Hidden genetics behind glomerular scars: an opportunity to understand the heterogeneity of focal segmental glomerulosclerosis?

Focal segmental glomerulosclerosis (FSGS) is a complex disease which describes different kinds of kidney defects, not exclusively linked with podocyte defects. Since nephrin mutation was first described in association with early-onset nephrotic syndrome (NS), many advancements have been made in understanding genetic patterns associated with FSGS. New genetic causes of FSGS have been discovered, displaying unexpected genotypes, and recognizing possible site of damage. Many recent large-scale sequencing analyses on patients affected by idiopathic chronic kidney disease (CKD), kidney failure (KF) of unknown origin, or classified as FSGS, have revealed collagen alpha IV genes, as one of the most frequent sites of pathogenic mutations. Also, recent interest in complex and systemic lysosomal storage diseases, such as Fabry disease, has highlighted GLA mutations as possible causes of FSGS. Tubulointerstitial disease, recently classified by KDIGO based on genetic subtypes, when associated with UMOD variants, may phenotypically gain FSGS features, as well as ciliopathy genes or others, otherwise leading to completely different phenotypes, but found carrying pathogenic variants with associated FSGS phenotype. Thus, glomerulosclerosis may conceal different heterogeneous conditions. When a kidney biopsy is performed, the principal objective is to provide an accurate diagnosis. The broad spectrum of phenotypic expression and genetic complexity is demonstrating that a combined path of management needs to be applied. Genetic investigation should not be reserved only to selected cases, but rather part of medical management, integrating with clinical and renal pathology records. FSGS heterogeneity should be interpreted as an interesting opportunity to discover new pathways of CKD, requiring prompt genotype-phenotype correlation. In this review, we aim to highlight how FSGS represents a peculiar kidney condition, demanding multidisciplinary management, and in which genetic analysis may solve some otherwise unrevealed idiopathic cases. Unfortunately there is not a uniform correlation between specific mutations and FSGS morphological classes, as the same variants may be identified in familial cases or sporadic FSGS/NS or manifest a variable spectrum of the same disease. These non-specific features make diagnosis challenging. The complexity of FSGS genotypes requires new directions. Old morphological classification does not provide much information about the responsible cause of disease and misdiagnoses may expose patients to immunosuppressive therapy side effects, mistaken genetic counseling, and misguided kidney transplant programs.

Polydopamine-Coated Liposomes for Methylene Blue Delivery in Anticancer Photodynamic Therapy: Effects in 2D and 3D Cellular Models.

Photodynamic therapy (PDT) is a therapeutic option for cancer, in which photosensitizer (PS) drugs, light, and molecular oxygen generate reactive oxygen species (ROS) and induce cell death. First- and second-generation PSs presented with problems that hindered their efficacy, including low solubility. Thus, second-generation PSs loaded into nanocarriers were produced to enhance their cellular uptake and therapeutic efficacy. Among other compounds investigated, the dye methylene blue (MB) showed potential as a PS, and its photodynamic activity in tumor cells was reported even in its nanocarrier-delivered form, including liposomes. Here, we prepared polydopamine (PDA)-coated liposomes and efficiently adsorbed MB onto their surface. lipoPDA@MB vesicles were first physico-chemically characterized and studies on their light stability and on the in vitro release of MB were performed. Photodynamic effects were then assessed on a panel of 2D- and 3D-cultured cancer cell lines, comparing the results with those obtained using free MB. lipoPDA@MB uptake, type of cell death induced, and ability to generate ROS were also investigated. Our results show that lipoPDA@MB possesses higher photodynamic potency compared to MB in both 2D and 3D cell models, probably thanks to its higher uptake, ROS production, and apoptotic cell death induction. Therefore, lipoPDA@MB appears as an efficient drug delivery system for MB-based PDT.

Solanum lycopersicum (Tomato)-Derived Nanovesicles Accelerate Wound Healing by Eliciting the Migration of Keratinocytes and Fibroblasts.

