Renal-specific loss of ferroportin disrupts iron homeostasis and attenuates recovery from acute kidney injury.

Chronic kidney disease is increasing at an alarming rate and correlates with the increase in diabetes, obesity, and hypertension that disproportionately impact socioeconomically disadvantaged communities. Iron plays essential roles in many biological processes including oxygen transport, mitochondrial function, cell proliferation, and regeneration. However, excess iron induces the generation and propagation of reactive oxygen species, which lead to oxidative stress, cellular damage, and ferroptosis. Iron homeostasis is regulated in part by the kidney through iron resorption from the glomerular filtrate and exports into the plasma by ferroportin (FPN). Yet, the impact of iron overload in the kidney has not been addressed. To test more directly whether excess iron accumulation is toxic to kidneys, we generated a kidney proximal tubule-specific knockout of FPN. Despite significant intracellular iron accumulation in FPN mutant tubules, basal kidney function was not measurably different from wild type kidneys. However, upon induction of acute kidney injury (AKI), FPN mutant kidneys exhibited significantly more damage and failed recovery, evidence for ferroptosis, and increased fibrosis. Thus, disruption of iron export in proximal tubules, leading to iron overload, can significantly impair recovery from AKI and can contribute to progressive renal damage indicative of chronic kidney disease. Understanding the mechanisms that regulate iron homeostasis in the kidney may provide new therapeutic strategies for progressive kidney disease and other ferroptosis-associated disorders.NEW & NOTEWORTHY Physiological iron homeostasis depends in part on renal resorption and export into the plasma. We show that specific deletion of iron exporters in the proximal tubules sensitizes cells to injury and inhibits recovery. This can promote a chronic kidney disease phenotype. Our paper demonstrates the need for iron balance in the proximal tubules to maintain and promote healthy recovery after acute kidney injury.

DNA methylation-mediated epigenetic regulation of oncogenic RPS2 as a novel therapeutic target and biomarker in hepatocellular carcinoma.

Ribosomal Protein S2 (RPS2) has emerged as a potential prognostic biomarker due to its involvement in key cellular processes and its altered expression pattern in certain types of cancer. However, its role in hepatocellular carcinoma (HCC) has yet to be investigated. Herein, we analyzed RPS2 mRNA expression and promoter methylation in HCC patient samples and HepG2 cells. Subsequently, loss-of-function experiments were conducted to determine the function of RPS2 in HCC cells in vitro. Our results revealed that RPS2 mRNA expression is significantly elevated, and its promoter is hypomethylated in HCC patient samples compared to controls. In addition, 5-Azacytidine treatment in HepG2 cells decreased RPS2 promoter methylation level and increased its mRNA expression. RPS2 knockdown in HepG2 cells suppressed cell proliferation and promoted apoptosis. Functional pathway analysis of genes positively and negatively associated with RPS2 expression in HCC showed enrichment in ribosomal biogenesis, translation machinery, cell cycle regulation, and DNA processing. Furthermore, utilizing drug-protein 3D docking, we found that doxorubicin, sorafenib, and 5-Fluorouracil, showed high affinity to the active sites of RPS2, and in vitro treatment with these drugs reduced RPS2 expression. For the first time, we report on DNA methylation-mediated epigenetic regulation of RPS2 and its oncogenic role in HCC. Our findings suggest that RPS2 plays a significant role in the development and progression of HCC, hence its potential prognostic and therapeutic utility. Moreover, as epigenetic changes happen early in cancer development, RPS2 may serve as a potential biomarker for tumor progression.

ß-Thalassemia and Diabetes Mellitus: Current State and Future Directions.

ß-Thalassemia major is a congenital hemoglobin disorder that requires regular blood transfusion. The disease is often associated with iron overload and diabetes mellitus, among other complications. Pancreatic iron overload in ß-thalassemia patients disrupts ß-cell function and insulin secretion and induces insulin resistance. Several risk factors, including family history of diabetes, sedentary lifestyle, obesity, gender, and advanced age increase the risk of diabetes in ß-thalassemia patients. Precautionary measures such as blood glucose monitoring, anti-diabetic medications, and healthy living in ß-thalassemia patients notwithstanding, the prevalence of diabetes in ß-thalassemia patients continues to rise. This review aims to address the relationship between ß-thalassemia and diabetes in an attempt to understand how the pathology and management of ß-thalassemia precipitate diabetes mellitus. The possible employment of surrogate biomarkers for early prediction and intervention is discussed. More work is still needed to better understand the molecular mechanism(s) underlying the link between ß-thalassemia and diabetes and to identify novel prognostic and therapeutic targets.

