Flavonoids derived from medicinal plants as a COVID-19 treatment.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 disease. Through its viral spike (S) protein, the virus enters and infects epithelial cells by utilizing angiotensin-converting enzyme 2 as a host cell's receptor protein. The COVID-19 pandemic had a profound impact on global public health and economies. Although various effective vaccinations and medications are now available to prevent and treat COVID-19, natural compounds derived from medicinal plants, particularly flavonoids, demonstrated therapeutic potential to treat COVID-19 disease. Flavonoids exhibit dual antiviral mechanisms: direct interference with viral invasion and inhibition of replication. Specifically, they target key viral molecules, particularly viral proteases, involved in infection. These compounds showcase significant immunomodulatory and anti-inflammatory properties, effectively inhibiting various inflammatory cytokines. Additionally, emerging evidence supports the potential of flavonoids to mitigate the progression of COVID-19 in individuals with obesity by positively influencing lipid metabolism. This review aims to elucidate the molecular structure of SARS-CoV-2 and the underlying mechanism of action of flavonoids on the virus. This study evaluates the potential anti-SARS-CoV-2 properties exhibited by flavonoid compounds, with a specific interest in their structure and mechanisms of action, as therapeutic applications for the prevention and treatment of COVID-19. Nevertheless, a significant portion of existing knowledge is based on theoretical frameworks and findings derived from in vitro investigations. Further research is required to better assess the effectiveness of flavonoids in combating SARS-CoV-2, with a particular emphasis on in vivo and clinical investigations.

Malignant Melanoma of the Middle Ear: Case Report.

We present a case of malignant melanoma in the middle ear in a 63-year-old woman who presented with severe pain on the right side of her face and head, tinnitus, photophobia, and hemorrhagic discharge from the right ear, as well as right facial nerve paralysis. After more than two years of conservative treatment for otitis media and sclerotic mastoiditis, a pathologically enlarged lymph node on the right side of the neck appears. It is removed, and the histopathological examination reveals that it is metastatic malignant melanoma. Imaging examinations reveal a tumoral lesion in the middle ear with bone infiltration. The right middle ear is operated on, and the tissue sent for testing reveals melanoma. The patient was treated with Nivolumab after the operation and is now in sustainably good condition.

Evaluation of single and combined effects of mancozeb and metalaxyl on the transcriptional and biochemical response of zebrafish (Danio rerio).

Mancozeb and metalaxyl are fungicidal agents frequently used in combination to control fungi in crops that may affect non-target organisms when entering ecosystems. This study aims to evaluate the environmental effects of Mancozeb (MAN) and Metalaxyl (MET), alone and in combination, on zebrafish (Danio rerio) as an experimental model. The oxidative stress biomarkers and the transcription of genes involved in detoxification in zebrafish (Danio rerio) were assessed after co-exposure to MAN (0, 5.5, and 11 µg L-1) and MET (0, 6.5, and 13 mg L-1) for 21 days. Exposure to MAN and MET induced a significant increase in the expression of genes related to detoxification mechanisms (Ces2, Cyp1a, and Mt2). Although Mt1 gene expression increased in fish exposed to 11 µg L-1 of MAN combined with 13 mg L-1 of MET, Mt1 expression was down-regulated significantly in other experimental groups (p < 0.05). The combined exposure to both fungicides showed synergistic effects in the expression levels that are manifested mainly at the highest concentration. Although a significant (p < 0.05) increase in alkaline phosphatase (ALP) and transaminases (AST and ALT), catalase activities, the total antioxidant capacity, and malondialdehyde (MDA) contents in the hepatocytes of fish exposed to MAN and MET alone and in combination was detected, lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT) activities, and hepatic glycogen content decreased significantly (p < 0.05). Overall, these results emphasize that combined exposure to MET and MAN can synergistically affect the transcription of genes involved in detoxification (except Mt1 and Mt2) and biochemical indicators in zebrafish.

The mechanisms underlying the role of Vitex agnus-castus in mastalgia.

