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Intracellular Peptide Turnover: Properties and Physiological Significance of the Major Peptide Hydrolases of Brain Cytosol
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
Although moderate inhibition of prolyl oligopeptidase can be obtained with chloromethyl ketone derivatives60, the first highly potent and specific inhibitor synthesized was a peptide aldehyde, Z-Pro-Prolinal5. Peptide aldehydes by forming a hemiacetal adduct with the active site serine act as transition state analog inhibitors67. Z-Pro-Prolinal is of interest because it crosses the blood brain barrier to inhibit the brain enzyme. Thus 60 min after an intraperitoneal dose of 0.5 mg/kg to mice, the brain enzyme was 50% inhibited68. Moreover at this time point, a dose as low as 5μg/kg, still produced 39% inhibition of the brain enzyme. Inhibition is long lasting, and significant inhibition of the brain enzyme is seen 6.5 h following a dose of 5 mg/kg. A series of prolinal derivatives were synthesized and their inhibitory potencies were compared. Within this series Z-Pro-Prolinal was the most potent, inhibiting the bovine brain enzyme with a Ki of 0.21 nM69. The most potent inhibitors thus far described are derivatives of thioproline. The Ki of Z-thiopro-thioprolinal is 10 pM70. It should be noted that prolinal derivatives must be used with caution in in vivo studies. Z-Pro-Prolinal also inhibits the serine-type carboxypeptidase lysosomal Pro-X carboxypeptidase (EC 3.4.16.2) (Ki = 2.6X10−7M)71.
Micronutrients in Healthy Aging and Age-Related Decline in Organ Functions
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
In a model of prematurely aging mice, treatment with NAC plus thioproline increased chemotaxis, phagocytosis, and IL-beta release, and decreased superoxide levels and TNF-alpha production.163 This suggests that antioxidant supplementation can protect against early decline in immune function in prematurely aging mice. These antioxidants also reversed age-related behavioral dysfunction in prematurely aging mice.164
The role of radiation induced oxidative stress as a regulator of radio-adaptive responses
Published in International Journal of Radiation Biology, 2020
Mohsen Sisakht, Maryam Darabian, Amir Mahmoodzadeh, Ali Bazi, Sayed Mohammad Shafiee, Pooneh Mokarram, Zahra Khoshdel
Radiation, either low or high dose, can affect the phenotype, fate and function of lymphocytes (Candeias et al. 2017). At 3 h post exposure to gamma radiation (2 Gy), all CD4+, CD8+ lymphocytes, and natural killer cells revealed elevated expression of genes involved in Tp53 singling (Moreno-Villanueva et al. 2019). T leukemic lymphocytes also showed increased expression of Tp53 in response to ionizing radiation (1–10 Gy) (Tichy et al. 2007). In another report, lymphocytes from mice exposed to whole body gamma radiation showed high expression of caspase 3 and apoptosis rate (Park, Loh et al. 2015). The role of Fas-FasL (Caricchio et al. 1998) and ubiquitination (Delic et al. 1993) pathways in induction of apoptosis in lymphocytes exposed to radiation have been shown. Furthermore, lymphocytes from mice exposed to gamma radiation represented low expression of Bcl-2 and high levels of Bax and caspase-3 (4 Gy) (Guida et al. 2016). In exposure to low dose (0.01 Gy) gamma radiation, NF-kB and p38MAPK pathways were activated in CD4+ lymphocytes after 21 days; nevertheless, lymphocytic kinases (Lck and Zap-70) were unaffected (Rizvi et al. 2011). Also, B lymphocytes exposed to ionizing radiation (1000–4000 cGy) have shown activated NF-kB and protein kinase C pathways (Uckun et al. 1993) In addition to increased number of CD4+ and CD3+ T cells, lymphocytes from patients with hepatocellular carcinoma showed increased expression of IL-12 and decreased production of IL-4 and IL-10 at 1-month after microwave ablation therapy (Zhang et al. 2017). The role of ATM kinase in adaptive responses of leukemic T lymphocytes to ionizing radiation (1–10 Gy) has been shown (Tichy et al. 2007). Higher DNA DSBs in lymphocytes of patients with breast cancer in exposition to gamma-radiation (1 Gy) compared to cells of normal individuals suggest lower ability of lymphocytes from cancerous patients to activate DNA repair mechanisms (Vorob’eva et al. 2011). Protective effects of anti-oxidative agents (N-acetyl cysteine (NAC), glutathione (GSH) and thioproline (TP)) on DNA modifications following gamma-radiation (2–4 Gy) in lymphocytes proposed a role for oxidative markers in inducing DNA toxicity in irradiated lymphocytes (Tiwari et al. 2009). In exposition to gamma radiation (0.05–1 Gy), lymphocytes isolated from patients with prostate cancer represented higher expressions of CD95 (apoptotic marker), CD69 (marker of non-active lymphocytes) while lower expression of Ki67 (proliferative marker) compared to lymphocytes from normal individuals (Pelevina et al. 2015). Signaling molecules of cAMP and NO were decreased and increased respectively in peripheral blood lymphocytes irradiated with UV (151–4530 J/m(2)) (Nakvasina et al. 2011). Irradiation (x-rays, 2 Gy) furthermore augmented the stimulating activity of DCs to induce proliferation of T lymphocytes and release of inflammatory cytokines (Persa et al. 2018).