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The Americas
Published in Michael J. O’Dowd, The History of Medications for Women, 2020
A more recent pharmaceutical is the New/Old plant wonder drug obtained from Gossypium herbaceum, cotton, or Levant cotton, which is now being touted for its hemostatic properties. Cotton is thought to have originated in India and was carried by traders to ancient Egypt c. 500 BC. Remains of the plant have also been found among archeological artifacts of ancient Peru c. 2000 BC. Apart from antibacterial and antiviral effects, its active constituent, gossypol, causes male infertility and stimulates the uterus. Cotton seed was used centuries ago by some North American Indian tribes to induce labor pains, and it was listed for its abortifacient properties in the USP from 1863 to 1950. It is still available as a herbal medication for treatment of amenorrhea (British Herbal Pharmacopoeia, 1991).
The Bioenergetics of Mammalian Sperm Motility
Published in Claude Gagnon, Controls of Sperm Motility, 2020
The male contraceptive effects in humans of gossypol, a constituent of cottonseed oil, have been extensively investigated in China. The compound is an effective male contraceptive and severe oligozoospermia/azoospermia was attained in more than 99% of subjects after 2 to 3 months of treatment. The decline in the number of spermatozoa was preceded by a decrease in their motility.171 The action of gossypol is poorly reversible and it has a number of side effects, including hypokalemic paralysis in a small proportion of men, and it is unlikely that it will be developed into a viable contraceptive for human use.172,173 The primary site of action is probably in the testis and may involve an effect on the coupling of electron transport to ATP synthesis in the mitochondria of spermatids.173 However, it has a number of effects on the energy metabolism of spermatozoa. First, it acts as an uncoupler and as the concentration is increased, an inhibitor of mitochondrial respiration (Figure 9).148,176 20 μM of gossypol can also inhibit sperm glycolysis possibly through the inhibition of LDH-C4.177,178 Gossypol binds to the NAD binding site of the enzyme and it is difficult to see how this effect can be specific because this site is strongly conserved among NAD-dependent dehydrogenases.179
Environmental toxicants on Leydig cell function
Published in C. Yan Cheng, Spermatogenesis, 2018
Leping Ye, Xiaoheng Li, Xiaomin Chen, Qingquan Lian, Ren-Shan Ge
Gossypol is a polyphenolic compound isolated from cotton seeds.252 Gossypol exposure could come from the ingestion of cotton-seed oils and materials. Gossypol was once developed as a male contraceptive,253 but it apparently has some severe side effects, including an effect on Leydig cell function. Men with long-term ingestion of crude cotton seed oil that contains gossypol had abnormal Leydig cell function.254 Gossypol inhibited hCG-induced testosterone production in cultured canine Leydig cells.255 Gossypol at 10–20 μM in vitro also inhibited basal and LH-stimulated testosterone production in mouse Leydig cells.256 Gossypol contains enantiomers, (+) gossypol and (-) gossypol, and only the (-) gossypol was found to have the antifertility function.257 However, at ≥21 μM both enantiomers inhibited LH-stimulated testosterone production in mouse Leydig cells.257 At higher concentrations, gossypol inhibited cAMP production in Leydig cells.258 Further studies showed that gossypol directly inhibited some steroidogenic enzymes in Leydig cells. Gossypol inhibited bovine CYP11A1 activity at 30 μM.259 Gossypol inhibited human and rat Leydig cell 3β-HSD activities with IC50 values of 3 and 0.2 μM, respectively.260 Gossypol inhibited human and rat 17β-HSD3 in a clear enantiomer-specific manner, with (−)-gossypol in inhibition of human and rat enzyme activities (IC50 values of 0.36 and 3.43 μM, respectively) and (+)-gossypol inhibition of human and rat enzyme activities (IC50 values of 1.13 and 10.93 μM, respectively).260 Gossypol inhibited SRD5A1 more potently than SRD5A2 activity.261 As well, gossypol inhibited the glucocorticoid metabolizing enzyme, human and rat 11β-HSD2, with IC50 values of about 1 μM.262