Sclareol induces cell cycle arrest and ROS-mediated apoptosis and ferroptosis in lung adenocarcinoma cells.

Sclareol (SC) has shown significant anticancer activity against breast and colon cancers among others. However, its ability to precipitate similar anticancer effects in lung cancer has yet to be investigated. To address this issue, SC-treated lung adenocarcinoma cells (A549) were assessed for viability and functional competence as well as the expression of genes related to apoptosis and cell cycling. Our results demonstrated that SC treatment inhibited A549 cell clonogenic features and reduced their migration and invasion potential in a dose-dependent manner. Mechanistically, SC treatment downregulated the expression of cyclin D1 and survivin and upregulated that of p21 and p16, which was associated with a significant increase in the percentage of SubG0 cells. SC treatment is also associated with the induction of both the extrinsic and intrinsic apoptotic pathways, as evidenced by the increased expression and splitting of PARP1 and procaspases 3 and 9 and the reduced expression of antiapoptotic proteins Bcl-2 and Bcl-xL. Increased cell death in SC-treated cells is likely to have resulted from the induction of ferroptosis as suggested by the reduced expression of FPN and the inhibition of the anti-ferroptosis regulator GPX4. In conclusion, the data presented here suggest that SC can reduce lung carcinoma cell growth and metastasis and promote cell death.

SARS-CoV-2-induced hypomethylation of the ferritin heavy chain (FTH1) gene underlies serum hyperferritinemia in severe COVID-19 patients.

High serum ferritin (hyperferritinemia), a reliable hallmark of severe COVID-19 often associates with a moderate decrease in serum iron (hypoferremia) and a moderate increase in serum hepcidin. This suggests that hyperferritinemia in severe COVID-19 is reflective of inflammation rather than iron overload. To test this possibility, the expression status of ferritin heavy chain (FTH1), transferrin receptor 1 (TFRC), hepcidin (HAMP), and ferroportin (SLC40A1) genes and promoter methylation status of FTH1 and TFRC genes were examined in blood samples obtained from COVID-19 patients showing no, mild or severe symptoms and in healthy-donor monocytes stimulated with SARS-CoV-2-derived peptides. Severe COVID-19 samples showed a significant increase in FTH1 expression and hypomethylation relative to mild or asymptomatic COVID-19 samples. S-peptide treated monocytes also showed a significant increase in FTH1 expression and hypomethylation relative to that in controls; treatment with ECD or NP did not change FTH1 expression nor its methylation status. In silico and in vitro analysis showed a significant increase in the expression of the TET3 demethylase in S peptide-treated monocytes. Findings presented here suggest that S peptide-driven hypomethylation of the FTH1 gene promoter underlies hyperferritinemia in severe COVID-19 disease.

Long-COVID, Metabolic and Endocrine Disease.

In the aftermath of the corona pandemic, long-COVID or post-acute COVID-19 syndrome still represents a great challenge, and this topic will continue to represent a significant health problem in the coming years. At present, the impact of long-COVID on our health system cannot be fully assessed but according to current studies, up to 40% of people who have been infected with SARS-CoV-2 suffer from clinically relevant symptoms of long-COVID syndrome several weeks to months after the acute phase. The main symptoms are chronic fatigue, dyspnea, and various cognitive symptoms. Initial studies have shown that people with overweight and diabetes mellitus have a higher risk of developing long-COVID associated symptoms. Furthermore, repeated treatment of acute COVID-19 and long-COVID with steroids can contribute to long-term metabolic and endocrine disorders. Therefore, a structured program with rehabilitation and physical activity as well as optimal dietary management is of utmost importance, especially for patients with metabolic diseases and/or long-COVID. Furthermore, the removal of autoantibodies and specific therapeutic apheresis procedures could lead to a significant improvement in the symptoms of long-COVID in individual patients.