Plant-derived nanovesicles have been considered interesting in medicine for their breakthrough biological effects, including those relevant to wound healing. However, tomato-derived nanovesicles (TDNVs) have not been studied for their effects on wound closure yet. TDNVs were isolated from Solanum lycopersicum (var. Piccadilly) ripe tomatoes by ultracentrifugation. Extract (collected during the isolation procedure) and NVs (pellet) were characterized by transmission electron microscopy and laser Doppler electrophoresis. Wound healing in the presence of Extract or NVs was analyzed by a scratch assay with monocultures of human keratinocytes (HUKE) or NIH-3T3 mouse fibroblasts. Cell proliferation and migration were studied by MTT and agarose spot assay, respectively. The vesicles in the Extract and NV samples were nanosized with a similar mean diameter of 115 nm and 130 nm, respectively. Both Extract and NVs had already accelerated wound closure of injured HUKE and NIH-3T3 monocultures by 6 h post-injury. Although neither sample exerted a cytotoxic effect on HUKE and NIH-3T3 fibroblasts, they did not augment cell proliferation. NVs and the Extract increased cell migration of both cell types. NVs from tomatoes may accelerate wound healing by increasing keratinocyte and fibroblast migration. These results indicate the potential therapeutic usefulness of TDNVs in the treatment of chronic or hard-to-heal ulcers.

Refractory IgA Nephropathy: A Challenge for Future Nephrologists.

IgA nephropathy (IgAN) represents the most prevalent form of primary glomerulonephritis, and, on a global scale, it ranks among the leading culprits behind end-stage kidney disease (ESKD). Presently, the primary strategy for managing IgAN revolves around optimizing blood pressure and mitigating proteinuria. This is achieved through the utilization of renin-angiotensin system (RAS) inhibitors, namely, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As outlined by the KDIGO guidelines, individuals who continue to show a persistent high risk of progressive ESKD, even with comprehensive supportive care, are candidates for glucocorticoid therapy. Despite these therapies, some patients have a disease refractory to treatment, defined as individuals that present a 24 h urinary protein persistently >1 g after at least two rounds of regular steroids (methylprednisolone or prednisone) and/or immunosuppressant therapy (e.g., mycophenolate mofetil), or who do not tolerate regular steroids and/or immunosuppressant therapy. The aim of this Systematic Review is to revise the current literature, using the biomedical database PubMed, to investigate possible therapeutic strategies, including SGLT2 inhibitors, endothelin receptor blockers, targeted-release budesonide, B cell proliferation and differentiation inhibitors, fecal microbiota transplantation, as well as blockade of complement components.

The Human Virome and Its Crosslink with Glomerulonephritis and IgA Nephropathy.

The prokaryotic, viral, fungal, and parasitic microbiome exists in a highly intricate connection with the human host. In addition to eukaryotic viruses, due to the existence of various host bacteria, phages are widely spread throughout the human body. However, it is now evident that some viral community states, as opposed to others, are indicative of health and might be linked to undesirable outcomes for the human host. Members of the virome may collaborate with the human host to retain mutualistic functions in preserving human health. Evolutionary theories contend that a particular microbe's ubiquitous existence may signify a successful partnership with the host. In this Review, we present a survey of the field's work on the human virome and highlight the role of viruses in health and disease and the relationship of the virobiota with immune system control. Moreover, we will analyze virus involvement in glomerulonephritis and in IgA nephropathy, theorizing the molecular mechanisms that may be responsible for the crosslink with these renal diseases.

Polymer Encapsulated Liposomes for Oral Co-Delivery of Curcumin and Hydroxytyrosol.

