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Pathophysiology, Volume 28, Issue 3 (September 2021) – 8 articles

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20 pages, 1475 KiB  
Review
Molecular Functions of Hydrogen Sulfide in Cancer
by Rodney E. Shackelford, Islam Z. Mohammad, Andrew T. Meram, David Kim, Fawaz Alotaibi, Stavan Patel, Ghali E. Ghali and Christopher G. Kevil
Pathophysiology 2021, 28(3), 437-456; https://doi.org/10.3390/pathophysiology28030028 - 20 Sep 2021
Cited by 24 | Viewed by 4430
Abstract
Hydrogen sulfide (H2S) is a gasotransmitter that exerts a multitude of functions in both physiologic and pathophysiologic processes. H2S-synthesizing enzymes are increased in a variety of human malignancies, including colon, prostate, breast, renal, urothelial, ovarian, oral squamous cell, and [...] Read more.
Hydrogen sulfide (H2S) is a gasotransmitter that exerts a multitude of functions in both physiologic and pathophysiologic processes. H2S-synthesizing enzymes are increased in a variety of human malignancies, including colon, prostate, breast, renal, urothelial, ovarian, oral squamous cell, and thyroid cancers. In cancer, H2S promotes tumor growth, cellular and mitochondrial bioenergetics, migration, invasion, angiogenesis, tumor blood flow, metastasis, epithelia–mesenchymal transition, DNA repair, protein sulfhydration, and chemotherapy resistance Additionally, in some malignancies, increased H2S-synthesizing enzyme expression correlates with a worse prognosis and a higher tumor stage. Here we review the role of H2S in cancer, with an emphasis on the molecular mechanisms by which H2S promotes cancer development, progression, dedifferentiation, and metastasis. Full article
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42 pages, 8433 KiB  
Article
Proton Quantum Tunneling: Influence and Relevance to Acidosis-Induced Cardiac Arrhythmias/Cardiac Arrest
by Omar Ababneh, Abdallah Barjas Qaswal, Ahmad Alelaumi, Lubna Khreesha, Mujahed Almomani, Majdi Khrais, Oweiss Khrais, Ahmad Suleihat, Shahed Mutleq, Yazan Al-olaimat and Sager Nawafleh
Pathophysiology 2021, 28(3), 400-436; https://doi.org/10.3390/pathophysiology28030027 - 3 Sep 2021
Cited by 3 | Viewed by 4326
Abstract
Acidosis and its associated pathologies predispose patients to develop cardiac arrhythmias and even cardiac arrest. These arrhythmias are assumed to be the result of membrane depolarization, however, the exact mechanism of depolarization during acidosis is not well defined. In our study, the model [...] Read more.
Acidosis and its associated pathologies predispose patients to develop cardiac arrhythmias and even cardiac arrest. These arrhythmias are assumed to be the result of membrane depolarization, however, the exact mechanism of depolarization during acidosis is not well defined. In our study, the model of quantum tunneling of protons is used to explain the membrane depolarization that occurs during acidosis. It is found that protons can tunnel through closed activation and inactivation gates of voltage-gated sodium channels Nav1.5 that are present in the membrane of cardiac cells. The quantum tunneling of protons results in quantum conductance, which is evaluated to assess its effect on membrane potential. The quantum conductance of extracellular protons is higher than that of intracellular protons. This predicts an inward quantum current of protons through the closed sodium channels. Additionally, the values of quantum conductance are influential and can depolarize the membrane potential according to the quantum version of the GHK equation. The quantum mechanism of depolarization is distinct from other mechanisms because the quantum model suggests that protons can directly depolarize the membrane potential, and not only through indirect effects as proposed by other mechanisms in the literature. Understanding the pathophysiology of arrhythmias mediated by depolarization during acidosis is crucial to treat and control them and to improve the overall clinical outcomes of patients. Full article
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13 pages, 1297 KiB  
Article
Clinical Presentation of Hepatocellular Carcinoma in African Americans vs. Caucasians: A Retrospective Analysis
by Hrishikesh Samant, Kapil Kohli, Krunal Patel, Runhua Shi, Paul Jordan, James Morris, Annie Schwartz and Jonathan Steven Alexander
Pathophysiology 2021, 28(3), 387-399; https://doi.org/10.3390/pathophysiology28030026 - 31 Aug 2021
Cited by 3 | Viewed by 3227
Abstract
Hepatocellular carcinoma (HCC) remains an important form of cancer-related morbidity and mortality in the U.S. and worldwide. Previous U.S.-based studies on survival suggest ethnic disparities in HCC patients, but the complex interplay of multiple factors that contribute are still incompletely understood. Here we [...] Read more.