Fisetin Deters Cell Proliferation, Induces Apoptosis, Alleviates Oxidative Stress and Inflammation in Human Cancer Cells, HeLa.

BACKGROUND: Fisetin, a flavonol profusely found in vegetables and fruits, exhibited a myriad of properties in preclinical studies to impede cancer growth. PURPOSE: This study was proposed to delineate molecular mechanisms through analysing the modulated expression of various molecular targets in HeLa cells involved in proliferation, apoptosis and inflammation. METHODS: MTT assay, flow cytometry, nuclear morphology, DNA fragmentation and Annexin-Pi were performed to evaluate the anti-cancer potential of fisetin. Furthermore, qPCR and proteome profiler were performed to analyse the expression of variety of gene related to cell death, cell proliferation, oxidative stress and inflammation and cancer pathways. RESULTS: Fisetin demonstrated apoptotic inducing ability in HeLa cells, which was quite evident through nuclear morphology, DNA ladder pattern, decreased TMRE fluorescent intensity, cell cycle arrest at G2/M and increased early and late apoptosis. Furthermore, fisetin treatment modulated pro-apoptotic genes such as APAF1, Bad, Bax, Bid and BIK at both transcript and protein levels and anti-apoptotic gene Bcl-2, BIRC8, MCL-1, XIAP/BIRC4, Livin/BIRC7, clap-2/BIRC3, etc. at protein levels to mitigate cell proliferation and induce apoptosis. Interestingly, the aforementioned alterations consequently led to an elevated level of Caspase-3, Caspase-8 and Caspase-9, which was found to be consistent with the transcript and protein level expression. Moreover, fisetin downregulated the expression of AKT and MAPK pathways to avert proliferation and enhance apoptosis of cancer cells. Fisetin treatment also improves oxidative stress and alleviates inflammation by regulating JAK-STAT/NF-kB pathways. CONCLUSION: Together, these studies established that fisetin deters human cervical cancer cell proliferation, enhances apoptosis and ameliorates inflammation through regulating various signalling pathways that may be used as a therapeutic regime for better cancer management.

Estrogen-induced disruption of intracellular iron metabolism leads to oxidative stress, membrane damage, and cell cycle arrest in MCF-7 cells.

It is well established that several forms of cancer associate with significant iron overload. Recent studies have suggested that estrogen (E2) disrupts intracellular iron homeostasis by reducing hepcidin synthesis and maintaining ferroportin integrity. Here, the ability of E2 to alter intracellular iron status and cell growth potential was investigated in MCF-7 cells treated with increasing concentrations of E2. Treated cells were assessed for intracellular iron status, the expression of key proteins involved in iron metabolism, oxidative stress, cell survival, growth, and apoptosis. E2 treatment resulted in a significant reduction in hepcidin expression and a significant increase in hypoxia-inducible factor 1 alpha, ferroportin, transferrin receptor, and ferritin expression; a transient decrease in labile iron pool; and a significant increase in total intracellular iron content mainly at 20 nM/48 h E2 dose. Treated cells also showed increased total glutathione and oxidized glutathione levels, increased superoxide dismutase activity, and increased hemoxygenase 1 expression. Treatment with E2 at 20 nM for 48 h resulted in a significant reduction in cell growth (0.35/1 migration rate) and decreased cell survival (<80%) as compared with controls. Survivin expression significantly increased at 24 h post treatment with 5, 10, or 20 nM; however, that of γ-H2AX increased only after survivin levels dropped and only at the 20 nM E2 dose. Minimal upregulation and splitting of caspase 9 was only evident in cells treated with 20 nM E2; no changes in caspase 3 expression were evident. Although Annexin V staining studies showed that E2 treatment did not induce apoptosis, scanning electron microscopy studies showed marked membrane blebbing at 20 nM/48 h of E2. These findings suggest that estrogen treatment disrupts intracellular iron metabolism and precipitates adverse effects concerning cell viability, membrane integrity, and growth potential.

Immunotherapy of Fungal Infections.

