injury can result in neuronal death and/or functional impairment, which leads to further damage and dysfunction after recovery of blood supply. Cerebral ischemia/reperfusion injury (CIRI) often causes irreversible brain damage and neuronal injury and death, which involves many complex pathological processes including oxidative stress, amino acid toxicity, the release of endogenous substances, inflammation and apoptosis. Oxidative stress and inflammation are interactive and play critical roles in ischemia/reperfusion injury in the brain. Oxidative stress is important in the pathological process of ischemic stroke and is critical for the cascade development of ischemic injury. Oxidative stress is caused by reactive oxygen species (ROS) during cerebral ischemia and is more likely to lead to cell death and ultimately brain death after reperfusion. During reperfusion especially, superoxide anion free radicals, hydroxyl free radicals, and nitric oxide (NO) are produced, which can cause lipid peroxidation, inflammation and cell apoptosis. Inflammation alters the balance between pro-inflammatory and anti-inflammatory factors in cerebral ischemic injury. Inflammatory factors can therefore stimulate or exacerbate inflammation and aggravate ischemic injury. Neuroprotective therapies for various stages of the cerebral ischemia cascade response have received widespread attention. At present, neuroprotective drugs mainly include free radical scavengers, anti-inflammatory agents, and anti-apoptotic agents. However, the molecular mechanisms of the interaction between oxidative stress and inflammation, and their interplay with different types of programmed cell death in ischemia/reperfusion injury are unclear. The development of a suitable method for combination therapy has become a hot topic.

Resveratrol prevents benzo(a)pyrene-induced disruption of mitochondrial homeostasis via the AMPK signaling pathway in primary cultured neurons

Exposure to benzo(a)pyrene (BaP) has been shown to cause mitochondrial dysfunction and injury to neural cells. Resveratrol (RSV) has been studied as an antioxidant, anti-inflammatory, anti-apoptotic, and anticancer agent and can modulate mitochondrial function in vitro and in vivo. However, the molecular mechanisms underlying RSV’s protection against mitochondrial dysfunction have not been fully elucidated. To investigate whether RSV can effectively prevent BaP-induced mitochondrial dysfunction, we tested the effects of RSV in primary neuronal models. Our results confirmed that neurons exhibited mitochondrial dysfunction and apoptosis in the mitochondrial pathway after BaP-treatment, and that pretreatment with RSV could reduce that dysfunction. Further, our results indicated that RSV pretreatment enhanced mitochondrial biogenesis via the AMPK/PGC-1α pathway and activated mitophagy via the PINK1-Parkin and AMPK/ULK1 pathways, thereby coordinating mitochondrial homeostasis. We also found that RSV could alleviate mitochondrial network fragmentation caused by BaP. This work provided insights into the role of RSV in preventing BaP-induced primary neuronal apoptosis in the mitochondrial pathway, mainly via regulation of mitochondrial biogenesis and mitophagy through AMPK pathway, thus maintaining the integrity of the mitochondrial network.

Modulating Effect of Gum Arabic on Cisplatin-induced Testicular Damage in Albino Wister Rats

The current study has been designed to evaluate the impact of cisplatin on the spermatogenesis, histopathological pictures, DNA damage, and oxidative stress parameters in the testicular tissues for a long period of time. Additionally, we clarify the conservative effect of gum arabic against all of the above toxicological parameters. Twenty male Wister rats were used and divided into four equal groups (n = 5). Group 1 was used as a control negative group. Group 2 was received gum arabic (7.5 mg/kg bwt) daily in drinking water. Group 3 was administered with a single i.p. dose of cisplatin (7 mg/kg bwt). Group 4 was received both cisplatin and gum arabic. Body and testis weights, epididymal sperm analysis, blood testosterone level, testis oxidative stress markers, histopathological pictures, and immunohistochemical staining of the testicular tissues were done. Our results showed that the cisplatin administration led to a significant reduction in the body and testis weights, sperm count, sperm motility, blood testosterone level, and testicular antioxidants. Additionally, it led to a significant elevation of sperm apoptosis, testicular malondialdehyde levels, DNA damage, histopathological alteration, and caspase-3 immunostaining reactions. On the other hand, pretreatment of rats with gum arabic was improved all of the previous parameters. From our findings, we can conclude that the gum arabic could be used as an antioxidant and anti-apoptotic agent to alleviate the toxicity of cisplatin on the testis.

A smart ATP-responsive chemotherapy drug-free delivery system using a DNA nanostructure for synergistic treatment of breast cancer in vitro and in vivo

This study demonstrated a chemotherapy drug-free delivery system for breast cancer treatment based on a simple DNA nanostructure composed of sequence 1 containing ATP and AS1411 aptamers and sequence 2 containing antimiR-21. The DNA nanostructure was used for co-delivery of KLA peptide and antimiR-21 as antiapoptotic agents. These therapeutic agents could not be internalised into eukaryotic cells freely which is one of the great features of this targeting platform. The presented delivery system was ATP-responsive, leading to disassembly of the DNA nanostructure in high ATP concentration of cancer cells and restoration of the function of antimiR-21 in these cells. The DNA nanostructure was associated with high cellular uptake by MCF-7 and 4T1 cells due to expression of nucleolin as target of AS1411 on their plasma membranes, while the developed targeting platform could not be internalised into CHO cells because of lack of the active targeting moiety on their surfaces. Furthermore, the results showed that co-delivery of antimiR-21 and KLA peptide using the DNA nanostructure could efficiently prohibit tumour growth in vitro and in vivo and induce a synergistic anticancer activity. Thus, this work provides a new ATP-responsive nanotargeting delivery system and synergistic chemotherapy drug-free regimen for cancer treatment.