Medicinal plants exert therapeutic effects or have beneficial healing functions on the human or animal body. Medicinal plants are widely used in traditional medicine as an interesting alternative and/or complementary to science-based medicine. Compared to chemical drugs, medicinal plants have a lower risk of side effects, are eco-friendly, and have cost-effective production. This encouraged researchers to extensively exploit them for their therapeutic use. One of the most well-known medicinal plants is Vitex agnus-castus L., which belongs to the Verbenaceae family. This shrub tree is mainly grown in tropical and sub-tropical regions. The parts of VAC, especially berries and leaves, contain essential oils, flavonoids, and diterpenes. Many medical benefits of VAC have already been reported, including mastalgia, regulating menstrual cycles and premenstrual complaints, and infertility. Respiratory and cardiovascular effects are also reported. In this review, we will analyze and characterize the known roles of VAC in mastalgia, as well as the mechanism of action reported in in vitro and/or in vivo studies, and show the potential for alternative therapeutic uses in mastalgia, also known as breast pain (Fig. 2, Ref. 40). Keywords: mastalgia, Vitex agnus-castus, therapy, traditional medicine.

The role of interleukin­7 serum level as biological marker in breast cancer: a cross­sectional, observational, and analytical study.

BACKGROUND: The important role that the immune system plays in malignant diseases is well known. The action of interleukin-7 (IL-7) as a cytokine has been observed in many cellular processes, both in normal cells of the immune system and in some cancer cells. The aim of this study has been to explore whether there is any elevation of interleukin-7 serum levels in early invasive breast cancer (EIBC) patients in comparison with healthy controls. In addition, the correlation between the IL-7 serum level and the histopathological characteristics of the tumor has been evaluated. METHODS: This cross-sectional, observational, and analytical study included 213 consecutive patients with EIBC (113 from Croatia and 100 from Kosovo) and 62 healthy participants as the control group (30 from Croatia and 32 from Kosovo). Blood samples have been taken from patients confirmed with breast cancer (BC) by biopsy, prior to surgical intervention and other oncological treatments, as well as from healthy participants. A serum IL-7 level has been measured, using the "Sandwich" ELISA Immunoenzyme test. In addition, after the surgical intervention, histopathological specimen examinations and immunohistochemistry have been performed and analyzed. The differences in the distribution of the numerical variables have been analyzed with the Mann-Whitney U test and Kruskal-Wallis ANOVA test. Correlations have been tested with Pearson coefficients. A P-value < 0.05 has been accepted as statistically significant. RESULTS: The serum level of IL-7 in EIBC patients was significantly higher than in control cases (P 0.001). Patients with invasive lobular carcinoma (ILC) seem to have a lower IL-7 serum level compared to other histological subtypes, and the difference has been significant (P = 0.043). There has been no correlation between IL-7 serum level and histopathological characteristics of the tumor, with neither age nor menopausal status of the patients. CONCLUSIONS: Noting the significant increase in the IL-7 serum level in the EIBC patients as compared to the healthy control group, the use of IL-7 as a potential diagnostic indicator for BC, as well as in the follow-up of the patients after treatment, can be assumed. The lack of correlation with tumor size, lymph node metastasis, and all other histopathological characteristics of the tumor questions its use as a prognostic indicator.

Vasorelaxant Effects of the Vitex Agnus-Castus Extract.