Fungal organisms are ubiquitous in the environment. Pathogenic fungi, although relatively few in the whole gamut of microbial pathogens, are able to cause disease with varying degrees of severity in individuals with normal or impaired immunity. The disease state is an outcome of the fungal pathogen's interactions with the host immunity, and therefore, it stands to reason that deep/invasive fungal diseases be amenable to immunotherapy. Therefore, antifungal immunotherapy continues to be attractive as an adjunct to the currently available antifungal chemotherapy options for a number of reasons, including the fact that existing antifungal drugs, albeit largely effective, are not without limitations, and that morbidity and mortality associated with invasive mycoses are still unacceptably high. For several decades, intense basic research efforts have been directed at development of fungal immunotherapies. Nevertheless, this approach suffers from a severe bench-bedside disconnect owing to several reasons: the chemical and biological peculiarities of the fungal antigens, the complexities of host-pathogen interactions, an under-appreciation of the fungal disease landscape, the requirement of considerable financial investment to bring these therapies to clinical use, as well as practical problems associated with immunizations. In this general, non-exhaustive review, we summarize the features of ongoing research efforts directed towards devising safe and effective immunotherapeutic options for mycotic diseases, encompassing work on antifungal vaccines, adoptive cell transfers, cytokines, antimicrobial peptides (AMPs), monoclonal antibodies (mAbs), and other agents.

Prevalence and epidemiological characteristics of vaginal candidiasis in the UAE.

Vaginal candidiasis (VC) continues to be a health problem to women worldwide. Although the majority of VC cases are caused by Candida albicans (C. albicans), non-albicans Candida spp. like C. glabrata and C. tropicalis are emerging as important and potentially resistant opportunistic agents of VC. The objective of this study was to evaluate the prevalence and epidemiology of VC in the UAE through retrospective analysis of pertinent data compiled by the microbiology and infection control unit at Latifa Hospital, Dubai between 2005 and 2011. The incidence of VC significantly increased from 10.76% in 2005 to 17.61% in 2011; average prevalence was 13.88%. C. albicans occurred at a frequency of 83.02%, C. glabrata at 16.5% and C. tropicalis at 1.2%. A single C. dubliniensis isolate was identified in the sample population. The percentage of C. albicans significantly decreased from 83.02% in the sample population as a whole to 60.8% in subjects over 45 years of age (P < 0.01) and that of C. glabrata, C. tropicalis and C. krusei significantly increased from 13.88%, 0.9% and 0.03% to 29.7%, 6.7% and 1.4% (P < 0.05) respectively. The incidence of VC in the UAE is on the rise and the frequency of non-albicans Candida spp. is noticeably increasing especially in postmenopausal women.

Inhibition of PRMT5-mediated regulation of DKK1 sensitizes colorectal cancer cells to chemotherapy.

The Dickkopf family proteins (DKKs) are strong Wnt signaling antagonists that play a significant role in colorectal cancer (CRC) development and progression. Recent work has shown that DKKs, mainly DKK1, are associated with the induction of chemoresistance in CRC and that DKK1 expression in cancer cells correlates with that of protein arginine N-methyltransferase 5 (PRMT5). This points to the presence of a regulatory loop between DKK1 and PRMT5. Herein, we addressed the question of whether PRMT5 contributes to DKK1 expression in CRC and hence CRC chemoresistance. Both in silico and in vitro approaches were used to explore the relationship between PRMT5 and different DKK members. Our data demonstrated that DKK1 expression is significantly upregulated in CRC clinical samples, KRAS-mutated CRC in particular and that the levels of DKK1 positively correlate with PRMT5 activation. Chromatin immunoprecipitation (ChIP) data indicated a possible epigenetic role of PRMT5 in regulating DKK1, possibly through the symmetric dimethylation of H3R8. Knockdown of DKK1 or treatment with the PRMT5 inhibitor CMP5 in combination with doxorubicin yielded a synergistic anti-tumor effect in KRAS mutant, but not KRAS wild-type, CRC cells. These findings suggest that PRMT5 regulates DKK1 expression in CRC and that inhibition of PRMT5 modulates DKK1 expression in such a way that reduces CRC cell growth.

PRMT5 Mediated HIF1α Signaling and Ras-Related Nuclear Protein as Promising Biomarker in Hepatocellular Carcinoma.