Curcumin (Cur) is a hydrophobic polyphenol from the rhizome of Curcuma spp., while hydroxytyrosol (HT) is a water-soluble polyphenol from Olea europaea. Both show outstanding antioxidant properties but suffer from scarce bioavailability and low stability in biological fluids. In this work, the co-encapsulation of Cur and HT into liposomes was realized, and the liposomal formulation was improved using polymers to increase their survival in the gastrointestinal tract. Liposomes with different compositions were formulated: Type 1, composed of phospholipids and cholesterol; Type 2, also with a PEG coating; and Type 3 providing an additional shell of Eudragit® S100, a gastro-resistant polymer. Samples were characterized in terms of size, morphology, ζ-potential, encapsulation efficiency, and loading capacity. All samples were subjected to a simulated in vitro digestion and their stability was investigated. The Eudragit®S100 coating demonstrated prevention of early releases of HT in the mouth and gastric phases, while the PEG shell reduced bile salts and pancreatin effects during the intestinal digestion. In vitro antioxidant activity showed a cumulative effect for Cur and HT loaded in vesicles. Finally, liposomes with HT concentrations up to 40 µM and Cur up to 4.7 µM, alone or in combination, did not show cytotoxicity against Caco-2 cells.

Identification of a Region in Shigella flexneri WzyB Disrupting the Interaction with WzzpHS2.

Shigella flexneri can synthesize polysaccharide chains having complex sugars and a regulated number of repeating units. S. flexneri lipopolysaccharide O antigen (Oag) is synthesized by the Wzy-dependent pathway, which is the most common pathway used in bacteria for polysaccharide synthesis. The inner membrane protein WzyB polymerizes the Oag repeat units into chains, while the polysaccharide copolymerases WzzB and WzzpHS2 determine the average number of repeat units or "the modal length," termed short type and very long type. Our data show for the first time a direct interaction between WzyB and WzzpHS2, with and without the use of the chemical cross-linker dithiobis (succinimidyl propionate) (DSP). Additionally, mutations generated via random and site-directed mutagenesis identify a region of WzyB that caused diminished function and significantly decreased very long Oag chain polymerization, and that affected the aforementioned interaction. These results provide insight into the mechanisms underlying the regulation of Oag biosynthesis. IMPORTANCE Complex polysaccharide chains are synthesized by bacteria, usually at a regulated number of repeating units, which has broad implications for bacterial pathogenesis. One example is the O antigen (Oag) component of lipopolysaccharide that is predominantly synthesized by the Wzy-dependent pathway. Our findings show for the first time a direct physical interaction between WzyB and WzzpHS2. Additionally, a set of Wzy mutant constructs were generated, revealing a proposed active site/switch region involved in the activity of WzyB and the physical interaction with WzzpHS2. Combined, these findings further understanding of the Wzy-dependent pathway. The identification of a novel interaction with the polysaccharide copolymerase WzzpHS2 and the region of WzyB that is involved in this aforementioned interaction and its impact on WzyB Oag synthesis activity have significant implication for the prevention/treatment of bacterial diseases and discovery of novel biotechnologies.

High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis. The role of the microbiota and mucosal immunity in the pathogenesis of IgAN remains a key element. To date, the hypothetical relationship between commensal bacteria, elevated tumour necrosis factor (TNF) superfamily member 13 [also known as B-cell activating factor (BAFF)] levels, perturbed homoeostasis of intestinal-activated B cells and intestinal IgA class switch has not been clearly shown in IgAN patients. METHODS: We studied the intestinal-renal axis connections, analysing levels of BAFF, TNF ligand superfamily member 13 (APRIL) and intestinal-activated B cells in IgAN patients, healthy subjects (HSs) and patients with non-IgA glomerulonephritides. RESULTS: IgAN patients had increased serum levels of BAFF cytokine, correlating with higher amounts of five specific microbiota metabolites, and high APRIL cytokine serum levels. We also found that subjects with IgAN have a higher level of circulating gut-homing (CCR9+ ß7 integrin+) regultory B cells, memory B cells and IgA+ memory B cells compared with HSs. Finally, we found that IgAN patients had high levels of both total plasmablasts (PBs) and intestinal-homing PBs. Interestingly, PBs significantly increased in IgAN but not in patients with other glomerulonephritides. CONCLUSIONS: Our results demonstrate a significant difference in the amount of intestinal-activated B lymphocytes between IgAN patients and HSs, confirming the hypothesis of the pathogenic role of intestinal mucosal hyperresponsiveness in IgAN. The intestinal-renal axis plays a crucial role in IgAN and several factors may contribute to its complex pathogenesis and provide an important area of research for novel targeted therapies to modulate progression of the disease.