Hepatocellular carcinoma (HCC) remains an important form of cancer-related morbidity and mortality in the U.S. and worldwide. Previous U.S.-based studies on survival suggest ethnic disparities in HCC patients, but the complex interplay of multiple factors that contribute are still incompletely understood. Here we considered the influences of risk factors contributing towards HCC survival, including ethnic background, over ten years at a premier academic medical center with a majority (57.20%) African American (AA) population. Retrospective HCC data were collected from 2008–2018 at LSUHSC-Shreveport, an urban tertiary medical center. Data included demographics, comorbidities, liver disease characteristics, and tumor parameters. Statistical analysis was performed using Chi Square and one-way ANOVA. Results: 229 HCC patients were identified (male 78.6%). The mean HCC age at diagnosis was 61 years (SD = 7.3). Compared to non-Hispanic Caucasians (42.7%), AA patients (57.2% of total) were older at presentation, had more frequent diabetes/dyslipidemia/NAFLD (45 (34.3%) compared with 19 (19.3%) in non-Hispanic Caucasians, p = 0.02), and had a larger HCC burden at diagnosis. We conclude that compared to white patients, despite having similar BMI and MELD scores and rates of portal vein thrombosis, AA patients with HCC in our cohort were older at presentation, had a significantly increased incidence of modifiable metabolic risk factors including diabetes, higher AFP values, increased incidence of gallstones, and larger sized HCCs, and were more likely to be outside Milan criteria. These findings have important prognostic and diagnostic implications for developing a more targeted HCC surveillance program. Full article
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14 pages, 2821 KiB  
Case Report
Neuroendocrine Tumors: Clinical, Histological and Immunohistochemical Perspectives and Case Report—Mature Teratoma in a 16-Year-Old Girl
by Elżbieta Sowińska-Przepiera, Dariusz Starzyński, Anhelli Syrenicz, Ireneusz Dziuba, Barbara Wiszniewska and Sylwia Rzeszotek
Pathophysiology 2021, 28(3), 373-386; https://doi.org/10.3390/pathophysiology28030025 - 27 Aug 2021
Cited by 1 | Viewed by 3427
Abstract
A mature teratoma is a germinal neoplasm that differentiates from embryonic multipotent cells into three germ layers. There may also be glandular tissue. The literature describes a total of 658 cases of ovarian neuroendocrine neoplasms, mainly in women over 40 years of age. [...] Read more.
A mature teratoma is a germinal neoplasm that differentiates from embryonic multipotent cells into three germ layers. There may also be glandular tissue. The literature describes a total of 658 cases of ovarian neuroendocrine neoplasms, mainly in women over 40 years of age. The authors, together with a systemic review, present a case of a 16-year-old girl diagnosed with and treated for a neuroendocrine tumor. Case description: A 16-year-old girl visited the Paediatric Gynaecology Outpatient Clinic because of abdominal pains that intensified during menstruation. Standard painkillers and diastolic drugs were ineffective. An ultrasound examination revealed a large tumor with a heterogeneous structure in her right ovary. A sparing operation was carried out. During laparotomy, the lesion was enucleated, leaving healthy tissue. Histopathological examination revealed the typical features of teratoma, as well as the coexistence of a G1 neuroendocrine tumor. Immunohistochemical examination (IHC) showed the presence of markers characteristic for this type of tumor. The patient requires constant monitoring in the Endocrinology and Oncological Gynaecology Clinic. Conclusion: Tissue of neuroendocrine neoplasm within a teratoma is rare in this age group of patients; thus, there are currently no standards for long-term follow-up. This case adds to the body of evidence and demonstrates a possible good prognosis with non-aggressive behavior in G1 neuroendocrine tumors and teratomas in young patients. Full article
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19 pages, 4391 KiB  
Article
Local and Remote Effects of Mesenchymal Stem Cell Administration on Skin Wound Regeneration
by Ekaterina Silina, Victor Stupin, Konstantin Koreyba, Sergey Bolevich, Yulia Suzdaltseva and Natalia Manturova
Pathophysiology 2021, 28(3), 355-372; https://doi.org/10.3390/pathophysiology28030024 - 12 Aug 2021
Cited by 4 | Viewed by 2552
Abstract
Wound healing is an important medical problem. We evaluated the efficacy of locally administered mesenchymal stem cells (MSCs) isolated from human umbilical cords on the dynamics of skin wound healing. The study was conducted on the backs of Wistar rats, where two square [...] Read more.