This study was undertaken to describe and characterize the relaxing effects of the medicinal plant Vitex agnus-castus (VAC) extract on isolated rabbit arterial rings. The VAC extracts (VACE) were extracted with ethanol and tested in aorta rings (3-4 mm) of rabbits suspended in an organ bath (Krebs, 37°C, 95% O2/5% CO2) under a resting tension of 1 g to record isometric contractions. After the stabilization period (1-2 hours), contractions were induced by the addition of phenylephrine (0.5 µM) or high KCl (80 mM) and VACE was added on the plateau of the contractions. Experiments were performed to determine the effects and to get insights into the potential mechanism involved in VACE-induced relaxations. The cumulative addition of VACE (0.15-0.75 mg/mL) relaxed, in a concentration-dependent manner, the rabbit aorta rings precontracted either with phenylephrine- or with high KCl thus suggesting calcium channel blocking activities. The VACE effect appeared to be endothelium-dependent. The preincubation with L-NAME (the inhibitor of nitric oxide synthases (NOS)), ODQ (the selective inhibitor of guanylyl cyclase), and indomethacin (the cyclooxygenase inhibitor), downregulated VACE-induced relaxation of aorta rings precontracted with phenylephrine, whereas the bradykinin (stimulator of NOS) and zaprinast (phosphodiesterase inhibitor) further upregulated relaxant effects induced by VACE. These results revealed that the aorta relaxation effect of VACE was mainly endothelium-dependent and mediated by NO/cGMP and prostaglandins synthesis. This vasodilator effect of VACE may be useful to treat cardiovascular disorders, including hypertensive diseases.

Effects of Vinblastine and Vincristine on the function of chronic myeloid leukemic cells through expression of A20 and CYLD.

Chronic myelogenous leukemia (CML) is characterised by the translocation of regions of the BCR and ABL genes, leading to the fusion gene BCR-ABL forming the Philadelphia (Ph) chromosome. Vinblastine (Vinb) and Vincristine (Vinc) are Vinca alkaloids and frequently used in combination chemotherapy in leukemias and lymphomas. Deubiquitinating enzyme (DUB) genes such as A20, Otubain 1 and CYLD are known as inhibitors of functional activation of immune cells mediated through the NF-κB/STAT pathway. Little is known about the regulatory role of Vinb/Vinc on the function of CML cells and the contribution of the DUBs to those effects. In the end, the gene expression profile was determined by quantitative RT-PCR, physiological properties of CML cells by flow cytometry and cytokine production by ELISA. As a result, inactivated expression of the DUBs A20, CYLD, Otubain 1 and Cezanne and enhanced activation of CD11b+ and CD4T cells were observed in CML patients. Importantly, Vinc enhanced the expression of A20 and CYLD and inhibited the proliferation and survival of CML (K562) cells. The effects were abolished in the presence of A20 siRNA, while cell proliferation only depended on the presence of CYLD. In conclusion, the up-regulation of A20 by Vinc could involve inhibitory effects on the proliferation and survival of K562 cells. The events might contribute to the anticancer effect of Vinc on A20-sensitive CML cells.

Interactions between ACE2 and SARS-CoV-2 S Protein: Peptide Inhibitors for Potential Drug Developments Against COVID-19.

Angiotensin-converting enzyme (ACE) shares some homologies with ACE2. However, they are not inhibited by the same inhibitors, but both are associated primarily with the hypertensive disorder through the renin-angiotensin system (RAS). The principal activity of ACE2 is to metabolize Ang II into the vasodilatory Ang-(1-7). The ongoing COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought the ACE2 to the center of attention. This coronavirus uses the host cell ACE2 protein to enter and infect the epithelial cells. In light of the virus's entrance into human cells, the differences in the molecular basis of ACE2 among affected patients may cause their different responses to the virus. Many details about the specific interaction between the viral S protein and ACE2 are already reported. To date, some effective clinically approved vaccines are in use globally, and many others are under development, but no effective specific therapeutic drugs are available against COVID-19. Inhibitors, especially peptide inhibitors, have a great potential to be used for the treatment of COVID-19 and other possible emerging diseases caused by viral pathogens. As a result of the well-known viral protein structures and their host cell targets such as ACE2, antiviral peptides could be appropriately designed and optimized for therapeutic purposes. A better understanding of the structure and pathophysiology of the ACE2 receptor and the interplay between the viral S protein and ACE2 may help to find the solution for the virus treatment. This review summarizes the current understanding of S protein interaction with the ACE2 protein as a potential specific target against SARS-CoV-2 and strategies using peptides against COVID-19.