Modified "Blumgart-Type" Suture for Wirsung-Pancreaticogastrostomy: Technique and Results of a Pilot Study.

INTRODUCTION: Postoperative pancreatic fistula (POPF) represents the principal determinant of morbidity and mortality after pancreaticoduodenectomy. Since 1994 we have been performing pancreaticogastrostomy with duct-to-mucosa anastomosis (Wirsung-pancreaticogastric anastomosis [WPGA]), but postoperative morbidity, although limited, was still a concern. An original pancreas-transfixing suture technique, named "Blumgart's anastomosis" (BA), has shown efficacy at reducing fistula rates from pancreaticojejunostomy. Few cohort studies have shown that WPGA with pancreas-transfixing stitches may help reduce the rate of POPF. We designed a novel "Blumgart-type" modification of WPGA (B-WPGA) aiming at harnessing the full potential of the Blumgart design. METHODS: A prospective development study was designed around the application of B-WPGA after pancreaticoduodenectomy for primary periampullary tumors. It focused on describing the early iterations of this technique and on assessing the rate of POPF and delayed post-pancreatectomy hemorrhage (DPH) (primary outcomes), along with other perioperative outcomes. Technically, after mobilizing the pancreatic remnant for a few centimeters, the Wirsung duct is cannulated. A lozenge of seromuscular layer is excised from the posterior gastric wall, matching the shape and size of the pancreas's cut surface. Two to four transparenchymal pancreatic-to-gastric submucosa U stitches with 4/0 Gore-Tex are positioned cranially and caudally to the Wirsung duct, respectively, mounted on soft clamps, and tied onto the gastric serosa only after duct-to-mucosa anastomosis. Postoperative follow-up was standardized by protocol and included a pancreatic enzyme check on the drain output. RESULTS: From February 2018 to June 2019, in 15 continuous cases, B-WPGA was performed after pancreaticoduodenectomy. Indications for pancreaticoduodenectomy were mainly ampulla of Vater and pancreatic head adenocarcinomas. There was no operative mortality and no pancreatic anastomosis-related morbidity. Two events (13%) of transiently elevated amylase in the drain fluid, not matching the definition of POPF, were identified in patients with a soft pancreas on postoperative day 2. No DPHs were recorded after a minimum follow-up of 18.6 months. DISCUSSION/CONCLUSION: The principles of BA may be safely applied to the WPGA model. B-WPGA allows (1) gentle compression and closure of the small secondary ducts in the pancreatic remnant; (2) partial invagination of the pancreatic body in the gastric wall, with the pancreatic cut surface protected by the gastric submucosa; and (3) prevention of parenchymal fractures, as the pancreaticogastric stitches are tied onto the gastric serosa. Despite the limited number of cases in this study, the absence of mortality and anastomosis-related complications supports further reproduction of this technical variant. Larger studies are necessary to determine its efficacy.

Easy Preparation of Liposome@PDA Microspheres for Fast and Highly Efficient Removal of Methylene Blue from Water.

Mussel-inspired chemistry was usefully exploited here with the aim of developing a high-efficiency, environmentally friendly material for water remediation. A micro-structured material based on polydopamine (PDA) was obtained by using liposomes as templating agents and was used for the first time as an adsorbent material for the removal of methylene blue (MB) dye from aqueous solutions. Phospholipid liposomes were made by extrusion and coated with PDA by self-polymerization of dopamine under simple and mild conditions. The obtained Liposome@PDA microspheres were characterized by DLS and Zeta potential analysis, TEM microscopy, and FTIR spectroscopy. The effects of pH, temperature, MB concentration, amount of Liposome@PDA, and contact time on the adsorption process were investigated. Results showed that the highest adsorption capacity was obtained in weakly alkaline conditions (pH = 8.0) and that it could reach up to 395.4 mg g-1 at 298 K. In addition, adsorption kinetics showed that the adsorption behavior fits a pseudo-second-order kinetic model well. The equilibrium adsorption data, instead, were well described by Langmuir isotherm. Thermodynamic analysis demonstrated that the adsorption process was endothermic and spontaneous (ΔG0 = -12.55 kJ mol-1, ΔH0 = 13.37 kJ mol-1) in the investigated experimental conditions. Finally, the applicability of Liposome@PDA microspheres to model wastewater and the excellent reusability after regeneration by removing MB were demonstrated.