Wound healing is an important medical problem. We evaluated the efficacy of locally administered mesenchymal stem cells (MSCs) isolated from human umbilical cords on the dynamics of skin wound healing. The study was conducted on the backs of Wistar rats, where two square wounds were created by removing all layers of the skin. Four groups were studied in two series of experiments: (1) a Control_NaCl group (the wounds were injected with 0.9% NaCl solution) and a Control_0 group (intact wounds on the opposite side of the same rat’s back); (2) an MSC group (injected MSCs, local effect) and a Control_sc group (intact wounds on the opposite side of the back, remote MSC effect). The area and temperature of the wounds and the microcirculation of the wound edges were measured. Histological and morphometric studies were performed on days 3 and 7 after the wounds were created. The results showed that the injection trauma (Control_NaCl) slowed the regeneration process. In both MSC groups (unlike in either control group), we observed no increase in the area of the wounds; in addition, we observed inhibition of the inflammatory process and improved wound regeneration on days 1–3 in the remote group and days 1–5 in the local (injected) group. The MSC and Control_sc groups demonstrated improved microcirculation and suppression of leukocyte infiltration on day 3. On day 7, all the studied parameters of the wounds of the Control_0 group were the same as those of the wounds that received cell therapy, although in contrast to the results of the Control_ NaCl group, fibroblast proliferation was greater in the MSC and Control_sc groups. The dynamics of the size of the wounds were comparable for both local and remote application of MSCs. Thus, even a one-time application of MSCs was effective during the first 3–5 days after injury due to anti-inflammatory processes, which improved the regeneration process. Remote application of MSC, as opposed to direct injection, is advisable, especially in the case of multiple wounds, since the results were indistinguishable between the groups and injection trauma was shown to slow healing. Full article
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16 pages, 6007 KiB  
Article
Interaction of TLK1 and AKTIP as a Potential Regulator of AKT Activation in Castration-Resistant Prostate Cancer Progression
by Md Imtiaz Khalil, Christopher Madere, Ishita Ghosh, Rosalyn M. Adam and Arrigo De Benedetti
Pathophysiology 2021, 28(3), 339-354; https://doi.org/10.3390/pathophysiology28030023 - 20 Jul 2021
Cited by 7 | Viewed by 4035
Abstract
Prostate cancer (PCa) progression is characterized by the emergence of resistance to androgen deprivation therapy (ADT). AKT/PKB has been directly implicated in PCa progression, often due to the loss of PTEN and activation of PI3K>PDK1>AKT signaling. However, the regulatory network of AKT remains [...] Read more.
Prostate cancer (PCa) progression is characterized by the emergence of resistance to androgen deprivation therapy (ADT). AKT/PKB has been directly implicated in PCa progression, often due to the loss of PTEN and activation of PI3K>PDK1>AKT signaling. However, the regulatory network of AKT remains incompletely defined. Here, we describe the functional significance of AKTIP in PCa cell growth. AKTIP, identified in an interactome analysis as a substrate of TLK1B (that itself is elevated following ADT), enhances the association of AKT with PDK1 and its phosphorylation at T308 and S473. The interaction between TLK1 and AKTIP led to AKTIP phosphorylation at T22 and S237. The inactivation of TLK1 led to reduced AKT phosphorylation, which was potentiated with AKTIP knockdown. The TLK1 inhibitor J54 inhibited the growth of the LNCaP cells attributed to reduced AKT activation. However, LNCaP cells that expressed constitutively active, membrane-enriched Myr-AKT (which is expected to be active, even in the absence of AKTIP) were also growth-inhibited with J54. This suggested that other pathways (like TLK1>NEK1>YAP) regulating proliferation are also suppressed and can mediate growth inhibition, despite compensation by Myr-AKT. Nonetheless, further investigation of the potential role of TLK1>AKTIP>AKT in suppressing apoptosis, and conversely its reversal with J54, is warranted. Full article
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11 pages, 283 KiB  
Article
Isometric Handgrip Exercise Training Improves Spirometric Parameters and Pulmonary Capacity
by Ogbutor Udoji Godsday, Nwangwa Eze Kingsley, Nwogueze Bartholomew Chukwuebuka, Chukwuemeka Ephraim, Ezunu Emmanuel, Agbonifo-Chijiokwu Ejime and Igweh John Chukwuka
Pathophysiology 2021, 28(3), 328-338; https://doi.org/10.3390/pathophysiology28030022 - 20 Jul 2021
Cited by 1 | Viewed by 2916
Abstract
Decline in normal physiological pulmonary function has been attributed to premorbid conditions such as prehypertension. Research evidence suggests that physical activity reduces age-related decline in pulmonary function and improves the efficiency of the lungs in prehypertensive patients. However, there is a scarcity of [...] Read more.