Influence of Omega-3 Supplementation on Adult Male Rat Adrenal Cortex Exposed to Stress

ABSTRACT Background: Hypothalamus-pituitary- adrenal and sympathetic adreno-medullary axes are the systems mainly implicated in preserving body homeostasis during the stress and the adrenal gland is an important organ to both systems. Stress either subacute or chronic is usually linked with adrenal alterations. Omega-3 fatty acid (O3FAs) which is present in dietary fish oil is known to have beneficial effects on cardiovascular disease, autoimmune diseases and cancer. Also omega-3 fatty acids were mentioned to be considered as anti-apoptotic and anti-oxidant agents. Aim of the work: Evaluation of the role of Omega-3 supplementation on adrenal cortical cells during exposure to stress. Materials and Methods: 3 groups of adult male albino rats were used (10 rats each): group 1 (control), group 2 (stressed for 6 weeks) and group 3 (stressed + Omega -3-treated; 300 mg/kg Omega-3 plus once daily 5 days/week for 6 weeks). Then the rats were sacrificed and the adrenal glands were extracted and processed for light, electron microscopic, immunohistochemical and morphometric studies. Results: group II revealed signs of degeneration in adrenal cortical cells; disturbed arrangement, pyknotic nuclei, vacuolated cytoplasm and destructed organelles. There was reduction in ZF thickness with weak immunoexpression of Bcl-2. Omega-3 induced relative improvement of adrenal cortex in group III. This was evidenced by light, electron microscope and confirmed by morphometric and statistical results. Conclusion: Omega-3 FA supplementation influences sensitivity to stress and has strong anti-stress effects.

Exogenous Ghrelin Could Not Ameliorate 3,4-methylenedioxymethamphetamine-induced Acute Liver Injury in The Rat: Involved Mechanisms.

MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is often abused by youth as a recreational drug. MDMA abuse is a growing problem in different parts of the world. An important adverse consequence of the drug consumption is hepatotoxicity of different intensities. However, the underlying mechanism of this toxicity has not been completely understood. Ghrelin is a gut hormone with growth hormone stimulatory effect. It expresses in liver, albeit at a much lower level than in stomach, and exerts a hepatoprotective effect. In this study, we investigated hepatotoxicity effect of MDMA alone and its combination with ghrelin as a hepatoprotective agent. MDMA and MDMA+ ghrelin could transiently increase serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) followed by tissue necrosis. However, they could significantly decrease liver tumor necrosis factor-a (TNF-±) in both treatment groups. Unexpectedly, in MDMA treated rats, Bax, Bcl-xl, Bcl-2, Fas, Fas ligand (Fas-L), caspase 8, cytochrome c, caspase 3 gene expression, and DNA fragmentation were nearly unchanged. In addition, apoptosis in MDMA+ ghrelin group was significantly reduced when compared with MDMA treated animals. In all, MDMA could transiently increase serum transaminases and induce tissue necrosis and liver toxicity. Ghrelin, however, could not stop liver enzyme rise and MDMA hepatotoxicity. MDMA hepatotoxicity seems to be mediated via tissue necrosis than apoptotic and inflammatory pathways. Conceivably, ghrelin as an anti-inflammatory and anti-apoptotic agent may not protect hepatocytes against MDMA liver toxicity.

Antioxidant and anti-apoptotic effects of selenium nanoparticles against murine eimeriosis.

Eimeriosis is caused by a protozoan parasite of the genusEimeria and infection affecting most domestic animal species. The aim of this research was to comprehend the impact of selenium nanoparticles (SeNPs) on eimeriosis induced by Eimeria papillata in mouse jejunum, and how they work as antioxidants and anti-apoptotic agents against eimeriosis. The numbers of meronts, gamonts, and developing oocysts of E. papillata reduced after the infected mice were treated with the SeNPs. The levels of malondialdehyde (MDA), nitric oxide (NO), and other oxidative stress-related molecules, such as glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD), were assayed. E. papillata was able to change the redox status of the jejunal cells; this was confirmed by the elevation of the MDA and NO levels, and the decrease of the GSH levels and the activities of the antioxidant enzymes CAT and SOD. SeNP treatment significantly reversed this disturbance of the redox status. The expression levels of the apoptotic markers Bax and caspase-3 in the jejunal samples were evaluated using qRT-PCR. The SeNPs decreased the Bax and caspase-3 expression after being administered to the E. papillata-infected mice. Collectively, the SeNPs demonstrated antioxidant and anti-apoptotic activities against murine eimeriosis.