Polysaccharide co-polymerase WzzB/WzzE chimeras reveal transmembrane 2 region of WzzB is important for interaction with WzyB.

The ability of bacteria to synthesise complex polysaccharide chains at a controlled number of repeating units has wide implications for a range of biological activities that include: symbiosis, biofilm formation and immune system avoidance. Complex polysaccharide chains such as the O antigen (Oag) component of lipopolysaccharide and the enterobacterial common antigen (ECA) are synthesised by the most common polysaccharide synthesis pathway used in bacteria, known as the Wzy-dependent pathway. The Oag and ECA are polymerized into chains via the inner membrane proteins WzyB and WzyE, respectively, while the respective co-polymerases WzzB and WzzE modulate the number of repeat units in the chains or "the modal length" of the polysaccharide via a hypothesised interaction. Our data shows for the first time "cross-talk" between Oag and ECA synthesis in that WzzE is able to partially regulate Oag modal length via a potential interaction with WzyB. To investigate this, one or both of the transmembrane regions (TM1 and TM2) of WzzE and WzzB were swapped creating six chimera proteins. Several chimeric proteins showed significant increases Oag modal length control, while others reduced control. Additionally, co-purification experiments show an interaction between WzyB and WzzB for the first time without the use of a chemical cross-linker, and a novel interaction between WzyB and WzzE. These results suggest the TM2 region of Wzz proteins plays a critical role in Oag and ECA modal length control, presumably via the interaction with respective Wzy proteins, thus providing insight into the complex mechanism underlying the control of polysaccharide biosynthesis.ImportanceBacteria synthesise complex polysaccharide chains at a controlled number of repeating units, this has wide implications for a range of bacterial activities involved in virulence. Examples of complex polysaccharide chains include, the O antigen (Oag) component of lipopolysaccharide and the enterobacterial common antigen (ECA), both of these examples are predominantly synthesised by their own independent Wzy-dependent pathway. Our data show for the first time "cross-talk" between Oag and ECA synthesis and identifies novel physical protein-protein interactions between proteins in these systems. These findings further the understanding of how the system functions to control polysaccharide chain length which has great implications for novel biotechnologies and/or the combat of bacterial diseases.

Microbiome modulation to correct uremic toxins and to preserve kidney functions.

PURPOSE OF REVIEW: The association between dysbiosis and CKD is well established. This review focuses on the current understanding of microbiome, in normal individuals and CKD patients, in order to hypothesize how to correct uremic toxins levels and preserve the renal function and reduce associated comorbidities. Here we discuss our current opinion on microbiome modulation in order to manage the CKD-associated dysbiosis. RECENT FINDINGS: Emerging evidence confirms the role of gut microbiome in the progression of CKD. In this scenario, the need is felt to set up multifaceted approaches for dysbiosis management. Among many strategies able to improve gut wellness, a crucial approach is represented by the functional nutrition. At the same time, drug-based treatments show significant results in microbiome modulation. Furthermore, we examine here the potentialities of fecal microbiome transplantation (FMT) in CKD, an approach currently applied in Clostridium difficile infection. SUMMARY: The gut microbiome plays a pivotal role in the pathophysiology of CKD. The vicious cycle triggered by kidney function decline leads to gut dysbiosis. Considering the gut microbiome as a therapeutic target in CKD, multiple approaches aimed at its modulation should be envisioned to preserve kidney function. Dietary interventions and pharmacological strategies are able to improve microbiome dysbiosis, oxidative stress and fibrosis. Additionally, FMT could represent a promising novel therapy in the management of CKD-associated dysbiosis.

Ulipristal acetate before in vitro fertilization: efficacy in infertile women with submucous fibroids.