Protein arginine N-methyltransferase 5 (PRMT5) has been identified as a potential therapeutic target for various cancer types. However, its role in regulating the hepatocellular carcinoma (HCC) transcriptome remains poorly understood. In this study, publicly available databases were employed to investigate PRMT5 expression, its correlation with overall survival, targeted pathways, and genes of interest in HCC. Additionally, we utilized in-house generated NGS data to explore PRMT5 expression in dysplastic nodules compared to hepatocellular carcinoma. Our findings revealed that PRMT5 is significantly overexpressed in HCC compared to normal liver, and elevated expression correlates with poor overall survival. To gain insights into the mechanism driving PRMT5 overexpression in HCC, we analyzed promoter CpG islands and methylation status in HCC compared to normal tissues. Pathway analysis of PRMT5 knockdown in the HCC cells revealed a connection between PRMT5 expression and genes related to the HIF1α pathway. Additionally, by filtering PRMT5-correlated genes within the HIF1α pathway and selecting up/downregulated genes in HCC patients, we identified Ras-related nuclear protein (RAN) as a target associated with overall survival. For the first time, we report that PRMT5 is implicated in the regulation of HIF1A and RAN genes, suggesting the potential prognostic utility of PRMT5 in HCC.

Fat mass and obesity-associated (FTO) gene is essential for insulin secretion and ß-cell function: In vitro studies using INS-1 cells and human pancreatic islets.

AIMS: In this study, we investigated the role of the FTO gene in pancreatic ß-cell biology and its association with type 2 diabetes (T2D). To address this issue, human pancreatic islets and rat INS-1 (832/13) cells were used to perform gene silencing, overexpression, and functional analysis of FTO expression; levels of FTO were also measured in serum samples obtained from diabetic and obese individuals. RESULTS: The findings revealed that FTO expression was reduced in islets from hyperglycemic/diabetic donors compared to normal donors. This reduction correlated with decreased INS and GLUT1 expression and increased PDX1, GCK, and SNAP25 expression. Silencing of Fto in INS-1 cells impaired insulin release and mitochondrial ATP production and increased apoptosis in pro-apoptotic cytokine-treated cells. However, glucose uptake and reactive oxygen species production rates remained unaffected. Downregulation of key ß-cell genes was observed following Fto-silencing, while Glut2 and Gck were unaffected. RNA-seq analysis identified several dysregulated genes involved in metal ion binding, calcium ion binding, and protein serine/threonine kinase activity. Furthermore, our findings showed that Pdx1 or Mafa-silencing did not influence FTO protein expression. Overexpression of FTO in human islets promoted insulin secretion and upregulated INS, PDX1, MAFA, and GLUT1 expression. Serum FTO levels did not significantly differ between individuals with diabetes or obesity and their healthy counterparts. CONCLUSION: These findings suggest that FTO plays a crucial role in ß-cell survival, metabolism, and function and point to a potential therapeutic utility of FTO in T2D patients.

JAK/STAT signaling and cellular iron metabolism in hepatocellular carcinoma: therapeutic implications.

Iron metabolism plays a crucial role in the development and progression of hepatocellular carcinoma (HCC), the most common type of primary liver cancer. Iron is an essential micronutrient that is involved in many physiological processes, including oxygen transport, DNA synthesis, and cellular growth and differentiation. However, excessive iron accumulation in the liver has been linked to oxidative stress, inflammation, and DNA damage, which can increase the risk of HCC. Studies have shown that iron overload is common in patients with HCC and that it is associated with a poor prognosis and reduced survival rates. Various iron metabolism-related proteins and signaling pathways such as the JAK/STAT pathway are dysregulated in HCC. Moreover, reduced hepcidin expression was reported to promote HCC in a JAK/STAT pathway-dependent manner. Therefore, it is important to understand the crosstalk between iron metabolism and the JAK/STAT pathway to prevent or treat iron overload in HCC. Iron chelators can bind to iron and remove it from the body, but its effect on JAK/STAT pathway is unclear. Also, HCC can be targeted by using the JAK/STAT pathway inhibitors, but their effect on hepatic iron metabolism is not known. In this review, for the first time, we focus on the role of the JAK/STAT signaling pathway in regulating cellular iron metabolism and its association with the development of HCC. We also discuss novel pharmacological agents and their therapeutic potential in manipulating iron metabolism and JAK/STAT signaling in HCC.