Klotho-Dependent Role of 1,25(OH)2D3 in the Brain.

The antiaging protein Klotho is encoded by the Klotho gene first identified as an 'aging suppressor', in mice. Klotho deficiency is involved in premature aging and early death, while its overexpression is related to longevity. Klotho is mostly expressed in the kidney, but also in the brain, and in other organs. Two forms of Klotho, the cell membrane and secreted form, have pleiotropic activities that include regulation of general metabolism, oxidative stress, and mineral metabolism that correlates with its effect on accelerating aging. Membrane Klotho serves as an obligate co-receptor for the fibroblast growth factor (FGF), while secreted Klotho plays its role as a humoral factor. Klotho protein participates in the regulation of several biological activities, including regulation of calcium-phosphate homeostasis and PTH as well as vitamin D metabolism. The active form of vitamin D, 1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol), acts as a neurosteroid that participates in the regulation of multiple brain functions. It provides neuroprotection and suppresses oxidative stress, inhibits inflammation and inflammatory mediators, and stimulates various neurotrophins. Calcitriol is involved in many brain-related diseases, including multiple sclerosis, Alzheimer´s disease, Parkinson´s disease, and schizophrenia. This review covers the most recent advances in Klotho research and discusses Klotho-dependent roles of calcitriol in neuro-psycho-pathophysiology.

JAK2-mediated Intracellular Signaling.

Janus kinase-2 (JAK2) is a non-receptor tyrosine kinase that serves key roles as the intracellular signaling effector of the cytokine receptor, such as mediating effects of leptin, erythropoietin, interferon, and growth hormone. A lot of molecular underlying mechanisms of JAK2 participation are known, however, additional signaling mechanisms of its activation, regulation, and pleiotropic signaling roles are still being explored. Here, we review the current knowledge of JAK2-mediated cellular signaling at the molecular level. In the beginning, we will focus on the recent advances in JAK2 activation and regulation. A part of our review focuses on the JAK2 involvement in various diseases/conditions. Recent advances highlight the molecular regulatory mechanisms utilized by the JAK2 signaling, thus, enabling to consider alternative therapeutic strategies to treat various diseases/conditions mediated by JAK2 by using it as a therapeutic target.

Regulation of cell activation by A20 through STAT signaling in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the hematologic malignancy characterized by the aberrant proliferation of immature lymphoid cells. A20 is a deubiquitinase gene that inhibits functional activation of immune cells mediated through NF-κB/STAT pathways and frequently found inactivated in lymphoma. IL-6 is a pro-inflammatory cytokine secreted by immune cells under the pathogenic conditions and regulated by STAT signaling. Little is known about the role of A20 in regulating the function of ALL blasts and underlying molecular mechanisms. The present study, therefore, explored whether A20 expression contributes to IL-6 induced cell migration and activation of myeloid cells in ALL. To this end, blood samples of thirty-five adult ALL patients were examined. Gene expression profile was determined by quantitative RT-PCR, immunophenotype by flow cytometry, secretion of inflammatory cytokines by ELISA, and cell migration by a transwell migration assay. As a result, the expression of A20 was inactivated in ALL. Immunophenotypic analysis indicated that percent of CD11b+CD40+ expressing cells present in ALL was significantly reduced when transfected with PEM-T easy A20. Importantly, IL6-induced CXCL12-mediated migration of ALL blasts was dependent on the presence of A20. The inhibitory effects of A20 on activated myeloid cells and migration of ALL blasts were mediated through the STAT pathway upon IL-6 challenge. In addition, the CA-125 level was much higher in elderly females than either young female or male ALL patients or healthy donors. In conclusion, the inhibitory effects of A20 on activation of ALL blasts are expected to affect the immune response to treatment for adult ALL patients.