BACKGROUND: The presence of submucous fibroids strongly impacts on IVF results, therefore, these patients should be considered for surgical or medical treatment. The aim of this study was to assess the role of Ulipristal acetate (UPA), a selective progesterone receptor modulator, in restoring uterine cavity deformation due to submucous fibroids, in infertile patients attempting an IVF treatment. The secondary study outcome was to evaluate the impact of preconception UPA treatment on rate of biochemical pregnancy, ongoing pregnancy, and live birth compared to a control group without fibroids. METHODS: Infertile patients with submucosal fibroid (Type 1 and Type 2 according to FIGO classification) were enrolled in the study as fibroids group and received 1 to 3 treatment cycles of UPA, according to their response, as reflected by fibroid volume reduction and restoration of normal uterine cavity. Patients in control group were randomly selected from a general IVF cohort by a ratio of 2:1 with fibroids group, matched by age, BMI, type and cause of infertility and antral follicle count. The impact of UPA on fibroids volume reduction was evaluated. IVF outcome was compared between groups. RESULTS: Twenty-six patients underwent UPA treatment revealed a mean volume reduction of their fibroids of 41%. A total of 15 (57.6%) biochemical pregnancy were obtained, resulting in 13 (50%) ongoing pregnancy and 9 (34.6%) healthy babies were already delivered. Similar results were obtained in control group. CONCLUSION: Restoration of normal uterine cavity by UPA treatment prior to IVF treatment avoids surgery and establishes a pregnancy rate comparable to a control group without fibroids.

Preeclampsia and Glomerulonephritis: A Bidirectional Association.

PURPOSE OF REVIEW: We focus on the current understanding of preeclampsia (PE) in order to examine how it mediates glomerular injury and affects the course of glomerulonephritis (GNs). In addition, this review discusses the role of GNs on the development of PE. RECENT FINDINGS: In PE, the dysfunctional utero-placental perfusion causes the release into the mother's circulation of anti-angiogenic substances, leading to systemic endotheliosis. In preeclamptic patients, the imbalance between pro- and anti-angiogenic factors is responsible for the kidney injury, and PE may reveal a silent pre-existent GN or may induce the development of the disease. Moreover, in women with chronic kidney disease (CKD), it could accelerate the disease progression. In any case, GNs compromise renal function, making the kidney less responsive to physiological changes that occur during pregnancy and, at the same time, cause maternal vascular inflammation, representing a risk factor for PE development. Although a bidirectional correlation between GNs and PE has been demonstrated, the data are limited, and further large studies are warranted. Close collaboration between a multidisciplinary team of obstetricians and nephrologists is essential to establish the correct diagnosis and safely manage these vulnerable women and their fetuses.

Evaluation of different antiandrogenic progestins on clinical and biochemical variables in polycystic ovary syndrome.

Objectives: The aim of the study was to update the results of a previous study published 10 years ago and compare the effect on hyperandrogenism of a newer progestin, dienogest (DNG), in a combined oral contraceptive (COC) formulation with ethinylestradiol (EE), with that of COCs containing the same dose of EE in combination with drospirenone (DRSP) and chlormadinone acetate (CMA).Methods: Sixty women with polycystic ovary syndrome (PCOS) aged between 16 and 35 and requiring antiandrogenic contraceptive treatment were randomised to one of three treatment groups: EE 30 µg/DRSP 3 mg, EE 30 µg/CMA 2 mg, EE 30 µg/DNG 2 mg. We evaluated the effects of the three COCs on sex hormone-binding globulin (SHBG) and biochemical markers of hyperandrogenism.Results: After 3 months of treatment, serum androgen concentrations were significantly improved in all treatment groups. Serum concentrations of SHBG were significantly increased with all COC treatments (p < 0.0001). Interestingly, DRSP had a greater effect (+218%; p < 0.0001) on serum SHBG concentrations compared with DNG and CMA (p < 0.04 and p < 0.002, respectively). Serum concentrations of total testosterone significantly decreased in all groups (p < 0.0001). DRSP had a significantly greater effect on total testosterone concentrations compared with DNG (p = 0.002) and CMA (p < 0.0001).Conclusion: Our study showed that DNG exerted an important stimulatory effect on SHBG concentrations, which was less than that of DRSP but greater than that of CMA. Similar results were also obtained for dehydroepiandrosterone sulphate and total testosterone.

