KRG (100 mg/kg day) counteracts the changes of these heat stress-induced antioxidase index in the testes, which improved the resistance of testis to the heat-induced oxidative stress, and enhances the testicular physiological function as well

KRG (100 mg/kg day) counteracts the changes of these heat stress-induced antioxidase index in the testes, which improved the resistance of testis to the heat-induced oxidative stress, and enhances the testicular physiological function as well. heat shock, and redistribution is completed, while BCL-2 expression does not significantly change [25]. Distorting the ratio of BAX and BCL-2 induces apoptosis; while, opening mitochondrial PT pores releases cytochrome [26]. Releasing cytochrome forms a complex with apoptotic protease activating factor 1 (APAF-1) [27,28]. Delsoline The complex combines with caspase 9 and activates the caspase cascade via executioner caspases like caspases-3, -6, and -7 [29]. Additionally, p53-dependent or -independent pathways and p38 mitogen-activated protein kinase (MAPK)-signaling activation are involved in Delsoline mitochondria-mediated apoptosis of spermatogenic cells [30]. A similar process has also been found in pig testes [31]. Open in a Delsoline separate window Figure 2 Apoptosis pathways in spermatocytesHeat stress can induce spermatocyte damage. On one hand, BAX (pro-apoptotic protein) responds to heat stress and accumulates in the mitochondria, while BCL-2 is phosphorylated and loses activity. BAX is integrated into the outer mitochondrial membrane, causing a conformational change that releases cytochrome into the cytoplasm. Cytochrome interacts with APAF-1 to form a complex that Delsoline activates the caspase cascade. On the other hand, heat stress connects the death receptor FAS to its ligand FASL through p53. FAS recruits FAS-related death domain (FADD) through the shared death domain (DD) to form a complex, which is bound to the caspase-8 promoter, triggering the caspase cascade. Heat stress activates spermatocyte apoptosis by directly activating the p38-MAPK signaling pathway independently of p53 signals. Finally, heat stress also inhibits DNA repair-related genes, such as (involved in base excision repair), (involved in nucleotide excision repair), and (involved in double-strand break repair) and, eventually, spermatocyte replication and meiosis separation, resulting in reproductive damage. p53 signaling plays a very important role in these genes and signaling pathways. p53 causes cell death through FAS; it also disrupts the BCL-2/BAX balance and triggers mitochondria-related apoptosis. Another thermal stimulation-related cause of apoptosis during spermatogenesis is DNA damage [32]; heat affects the integrity of the sperm and leads to breaks in the DNA double strand. Heat stimulation altered chromosome structures and reduced chromatin material in rodents [33]. Furthermore, during meiosis, heat stress can also cause abnormal segregation of sex chromosomes and lead to the existence of unpaired Y chromosomes, which cause spermatocytes to undergo apoptosis [34]. DNA repair during spermatogenesis is essential for meiotic recombination and the repair of DNA damage in developing germ cells. Each testis has intact antioxidant-reducing capacity [35], involving a complex system with more than 130 genes related to gene protection. These gene proteins are involved in mismatch repair, nucleotide excision repair, basal excision repair, single-strand break repair, and double-strand break repair. Mismatch repair can fix small mismatches or loops. Nucleotide excision repair is primarily involved with reversing UV-induced and oxidative DNA damage. Basal excision repair mainly replaces abnormal (including oxidized) bases in DNA. However, many DNA repair genes, such as (base excision repair), (nucleotide excision repair), and (double-strand break repair), were found to be down-regulated after heat treatment at 43C [36]. In addition, there was reduced expression of polyADP ribose polymerase (PARP), which is involved in the detection of strand BM28 breaks and in signaling in base excision repair and nucleotide excision repair pathways [37]. A recent study found that Delsoline deleted in azoospermia-like (DAZL) has a role in the fate of germ cells. The endogenous Dazl protein is essential in the formation of stress particles in sperm formation and sperm cell survival during local heat stress. The stress particles are cytoplasmic dense granules responding to multiple stress of environment, which contain polyadenylated mRNAs, 40S ribosomal subunits, translation initiation factors, and some RNA-binding proteins. The transient appearances of them can store, degrade, or reinitiate messenger ribonucleoprotein when heat stress occurs, and bring a fast recovery against the damage of heat. It is widely believed that the production of reactive oxygen species (ROS) seems to be of utmost importance for apoptosis of germ cells and DNA damage [38]. ROS are molecules with at least one unpaired electron, making them highly unstable and extremely reactive for lipids, amino acids, and nucleic acids [39]. A 42C heat treatment generated oxidative stress in the testisby the up-regulation of ROS and down-regulation of antioxidants [40]. In normal testes, ROS are maintained at an acceptable level due to the antioxidants, and when the balance between ROS and antioxidants is oxidative stress will ensue, then.