Molecular Characterization of SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) is currently a new public health crisis threatening the world. This pandemic disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus has been reported to be originated in bats, and by yet unknown intermediary animals were transmitted to humans in China 2019. The SARS-CoV-2 spreads faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) but has reduced fatality. At present, the SARS-CoV-2 has caused about 1.16 million deaths with more than 43.4 million confirmed cases worldwide, resulting in a serious threat to public health globally with yet uncertain impact. The disease is transmitted by inhalation or direct contact with an infected person. The incubation period ranges from 1 to 14 days. COVID-19 is accompanied by various symptoms, including cough and fatigue. In most people, the disease is mild, but in some other people, such as in the elderly and people with chronic diseases, it may progress from pneumonia to a multi-organ dysfunction. Many people are reported asymptomatic. The virus genome is sequenced, but new variants are reported. Numerous biochemical aspects of its structure and function are revealed. To date, no clinically approved vaccines and/or specific therapeutic drugs are available to prevent or treat COVID-19. However, there are reported intensive researches on the SARS-CoV-2 to potentially identify vaccines and/or drug targets, which may help to overcome the disease. In this review, we discuss recent advances in understanding the molecular structure of SARS-CoV-2 and its biochemical characteristics.

Insight into the Mechanisms Underlying the Tracheorelaxant Properties of the Sideritis raeseri Extract.

Sideritis raeseri Boiss. and Heldr. (Lamiaceae), known as "mountain tea," is a native plant from the Mediterranean region, which is widely used in traditional medicine. This study evaluates the effects of the ethanol extract of Sideritis raeseri (SR) on airway smooth muscle activity and identifies the underlying mechanism. The S. raeseri extract (SRE) was extracted from air-dried parts of the shoot system of SR. The SRE (0.3-2 mg/mL) was tested in isolated rabbit tracheal rings, suspended in the organ bath, filled with Krebs solution, and bubbled with the carbogen mixture (95% O2/5% CO2) under a resting tension of 1 g in 37°C. In in vitro experiments, the SRE relaxed against acetylcholine-induced constriction in tracheal rings. Furthermore, SRE inhibited Ca2+-induced contractions in carbachol (CCh, 1 µM) as well as in the K+-depolarized trachea (80 mM). Our findings showed the NO/cGMP involvement in tracheorelaxant effects of SR. To this end, the effect of the SRE was potentiated by bradykinin (nitric oxide (NO) synthase activator, 100 nM), whereas it was inhibited by ODQ (inhibitor of NO-sensitive guanylyl cyclase, 10 µM) and L-NAME (NO synthase inhibitor, 100 µM), as well as indomethacin (cyclooxygenase inhibitor, 10 µM). These data suggest that the tracheorelaxant effect of the SRE is mediated at least partly by NO/cyclic guanosine monophosphate and cyclooxygenase-1-prostaglandin E2-dependent signaling. These findings indicate that the SRE may be used in various respiratory disorders.

Intracellular signaling of the AMP-activated protein kinase.

AMP-activated protein kinase (AMPK) is an essential cellular energy sensor that senses the cellular energy status and maintains cellular energy balance. The AMPK coordinates cellular and whole-body energy homeostasis through stimulating catabolic ATP-producing and suppressing anabolic ATP-consuming intracellular signaling pathways. AMPK induces autophagy and inhibits cell growth in response to starvation, a process that involves regulating certain intracellular signaling molecules. Recent advances demonstrated the AMPK to exert tumor suppressor activity realized through various signaling molecules by stimulating different cellular processes such as apoptosis, autophagy and cell growth and proliferation. AMPK can also be used to protect against metabolic syndrome. AMPK has previously been reported to be either directly or indirectly involved in the regulation of many different cellular transport proteins of high importance for cellular physiology and pathophysiology. Thus, AMPK provides a necessary link between cellular energy metabolism and cellular transport activities. A better understanding of the AMPK role in intracellular signaling under physiological and pathological conditions may represent a potential strategy for developing therapies for treating many different human diseases and disorders, in which AMPK plays a key role.

The Glycogen Synthase Kinase-3 in the Regulation of Ion Channels and Cellular Carriers.