Plasma metabolomics profiling identifies new predictive biomarkers for disease severity in COVID-19 patients.

Recently, numerous studies have reported on different predictive models of disease severity in COVID-19 patients. Herein, we propose a highly predictive model of disease severity by integrating routine laboratory findings and plasma metabolites including cytosine as a potential biomarker of COVID-19 disease severity. One model was developed and internally validated on the basis of ROC-AUC values. The predictive accuracy of the model was 0.996 (95% CI: 0.989 to 1.000) with an optimal cut-off risk score of 3 from among 6 biomarkers including five lab findings (D-dimer, ferritin, neutrophil counts, Hp, and sTfR) and one metabolite (cytosine). The model is of high predictive power, needs a small number of variables that can be acquired at minimal cost and effort, and can be applied independent of non-empirical clinical data. The metabolomics profiling data and the modeling work stemming from it, as presented here, could further explain the cause of COVID-19 disease prognosis and patient management.

SCAMP3 promotes breast cancer progression through the c-MYC-ß-Catenin-SQSTM1 growth and stemness axis.

The cellular trafficking protein secretory-carrier-membrane-protein 3 (SCAMP3) has been previously shown to promote hepatocellular carcinoma, melanoma, glioma and pancreatic adenocarcinoma. Moreover, previous work has shown that SCAMP3 regulates the epidermal growth factor receptor (EGFR) in triple negative breast cancer (TNBC). However, the oncogenic role of SCAMP3 in different molecular subtypes of breast cancer (BRCA) remains largely unknown. In this study, the role of SCAMP3 in different molecular subtypes of BRCA was investigated using in silico, in vitro and in vivo approaches. In silico analysis of BRCA patient samples showed that SCAMP3 is highly overexpressed in different BRCA molecular subtypes, advanced disease grades and lymph node metastatic stages. Depletion of SCAMP3 inhibited BRCA cell growth, stemness, clonogenic potential and migration and promoted autophagy and cellular senescence. The expression of stemness markers CD44 and OCT4A was reduced in SCAMP3-silenced MDA-MB-231 cells. SCAMP3 overexpression promoted cell proliferation, clonogenicity, tumor spheroid formation and migration in vitro and tumor growth in vivo. SCAMP3 promoted epithelial-mesenchymal-transition (EMT) by regulating E-cadherin expression. SCAMP3 enhanced in vivo tumor growth in MDA-MB-231 tumor xenograft mouse model. Mechanistically, SCAMP3 depletion inhibited ß-Catenin, c-MYC and SQSTM1 expression, while its overexpression increased the expression of the same oncogenic proteins. Increased SCAMP3 expression associated with increased chemoresistance in BRCA cells while its depletion associated with increased sensitivity to chemotherapy. BRCA patients with high SCAMP3 expression showed poor prognosis, decreased overall survival and relapse free survival relative to counterparts with reduced SCAMP3 expression. These findings suggest that SCAMP3 exerts a wide range of oncogenic effects in different molecular subtypes of BRCA by modulating the c-MYC-ß-Catenin-SQSTM1 axis that targets tumor growth, metastasis, stemness and chemoresistance.

GDF15 plays a critical role in insulin secretion in INS-1 cells and human pancreatic islets.

Mounting evidence points to a link between growth differentiation factor-15 (GDF15) expression and the onset and progression of diabetes mellitus. However, the exact role of GDF15 in pancreatic ß-cell function is unclear. To examine the role of GDF15 in ß-cell function, bioinformatics analysis and functional experiments involving GDF15 silencing and overexpression were performed in INS-1 cells and human islets. Public microarray and RNA-seq expression data showed that islets obtained from diabetic donors express high levels of GDF15 compared to islets obtained from normal donors. Moreover, analysis of RNA-seq expression data revealed that GDF15 expression correlates positively with that of insulin (INS), KCNJ11, GLUT1, MAFA, INSR and negatively with that of Glucokinase (GCK) and Alpha-Ketoglutarate Dependent Dioxygenase (FTO). No T2D-associated genetic variants in the GDF15 were found to pass genome-wide significance in the TIGER portal. Expression silencing of Gdf15 in INS-1 cells reduced insulin release, glucose uptake levels, increased reactive oxygen species (ROS) production and apoptosis levels. While Gdf15-silenced cells downregulated mRNA expression of Ins, Pdx1, Mafa, and Glut2 genes, its overexpression human islets was associated with increased insulin secretion and upregulated expression of MAFA and GLUT1 but not INS or GCK. Silencing of Pdx1 or Mafa in INS-1 cells did not affect the expression of GDF15. These findings suggest that GDF15 plays a significant role in pancreatic ß-cell function.