Ulva lactuca methanolic extract improves oxidative stress-related male infertility induced in experimental animals
Published in Archives of Physiology and Biochemistry, 2021
Doaa A. Ghareeb, Alshimaa Abd-Elgwad, Nihal El-Guindy, Galila Yacout, Hala H. Zaatout
High gossypol consumption has biological toxicity because it can bind macromolecules before and after absorption. On one hand, it can interact with the substrate and thereby blocking the action of the digestive enzymes such as pepsin. On the other hand, it directly binds with the enzyme and changing the ionic character of the active site or creating steric hindrance (Wong et al.1972). Gossypol and its metabolites exert pro- and anti-oxidant potential. It was reported that gossypol increased the formation of ROS and DNA scission (Kovacic 2003). Bender et al. (1988) found that vitamin E, ascorbate, glutathione (GSH) peroxidase, and other antioxidants were reduced by feeding rats high levels of gossypol. Gossypol leads to male reproductive system toxicity and assists in maintaining long-term infertility through decreasing sperm motility and count, inhibits spermatogenesis, affects acrosomal formation, and spermatozoal elongation processes and causes Sertoli cells toxicity (Randel et al.1992, Wang 2000).
Development and implementation of precision therapies targeting base-excision DNA repair in BRCA1-associated tumors
Published in Expert Review of Precision Medicine and Drug Development, 2019
Adel Alblihy, Katia A. Mesquita, Maaz T. Sadiq, Srinivasan Madhusudan
APE1 is upregulated or dysregulated in variable solid cancers such as ovarian, prostate, germ cell tumor and colon cancers. In addition, overexpression or altered levels of AP endonucleases has been demonstrated to increase the resistance of tumor cells to a number of chemotherapeutic agents in several cancers, confirming that APE1 is a critical target for cancer treatment. A large number of APE1 inhibitors have been studied and reviewed in 2012 [104]. E3330 and its analogues have potential clinical therapeutic value as specific inhibitors of the redox activity of APE1, but it does not affect APEI DNA activity [63]. Another APEI inhibitor is CTR0044876, which was the most potent and selective inhibitor, with an IC50 of 3.06 mm. It potentiated the cytotoxicity of TMZ and MMS in HT1080 fibrosarcoma cells. APE1 inhibitors induced synthetic lethality in BRCA2- and ATM-deficient cell lines [75,105]. Qian et al. (2014) showed that the Bcl-2 homology 3 (BH3)-mimetic agent gossypol can bind to the BH3 domain in B-cell lymphoma 2 (Bcl-2) and that Bcl-2 interact directly with the BH domains in APE1. As a result, gossypol inhibits the redox and repair activity of APE1 [106]. Small molecules such as ML199 and its analogues belong to a drug-like was developed to afford compounds that can competitively inhibit APE1 activity [107]. These findings reflect the rapid development and promising results of studies on APE1 inhibitors, which could replace PARPi.
Discovery of antimicrobial compounds targeting bacterial type FAD synthetases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
María Sebastián, Ernesto Anoz-Carbonell, Begoña Gracia, Pilar Cossio, José Antonio Aínsa, Isaías Lans, Milagros Medina
Gossypol, here 27, was used some years ago in China as a masculine contraceptive45, however, its side effects stopped its pharmacological use. More recently, 27 has demonstrated anticancer effects through the inhibition of antiapoptotic proteins belonging to the Bcl-2 family and of molecules implicated in tumour progression46,47. Additionally, 27 inhibits the HIV-1 replication in vitro48. 27 is a potent inhibitor of the CaFADS FMNAT activity, as shown by the low IC50 and residual FMNAT activity (Table 2), while does not affect the RFK one (Table 1, Figure 2). This compound competes with ATP for its binding at the FMNAT site (Table 3, Figures 4 and 6(C)). The lower Kd value for 27 when compared with that of FMN29, makes the inhibitor a preferred ligand for CaFADS.