Glycogen synthase kinase-3 (GSK-3) is a highly evolutionarily conserved and ubiquitously expressed serine/threonine kinase, an enzyme protein profoundly specific for glycogen synthase (GS). GSK-3 is involved in various cellular functions and physiological processes, including cell proliferation, differentiation, motility, and survival as well as glycogen metabolism, protein synthesis, and apoptosis. There are two isoforms of human GSK-3 (named GSK-3α and GSK-3ß) encoded by two distinct genes. Recently, GSK-3ß has been reported to function as a powerful regulator of various transport processes across the cell membrane. This kinase, GSK-3ß, either directly or indirectly, may stimulate or inhibit many different types of transporter proteins, including ion channel and cellular carriers. More specifically, GSK-3ß-sensitive cellular transport regulation involves various calcium, chloride, sodium, and potassium ion channels, as well as a number of Na+-coupled cellular carriers including excitatory amino acid transporters EAAT2, 3 and 4, high-affinity Na+ coupled glucose carriers SGLT1, creatine transporter 1 CreaT1, and the type II sodium/phosphate cotransporter NaPi-IIa. The GSK-3ß-dependent cellular transport regulations are a part of the kinase functions in numerous physiological and pathophysiological processes. Clearly, additional studies are required to examine the role of GSK-3ß in many other types of cellular transporters as well as further elucidating the underlying mechanisms of GSK-3ß-mediated cellular transport regulation.

Proton Pump Inhibitors Intake and Iron and Vitamin B12 Status: A Prospective Comparative Study with a Follow up of 12 Months.

BACKGROUND: Proton pump inhibitors (PPIs) represent the most widely prescribed antisecretory agents, but their prolonged use, may influence iron and vitamin B12 status, which could have important implications for clinical practice. AIM: We undertook this study aiming to investigate the association between PPIs use for 12 months and potential changes in iron and vitamin B12 status, as well as whether this potential association varies among four specific PPI drugs used in the study. METHODS: A total of 250 adult subjects were recruited into this study, of which 200 subjects were PPIs users while 50 subjects belonged to the control group. Serum iron, ferritin, vitamin B12, and homocysteine (Hcy) levels were measured before the start of the study and after 12 months. Mann - Whitney U test and Kruskal - Wallis test was used to compare the baseline characteristics of the study groups, while Wilcoxon test was used to analyse post - pre differences. RESULTS: Statistical analysis showed significant changes within PPIs group and specific PPIs subgroups between the two-time points in serum ferritin and vitamin B12 levels, respectively, while no significant changes in serum iron and homocysteine levels were shown. However, subsequent diagnosis of hypoferremia and hypovitaminosis B12 in the whole study sample at 12 months was established in only 3.8% and 2.9% of the subjects, respectively. CONCLUSION: PPIs use for 12 months did not result in clinically significant iron and/or vitamin B12 deficiency; thus, these findings argue routine screening under normal circumstances, although monitoring in elderly and malnourished may be of precious value.

The Human NADPH Oxidase, Nox4, Regulates Cytoskeletal Organization in Two Cancer Cell Lines, HepG2 and SH-SY5Y.

NADPH oxidases of human cells are not only functional in defense against invading microorganisms and for oxidative reactions needed for specialized biosynthetic pathways but also during the past few years have been established as signaling modules. It has been shown that human Nox4 is expressed in most somatic cell types and produces hydrogen peroxide, which signals to remodel the actin cytoskeleton. This correlates well with the function of Yno1, the only NADPH oxidase of yeast cells. Using two established tumor cell lines, which are derived from hepatic and neuroblastoma tumors, respectively, we are showing here that in both tumor models Nox4 is expressed in the ER (like the yeast NADPH oxidase), where according to published literature, it produces hydrogen peroxide. Reducing this biochemical activity by downregulating Nox4 transcription leads to loss of F-actin stress fibers. This phenotype is reversible by adding hydrogen peroxide to the cells. The effect of the Nox4 silencer RNA is specific for this gene as it does not influence the expression of Nox2. In the case of the SH-SY5Y neuronal cell line, Nox4 inhibition leads to loss of cell mobility as measured in scratch assays. We propose that inhibition of Nox4 (which is known to be strongly expressed in many tumors) could be studied as a new target for cancer treatment, in particular for inhibition of metastasis.