Innate and adaptive antifungal immune responses: partners on an equal footing.

Adaptive immunity has long been regarded as the major player in protection against most fungal infections. Mounting evidence suggest however, that both innate and adaptive responses intricately collaborate to produce effective antifungal protection. Dendritic cells (DCs) play an important role in initiating and orchestrating antifungal immunity; neutrophils, macrophages and other phagocytes also participate in recognising and eliminating fungal pathogens. Adaptive immunity provides a wide range of effector and regulatory responses against fungal infections. Th1 responses protect against most forms of mycoses but they associate with significant inflammation and limited pathogen persistence. By contrast, Th2 responses enhance persistence of and tolerance to fungal infections thus permitting the generation of long-lasting immunological memory. Although the role of Th17 cytokines in fungal immunity is not fully understood, they can enhance proinflammatory or anti-inflammatory responses or play a regulatory role in fungal immunity all depending on the pathogen, site/phase of infection and host immunostatus. T regulatory cells balance the activities of various Th cell subsets thereby permitting inflammation and protection on the one hand and allowing for tolerance and memory on the other. Here, recent developments in fungal immunity research are reviewed as means of tracing the emergence of a refined paradigm where innate and adaptive responses are viewed in the same light.

The Role of Estrogen Signaling in Cellular Iron Metabolism in Pancreatic ß Cells.

ABSTRACT: Several lines of evidence suggest that estrogen (17-ß estradiol; E2) protects against diabetes mellitus and plays important roles in pancreatic ß-cell survival and function. Mounting clinical and experimental evidence also suggest that E2 modulates cellular iron metabolism by regulating the expression of several iron regulatory genes, including hepcidin (HAMP), hypoxia-inducible factor 1-α, ferroportin (SLC40A1), and lipocalin (LCN2). However, whether E2 regulates cellular iron metabolism in pancreatic ß cells and whether the antidiabetic effects of E2 can be, at least partially, attributed to its role in iron metabolism is not known. In this context, pancreatic ß cells express considerable levels of conventional E2 receptors (ERs; mainly ER-α) and nonconventional G protein-coupled estrogen receptors and hence responsive to E2 signals. Moreover, pancreatic islet cells require significant amounts of iron for proper functioning, replication and survival and, hence, well equipped to manage cellular iron metabolism (acquisition, utilization, storage, and release). In this review, we examine the link between E2 and cellular iron metabolism in pancreatic ß cells and discuss the bearing of such a link on ß-cell survival and function.

The role of disrupted iron homeostasis in the development and progression of arthropathy.

Arthropathy or joint disease leads to significant pain and disability irrespective of etiology. Clinical and experimental evidence point to the presence of considerable links between arthropathy and iron overload. Previous work has suggested that iron accumulation in the joints is often associated with increased oxidative stress, disrupted matrix metabolism, and cartilage degeneration. However, key issues regarding the role of iron overload in the pathogenesis of arthropathy remain ambiguous. For example, significant gaps in our knowledge of the primary cellular targets of iron overload-induced damage and the exact molecular mechanism through which disrupted iron homeostasis leads to joint damage still exist. The exact signaling pathway that links iron metabolism and cellular damage in arthropathy also remains largely unmapped. In this review, we focus on the relationship between iron overload and arthropathy with special emphasis on the adversarial relationship between iron that accumulates in the joints over time and cartilage homeostasis. A better understanding of the mechanisms and pathways underlying iron-induced cartilage degeneration may help in defining new prognostic markers and therapeutic targets in arthropathy.