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Biochemical Aspects of Fatty Liver
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Furthermore, additional reasons for chronic liver damage after ethanol may be attributed to stomach and intestine damage, which can modify the absorption of nutrients. Moreover, the fact that a portion of the caloric intake is covered by ethanol may decrease the intake of other necessary nutrients. Thus, protein, fat, selenium, and vitamin deficiencies may develop. Increased iron absorption (Mazzanti et al., 1987; Nordmann et al., 1987) may also contribute. In any case, a change in the ionic pumps has been hypothesized as a possible further mechanism of damage. Acetaldehyde (Gonzales-Calvin et al., 1983) and HNE (Paradisi et al., 1982, 1985) are able to inhibit plasma-membrane ATPase, as well as adenylate cyclase (Dianzani, 1982; Dianzani and Poli, 1982, Dianzani et al., 1990). This enzyme, on the contrary, is stimulated by HNE at concentrations lower than 10 −6M after short-term (5-min) incubation. Stimulation of adenylate cyclase has been reported even after ethanol in vivo (Whetton et al., 1983).
Antifungals
Published in Rajendra Prasad, Mahmoud A. Ghannoum, Lipids of Pathogenic Fungi, 2017
A. S. Ibrahim, R. Prasad, M. A. Ghannoum
Further evidence supporting the interactions between the azoles and the plasma membrane was presented by Yamaguchi.48 He showed that the antifungal activity of both clotrimazole and miconazole is antagonized by several classes of lipids containing unsaturated fatty acids. Similar results were reported by Vanden Bossche and co-workers with ketoconazole.49 The drugs may alter the organization of the membrane lipids without necessarily binding to them.49 In addition to its direct action on the plasma membrane, azoles were shown to inhibit plasma membrane ATPase of C. albicans and other yeasts.50 Whether such an effect accounts for the rapid collapse of electrochemical gradients and the fall in intracellular ATP levels has not been ascertained. Surarit and Shepherd51 reported that miconazole and ketoconazole, at growth inhibitory concentrations, extensively inhibited plasma membrane ATPase, glucan synthase, adenylate cyclase, and 5’-nucleotidase of C. albicans when assayed in situ. In the same study, they also reported similar inhibition of plasma membrane enzymes by polyenes (nystatin and amphotericin B).
Potassium
Published in Linda M. Castell, Samantha J. Stear (Nottingham), Louise M. Burke, Nutritional Supplements in Sport, Exercise and Health, 2015
Potassium is the major intracellular cation in the body, with ~98% of the body’s potassium stores located inside the cells. The concentration intracellularly is maintained at about 145mM. Potassium’s major functions are to promote contractility of cardiac, smooth and skeletal muscle and influence the regulation of nerve conduction through the influx of sodium (Na+) and efflux of potassium (K+) on either side of the nerve terminal. The Na,K-ATPase, also known as the Na-K pump, is the primary active transporter system that maintains high K+ and low Na+ intracellular concentrations. The plasma membrane ATPase of all mammalian cells catalyzes the reaction: ATP→ADP+Pi, with obligatory requirements for both Na+ and K+ and Mg++ required for the dephosphorylation of ATP.
Five New Cases of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS), with One Case Showing a Novel Mutation
Published in Fetal and Pediatric Pathology, 2021
Alyssa Kalsbeek, Renee Dhar-Dass, Abdul Hanan, Eman Al-Haddad, Iman William, Adina Alazraki, Janet Poulik, Kasey McCollum, Aya Almashad, Bahig M. Shehata
We had one case of a missense mutation in ATP2B4 on Chromosome 1q32. This patient had a milder course with a delayed presentation at 11 months and the longest survival with the aid of multi-organ transplantation. These results seem to indicate that this infant presented with sporadic MMIHS. Familial forms of MMIHS are more often associated with high frequency polymorphisms in CHRNA3 and CHRNAB4 genes, which differ from the way in which the identified sporadic missense mutation in the genes ACTG2 and ATP2B4 lead to MMIHS. The differences in the molecular genetic basis between familial and sporadic forms of MMIHS are still being explored with varying hypothesis being studied. In another study on sporadic MMIHS, it was proposed that ACTG2 variants lead to the phenotypic expression of MMIHS [24]. The results of our study in the ACTG2 gene, but instead a different missense mutation which regulates calcium transport in the plasma membrane. Additional investigation is needed to explore the relationship between ATP2B4 gene mutations and MMIHS. These sporadic cases of MMIHS suggest that missense mutations may not lead to complete loss of function of the plasma membrane ATPase, which may also be related to clinically milder visceral myopathies, and better outcomes following multi-organ transplantation. This should be considered when forming a prognosis and treatment plan. Histologic findings from patients with MMIHS have shown vacuolar degeneration of smooth muscle cells, reactive interstitial fibrosis, and decreased staining of smooth muscle actin in the circular layer of the small bowel [17,24–26].
Computational approaches for the design of modulators targeting protein-protein interactions
Published in Expert Opinion on Drug Discovery, 2023
Ashfaq Ur Rehman, Beenish Khurshid, Yasir Ali, Salman Rasheed, Abdul Wadood, Ho-Leung Ng, Hai-Feng Chen, Zhiqiang Wei, Ray Luo, Jian Zhang
The 14-3-3 protein family is a particularly intriguing topic for PPI modulation research because it has been discovered to have hundreds of protein-protein interactions. PPIs play a role in a variety of biological processes, including cell cycle regulation, signal transduction, protein trafficking, apoptosis, and cancer [177]. 14-3-3 proteins are also involved in phosphorylation-dependent PPIs, which regulate cell cycle progression, the initiation and maintenance of DNA damage checkpoints [178]. Besides this, 14-3-3 proteins are also involved in the progression of many neuropathological disorders [179,180], bound to tau-tangles and enhancing their aggregation as seen in Alzheimer’s patients [181]. Using small molecules to modify these PPIs is a crucial method for creating new drugs. The literature has reported a variety of natural, semi synthetic and synthetic compounds that perform their physiological functions by stabilizing complexes of their target proteins [182]. Fusicoccin-A (FC-A), a metabolite generated by the fungus Phomopsis amygdali, is an example of a natural stabilizer and was the first stabilizer to be reported for 14-3-3/client PPIs. The plasma membrane H+-ATPase (PMA2) and 14-3-3 complex was discovered to be stabilized by FC-A, with a 90 times increase in the affinity [183]. It was also found to stabilize 14-3-3/cystic fibrosis transmembrane conductance regulator (CFTR) complex that resulted in enhanced delivery to the plasma membrane. By looking at the examples above and many more [180,184], it can be deduced that FC-A might act as a potential chemical tool for investigating the role of 14-3-3 in various pathologies.
Programmed cell death in human pathogenic fungi – a possible therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2018
Éva Leiter, László Csernoch, István Pócsi
Human lactoferrin also shows anticandidal activity by inducing apoptosis via interfering with the plasma membrane H+-ATPase (P3A-Type) and mitochondrial H+-ATPase (Andrés et al., 2016) as well as K+ channels [81]. PS flip-flop, ROS elevation, DNA fragmentation, nuclear condensation as apoptotic events were detected in C. albicans after lactoferrin treatment [82].