A New Vision of IgA Nephropathy: The Missing Link.

IgA Nephropathy (IgAN) is a primary glomerulonephritis problem worldwide that develops mainly in the 2nd and 3rd decade of life and reaches end-stage kidney disease after 20 years from the biopsy-proven diagnosis, implying a great socio-economic burden. IgAN may occur in a sporadic or familial form. Studies on familial IgAN have shown that 66% of asymptomatic relatives carry immunological defects such as high IgA serum levels, abnormal spontaneous in vitro production of IgA from peripheral blood mononuclear cells (PBMCs), high serum levels of aberrantly glycosylated IgA1, and an altered PBMC cytokine production profile. Recent findings led us to focus our attention on a new perspective to study the pathogenesis of this disease, and new studies showed the involvement of factors driven by environment, lifestyle or diet that could affect the disease. In this review, we describe the results of studies carried out in IgAN patients derived from genomic and epigenomic studies. Moreover, we discuss the role of the microbiome in the disease. Finally, we suggest a new vision to consider IgA Nephropathy as a disease that is not disconnected from the environment in which we live but influenced, in addition to the genetic background, also by other environmental and behavioral factors that could be useful for developing precision nephrology and personalized therapy.

Encapsulation of Curcumin-Loaded Liposomes for Colonic Drug Delivery in a pH-Responsive Polymer Cluster Using a pH-Driven and Organic Solvent-Free Process.

The present study aimed to develop and optimize liposome formulation for the colonic delivery of biologically active compounds. A strategy to facilitate such targeting is to formulate liposomes with a polymer coating sensitive to the pH shifts in the gastrointestinal tract. To this end, liposomes encapsulating curcumin-chosen as the biologically active compound model-and coated with the pH-responsive polymer Eudragit S100 were prepared and characterized. Curcumin was encapsulated into small unilamellar vesicles (SUVs) by the micelle-to-vesicle transition method (MVT) in a simple and organic solvent-free way. Curcumin-loaded liposomes were coated with Eudragit S100 by a fast and easily scalable pH-driven method. The prepared liposomes were evaluated for size, surface morphology, entrapment efficiency, stability, in vitro drug release, and curcumin antioxidant activity. In particular, curcumin-loaded liposomes displayed size lower than 100 nm, encapsulation efficiency of 98%, high stability at both 4 °C and 25 °C, high in vitro antioxidant activity, and a cumulative release that was completed within 200 min. A good Eudragit S100 coating which did not alter the properties of the curcumin-loaded liposomes was obtained. The present work therefore provides a fast and solvent-free method to prepare pH-responsive polymer-coated liposomes for the colonic delivery of biologically active compounds.

Treatment continuation and satisfaction in women using combined oral contraception with nomegestrol acetate and oestradiol: a multicentre, prospective cohort study (BOLERO).

OBJECTIVE: The aim of the study was to examine treatment continuation and satisfaction over 1 year among women receiving nomegestrol acetate (NOMAC)/oestradiol (E2) combined oral contraception (COC) in real-world clinical practice. METHODS: The 17ß-Estradiol and Nomegestrol Acetate (BOLERO) Study is an observational, non-interventional, prospective, multicentre cohort study of premenopausal women (aged 18-50 years) who received prescription NOMAC/E2 (2.5 mg/1.5 mg) for contraception during routine clinical practice. Assessments were carried out at enrolment and at 3, 6 and 12 months. Probability of treatment continuation through 12 months (primary outcome) was examined using Kaplan-Meier survival analysis. Secondary outcomes included treatment satisfaction, menstrual cycle-related symptoms, libido and adverse events (AEs). RESULTS: Of 298 enrolled women, 292 were evaluable. The probability of NOMAC/E2 continuation through 12 months was 73.7% (95% confidence interval [CI] 68.0%, 78.5%). Satisfaction with NOMAC/E2 increased from 56.9% (37/65) of women at initial evaluation to 89.2% (58/65) of women at 12 months. Physician ratings at 12 months showed satisfactory to very satisfactory in 84.0% (168/200) of women. Libido was not affected. Menstrual cycle-related symptoms significantly declined from enrolment (6.04 ± 4.32) to 3 months (3.25 ± 3.05) and 12 months (2.62 ± 2.74; p < .0001). Treatment-related AEs were reported by 38.7% (113/292) of women. CONCLUSION: The real-world experience of women receiving NOMAC/E2 indicated very good treatment continuation, high satisfaction and significantly improved menstrual cycle-related symptoms.