Clearing the outer mitochondrial membrane from harmful proteins via lipid droplets.

In recent years it turned out that there is not only extensive communication between the nucleus and mitochondria but also between mitochondria and lipid droplets (LDs) as well. We were able to demonstrate that a number of proteins shuttle between LDs and mitochondria and it depends on the metabolic state of the cell on which organelle these proteins are predominantly localized. Responsible for the localization of the particular proteins is a protein domain consisting of two α-helices, which we termed V-domain according to the predicted structure. So far we have detected this domain in the following proteins: mammalian BAX, BCL-XL, TCTP and yeast Mmi1p and Erg6p. According to our experiments there are two functions of this domain: (1) shuttling of proteins to mitochondria in times of stress and apoptosis; (2) clearing the outer mitochondrial membrane from pro- as well as anti-apoptotic proteins by moving them to LDs after the stress ceases. In this way the LDs are used by the cell to modulate stress response.

Regulation of Ion Channels, Cellular Carriers and Na(+)/K(+)/ATPase by Janus Kinase 3.

Janus kinase-3 (JAK3), a tyrosine kinase, is expressed in a variety of tissues, including the brain and is involved in the signaling of cytokine receptors. JAK3 participates in numerous functions, such as cell survival and proliferation, neuroprotection, apoptosis and the cellular response to hypoxia and ischemia-reperfusion. This kinase further contributes to the signaling of hematopoietic cell cytokine receptors, activation of dendritic cells, maturation, and immune suppression as well as to cell volume regulation. Recently, JAK3 has been demonstrated to be an important regulator of transport processes across the plasma membrane. Either directly or indirectly JAK3 affects the expression of transport proteins, including various ion channels, a number of cellular carriers and the Na+/K+ pump. More specifically, JAK3 is involved in the regulation of various potassium, sodium, and chloride ion channels, a wide variety of Na+-coupled cellular carriers including the high-affinity Na+ coupled glucose transporter SGLT1, the excitatory amino acid transporters EAAT1, EAAT2, EAAT3 and EAAT4, the peptide transporters PepT1 and PepT2, CreaT1 and theNa+/K+-ATPase. Via these transporters this kinase plays a role in various physiological and pathophysiological processes. Additional research is needed to investigate the effects of JAK3 on other cellular transporters and the underlying mechanisms.

The Relevance of JAK2 in the Regulation of Cellular Transport.

Janus kinase-2 (JAK2) is a non-receptor tyrosine kinase signaling molecule that mediates the effects of various hormones and cytokines, including interferon, erythropoietin, leptin, and growth hormone. It also fosters tumor growth and modifies the activity of several nutrient transporters. JAK2 contributes to the regulation of the cell volume, protectS cells during energy depletion, proliferation, and aids the survival of tumor cells. Recently, JAK2 was identified as a powerful regulator of transport processes across the plasma membrane. Either directly or indirectly JAK2 may stimulate or inhibit transporter proteins, including ion channels, carriers and Na(+)/K(+) pumps. As a powerful regulator of transport mechanisms across the cell membrane, JAK2 regulates a wide variety of potassium, calcium, sodium and chloride ion channels, multiple Na+-coupled cellular carriers including EAAT1-4, NaPi-IIa, SGLT1, BoaT1, PepT1-2, CreaT1, SMIT1, and BGT1 as well as Na(+)/K(+)-ATPase. These cellular transport regulations contribute to various physiological and pathophysiological processes and thus exerting JAK2-sensitive effects. Future investigations will be important to determine whether JAK2 regulates cell-surface expression of other transporters and further elucidate underlying mechanisms governing JAK2 actions.