Thyroid hormones T3 and T4 regulate human luteinized granulosa cells, counteracting apoptosis and promoting cell survival.

Fine and balanced regulation of cell proliferation and apoptosis are key to achieve ovarian follicle development from the primordial to the preovulatory stage and therefore assure female reproductive function. While gonadotropins are the major and most recognized regulators of follicle cell growth and function, other factors, both systemic and local, play equally important roles. This work is aimed at evaluating the effects of thyroid hormones (THs) on human granulosa luteinized (hGL) viability. Human GL cells derived from assisted reproduction treatments were exposed to T3 or T4. Cell viability was evaluated by MTT assay. Apoptosis was evaluated by the TUNEL assay and active caspase-3 staining. StAR, CYP19A1,Caspase-3, P53 and BAX mRNA were evaluated by real-time PCR. LC3-I/-II, AKT and pAKT were evaluated by western blot. T3 and T4 promoted cell viability in a dose-dependent modality and modulate StAR and CYP19A1 expression. T3 and to a lesser extent T4 mitigated cell death induced by serum starvation by inhibition of caspase-3 activity and expression of P53 and BAX; and attenuate cell death experimentally induced by C2-ceramide. Cell death derived from starvation appeared to be involved in autophagic processes, as the levels of autophagic markers (LC3-II/LC3-I ratio) decreased when starved cells were exposed to T3 and T4. This effect was associated with an increase in pAkt levels. From the present study, THs emerge as potent anti-apoptotic agents in hGL cells. This effect is achieved by inhibiting the apoptosis signalling pathway of BAX and caspase-3, while maintaining active the PI3K/AKT pathway.

Seminal plasma clusterin as a biomarker for spermatogenesis in patients with varicocele before and after varicocelectomy

Introduction: A varicoc ele is an abnormally dilated pampiniform plexus of veins. Hyperthermia, oxidative stress, and elevated apoptotic index have been described in men with varicocele and infertility. Clusterin (Clu) is a chaperone-like glycoprotein that is synthesized by Sertoli cells in high concentrations and is deposited onto the membranes of mature spermatozoa, giving rise to the possibility that it has a role in sperm development. Secreted form of Clu is a powerful anti-apoptotic agent. Aim: To explore Clu level in seminal plasma of infertile men with varicocele in comparison with normal healthy fertile patients and to compare the seminal plasma Clu level before and after varicocelectomy.Patients and methods: The study included 25 patients having varicocele with infertility (whether primary or secondary) for 12 months and 10 healthy volunteers of matched age and sex as control. For all the patients, sub-inguinal varicocelectomy was done. Semen analysis and seminal plasma Clu assay were carried out before and 3 months after varicocelectomy.Results: There was a statistically significant difference between patients and controls regarding sperm count, progressive motility, and seminal plasma Clu (P<0.01). Three months after varicocelectomy, the sperm count had a highly significant improvement in the patient’s group (mean ± SD=17.90 ± 8.86) compared with a preoperative count (mean ± SD=11.43 ± 7.56). There was a highly significant improvement in postoperative progressive motility in the patient’s group (mean ± SD=34.5 ± 20.2) compared with preoperative progressive motility (mean ± SD=22.05 ± 15.5).Clu showed a highly significant elevation in the patient group postoperatively (mean ± SD=10.73 ± 4.5) compared with preoperatively (mean ± SD=6.68 ± 3.8). Conclusion: Based on our study, we could suggest another way of contribution of varicocele to male infertility by affecting seminal plasma Clu level.

In vitro and in vivo evaluation of the neuroprotective activity of Uncaria hirsuta Haviland

The incidence of neurodegeneration leading to the conditions such as Alzheimer's and Parkinson's diseases are on the increase, they require the approaches that focus on protection prevention rather than treatment. Plants are rich sources of many compounds which possess medicinal properties. We sought to investigate the neuroprotective effects of Uncariahirsuta and its compounds on d-galactose-induced stress in BALB/c mice as well as 6-hydroxydopamine (6-OHDA)-induced stress in mouse nerve growth factor (mNGF)-differentiated PC12 cells. Our results demonstrate that the 95% ethanol extract of U. hirsuta reversed the d-galactose-induced learning and memory dysfunctions and decreased the malodialdehyde levels. Furthermore, the isolated compounds, 5β-carboxystrictosidine (1) and chlorogenic acid (2), protected mNGF-differentiated PC12 cells against toxicity induced by 6-OHDA by acting as antiapoptotic agents. The 50% inhibitory concentration (IC50) for intracellular reactive oxygen species (ROS) scavenging was found to be 24.5 (for 1) and 19.7 μM (for 2), and both 1 and 2 reduced intracellular calcium levels with respective IC50 values of 46.9 and 27 μM. Interestingly, both compounds inhibited caspase 3 and 9 activities with respective IC50 values of 25.6 and 24.5 μM for 1 and 19.4 and 16.3 μM for 2. Our results identify U. hirsuta and its active compounds as potential neuroprotective agents and deserve further evaluation for drug development for neuroprotection in the future.