Observational prospective study on Lactobacillus plantarum P 17630 in the prevention of vaginal infections, during and after systemic antibiotic therapy or in women with recurrent vaginal or genitourinary infections.

We performed a prospective cohort parallel observational study on the use of Lactobacillus plantarum P 17630 in the prevention of vaginal infections. Eligible were women with a diagnosis of bacterial vaginosis (<15 days) and documented history of recurrent vaginal infections; and/or cystitis (<15 days); and/or treatment with antibiotics for bacterial respiratory tract infections during the week before the study entry. Study subjects were prescribed Lactobacillus plantarum P 17630 > 100.000.000 UFC one vaginal capsule per day for 6 days, then a capsule per week for 16 weeks. Eligible subjects were enrolled in two parallel cohorts: 85 women using (group A) and 39 not using (group B) Lactobacillus plantarum P 17630. The risk of recurrent infection within 4 months from the study entry, was higher among untreated women: multivariate OR 2.6 (95%CI 0.7-9.4). The modification of presence/intensity or symptoms was significant in both the study groups (p < .001). Impact statement What is already known on this subject? The Lactobacillus plantarum P 17630 has been shown to be active in the treatment of bacterial vaginosis and vaginal candidiasis. No data are available on its efficacy in the prevention of recurrent vaginal or urological infection or as a prevention strategy during systemic treatment with antibiotics. What do the results of this study add? This observational study suggests that Lactobacillus plantarum given for 4 months may lower the risk of recurrent infection in women with recurrent vaginal or genitourinary infection or after antibiotic systemic treatment for bacterial respiratory tract infection. The finding, however, is not statistically significant, possibly due to the lower than expected rate of infection observed in our population and consequently the limited power of the study. What are the implications of these findings for clinical practice and/or further research? New studies are needed in order to evaluate in different populations the role of Lactobacillus plantarum in lowering the risk of recurrent infection in a high-risk populations.

Resistance of Dynamin-related Protein 1 Oligomers to Disassembly Impairs Mitophagy, Resulting in Myocardial Inflammation and Heart Failure.

We have reported previously that a missense mutation in the mitochondrial fission gene Dynamin-related protein 1 (Drp1) underlies the Python mouse model of monogenic dilated cardiomyopathy. The aim of this study was to investigate the consequences of the C452F mutation on Drp1 protein function and to define the cellular sequelae leading to heart failure in the Python monogenic dilated cardiomyopathy model. We found that the C452F mutation increased Drp1 GTPase activity. The mutation also conferred resistance to oligomer disassembly by guanine nucleotides and high ionic strength solutions. In a mouse embryonic fibroblast model, Drp1 C452F cells exhibited abnormal mitochondrial morphology and defective mitophagy. Mitochondria in C452F mouse embryonic fibroblasts were depolarized and had reduced calcium uptake with impaired ATP production by oxidative phosphorylation. In the Python heart, we found a corresponding progressive decline in oxidative phosphorylation with age and activation of sterile inflammation. As a corollary, enhancing autophagy by exposure to a prolonged low-protein diet improved cardiac function in Python mice. In conclusion, failure of Drp1 disassembly impairs mitophagy, leading to a downstream cascade of mitochondrial depolarization, aberrant calcium handling, impaired ATP synthesis, and activation of sterile myocardial inflammation, resulting in heart failure.