Decline in normal physiological pulmonary function has been attributed to premorbid conditions such as prehypertension. Research evidence suggests that physical activity reduces age-related decline in pulmonary function and improves the efficiency of the lungs in prehypertensive patients. However, there is a scarcity of data evidence relating to isometric exercise and pulmonary function. Furthermore, the interrelationship between the intensity and duration of isometric exercise and pulmonary function in these patients is still uncertain. Therefore, this study was undertaken to investigate the effect of isometric handgrip exercise on pulmonary function capacity in adults with prehypertension. To determine the effectiveness of isometric handgrip exercise on pulmonary function capacity in adults with prehypertension. A quasi experiment using a pre- and post-exercise method was carried out in two out-patients hospital settings. The sample comprised 192 sedentary pre-hypertensive subjects, aged between 30–50 years, that were randomly distributed into three groups of 64 participants each. The subjects performed, for 24 consecutive days, an isometric handgrip exercise at 30% Maximum Voluntary Contraction (M.V.C.). At the end of the 24 days, group one (GP1) discontinued, while group two (GP2) continued the exercise protocol for another 24 consecutive days and group three (GP3) continued with the exercise protocol for another 24 consecutive days but at 50% M.V.C. Determinants of lung function (outcomes) were Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), FEV1/FVC Ratio and Peak Expiratory Flow Rate (PEFR). The study shows that there was no statistically significant difference in the pre- and post-exercise outcomes for FEV1, FVC, FEV1/FVC Ratio and PEFR after 24 days for group 1. In group 2, there was a statistically significant difference in the FVC [(mean = 0.12 ± 0.12), (p = 0.002)], FEV1 [(mean = 0.15 ± 0.17), (p = 0.003)] and PEF [(mean = 0.85 ± 0.35), (p = 0.001)] after 48 days. In group 3, there was a statistically significant difference (p = 0.001) in all the outcomes assessed after 48 days. There was a between groups difference in favour of group 2 compared with group 1 for outcomes of FEV1 [(mean = 0.142 ± 0.68), (p = 0.005)] and PEF [(mean = 0.83 ± 0.19), (p = 0.0031)]. There was statistically significant difference in favour of group 3 compared to group 2, by increasing the exercise intensity from 30% to 50% M.V.C., for outcomes of FVC [mean change = 0.10 ± 0.052), (p = 0.005)], FEV1/FVC [mean change = 3.18 ± 0.75), (p = 0.017)] and PEF [(mean change = 0.86 ± 0.35), (p = 0.001)] after 48 days. Isometric handgrip exercise (after 48 days at 30% to 50% M.V.C.) improves outcomes of pulmonary function capacity in adults with prehypertension. Meanwhile, duration and/or increase in intensity of the isometric effort significantly contributed to the affects attained. Full article
8 pages, 572 KiB  
Brief Report
A Proteinase 3 Contribution to Juvenile Idiopathic Arthritis-Associated Cartilage Damage
by Eric K. Patterson, Nicolas Vanin Moreno, Douglas D. Fraser, Gediminas Cepinskas, Takaya Iida and Roberta A. Berard
Pathophysiology 2021, 28(3), 320-327; https://doi.org/10.3390/pathophysiology28030021 - 23 Jun 2021
Viewed by 2392
Abstract
A full understanding of the molecular mechanisms implicated in the etiopathogenesis of juvenile idiopathic arthritis (JIA) is lacking. A critical role for leukocyte proteolytic activity (e.g., elastase and cathepsin G) has been proposed. While leukocyte elastase’s (HLE) role has been documented, the potential [...] Read more.
A full understanding of the molecular mechanisms implicated in the etiopathogenesis of juvenile idiopathic arthritis (JIA) is lacking. A critical role for leukocyte proteolytic activity (e.g., elastase and cathepsin G) has been proposed. While leukocyte elastase’s (HLE) role has been documented, the potential contribution of proteinase 3 (PR3), a serine protease present in abundance in neutrophils, has not been evaluated. In this study we investigated: (1) PR3 concentrations in the synovial fluid of JIA patients using ELISA and (2) the cartilage degradation potential of PR3 by measuring the hydrolysis of fluorescently labeled collagen II in vitro. In parallel, concentrations and collagen II hydrolysis by HLE were assessed. Additionally, the levels of the co-secreted primary granule protein myeloperoxidase (MPO) were assessed in synovial fluid of patients diagnosed with JIA. We report the following levels of analytes in JIA synovial fluid: PR3—114 ± 100 ng/mL (mean ± SD), HLE—1272 ± 1219 ng/mL, and MPO—1129 ± 1659 ng/mL, with a very strong correlation between the PR3 and HLE concentrations (rs = 0.898, p < 1 × 10–6). Importantly, PR3 hydrolyzed fluorescently labeled collagen II as efficiently as HLE. Taken together, these novel findings suggest that PR3 (in addition to HLE) contributes to JIA-associated joint damage. Full article
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