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Quantifying APOL1, Human Leukocyte Antigen, and Other Genetic Contributions to Unexplained Kidney Failure.

RATIONALE & OBJECTIVE: Unexplained kidney failure (uKF) affects 15% of individuals needing kidney replacement therapy. The lack of a clear diagnosis creates uncertainty about recurrence, familial risk, and trial eligibility. This study sought to identify genetic variants underlying uKF. STUDY DESIGN: Genomic analyses conducted using whole-genome sequencing (WGS) were reviewed by a multidisciplinary team that identified candidate pathogenic variants. A case-control study was implemented for single and structural variants to perform gene-based and polygenic risk score (PRS) association testing.

Comparison between the Regenerative and Therapeutic Impacts of Bone Marrow Mesenchymal Stem Cells and Adipose Mesenchymal Stem Cells Pre-Treated with Melatonin on Liver Fibrosis.

BACKGROUND: The distinctive feature of liver fibrosis is the progressive replacement of healthy hepatic cells by the extracellular matrix protein, which is abundant in collagen I and III, with impaired matrix remodeling. The activation of myofibroblastic cells enhances the fibrogenic response of complex interactions of hepatic stellate cells, fibroblasts, and inflammatory cells to produce the excessive deposition of the extracellular protein matrix. This process is activated by multiple fibrogenic mediators and cytokines, such as TNF-α and IL-1β, accompanied with a decrease in the anti-fibroge

Clinical Significance of the Cystic Phenotype in Alport Syndrome.

RATIONALE & OBJECTIVE: Alport syndrome (AS) is the most common genetic glomerular disease caused by mutations that affect type IV collagen. However, the clinical characteristics and significance of AS with kidney cysts are not well defined. This study investigated the prevalence and clinical significance of cystic kidney phenotype in AS. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: One hundred-eight patients with AS and a comparison cohort of 79 patients with IgA nephropathy (IgAN). Clinical, genetic, and imaging data were collected from medical records. EXPOSURE: Cysti

Circulating microRNAs as novel biomarkers for measuring the potency of ginger extract against cyclophosphamide toxicity in rat renal tissues: molecular and histopathological study.

OBJECTIVE: This study aims to explore underlying molecular variations in the expression of miRNAs in kidney tissues of ginger-treated and non-treated cyclophosphamide (CP)-intoxicated rats. MATERIALS AND METHODS: A total of 40 adult male Wistar rats were randomly divided into four groups of 10 each: Group I (control: received normal food and water), Group II (received ginger at a dose of 300 mg/kg), Group III (received CP 75 mg/kg, i.p.), and Group IV (received the same dose of CP and ginger extract).  Rats received a single injection of 75 mg/kg CP on days 3, 4, 5, 19, 20, and 21. In CP-into

Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment.

Ascorbic acid has attracted substantial attention for its potential antitumor effects by acting as an antioxidant in vivo and as a cofactor in diverse enzymatic reactions. However, solid proof of its clinical efficacy against cancer and the mechanism behind its effect have not been established. Moreover, cancer forms cancer-specific microenvironments and interacts with various cells, such as cancer-associated fibroblasts (CAFs), to maintain cancer growth and progression; however, the effect of ascorbic acid on the cancer microenvironment is unclear. This review discusses the effects and mechan

Development of clinical utility of zoledronic acid and patient considerations in the treatment of osteoporosis.

Osteoporosis is a major health concern, which results in the increased risk of fractures. There is a high risk for the first or consecutive fractures leading to considerable morbidity and debilitating consequences if osteoporosis is untreated. Currently, bisphosphonates are the mainstay of treatment for osteoporosis though long-term persistence and adherence to bisphosphonates, especially those taken orally, remain low. This medication noncompliance has serious consequences on osteoporotic patients as it is associated with a significantly higher fracture risk. Intravenous (IV) zoledronic acid

The anti-angiogenic tyrosine kinase inhibitor Pazopanib kills cancer cells and disrupts endothelial networks in biomimetic three-dimensional renal tumouroids.

Pazopanib is a tyrosine kinase inhibitor used to treat renal cell carcinoma. Few in vitro studies investigate its effects towards cancer cells or endothelial cells in the presence of cancer. We tested the effect of Pazopanib on renal cell carcinoma cells (CAKI-2,786-O) in two-dimensional and three-dimensional tumouroids made of dense extracellular matrix, treated in normoxia and hypoxia. Finally, we engineered complex tumouroids with a stromal compartment containing fibroblasts and endothelial cells. Simple CAKI-2 tumouroids were more resistant to Pazopanib than 786-O tumouroids. Under hypoxia

Matrix metalloproteinases and tissue inhibitors in multiple myeloma: promote or inhibit?

Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) play a vital role in the pathogenesis of multiple myeloma (MM), especially for tumor invasion and osteolytic osteopathy. By breaking down extracellular matrix (ECM) components and releasing the proteins composing the ECM and growth factors, as well as their receptors, MMPs affect tissue integrity and promote cancer cell invasion and metastasis. A vital pathophysiological characteristic of MM is the progress of osteolytic lesions, which are brought on by interactions between myeloma cells and the bone marrow mic

The Rationale for Using Neridronate in Musculoskeletal Disorders: From Metabolic Bone Diseases to Musculoskeletal Pain.

Neridronate or ((6-amino-1-hydroxy-1-phosphonohexyl) phosphonic acid) is an amino-bisphosphonate (BP) synthetized in Italy in 1986. Bisphosphonates are molecules with a P-C-P bond in their structure that allows strong and selectively binding to hydroxyapatite (HAP) as well as osteoclasts inhibition through different mechanisms of action. Neridronate was initially used to treat Paget disease of the bone, demonstrating effectiveness in reducing bone turnover markers as well as pain. The interesting molecular properties of neridronate foster its wide use in several other conditions, such as osteo

Re-Cellularised Kidney Scaffold for Chikungunya Virus Propagation: A Novel Approach.

BACKGROUND: Re-emerging viral attacks are catastrophic for health and economy. It is crucial to grasp the viral life cycle, replication and mutation policies and attack strategies. It is also absolute to fathom the cost-efficient antiviral remedies earliest possible. METHODS: We propose to use a lab-grown organ (re-cellularized scaffold of sheep kidney) for viral culture and understand its interaction with extra-cellular matrices of the host tissue. RESULTS: Our findings showed that the chikungunya virus (CHIKV) could be better replicated in tissue-engineered bio models than cell culture. A

Megakaryocyte Contribution to Bone Marrow Fibrosis: many Arrows in the Quiver.

In Primary Myelofibrosis (PMF), megakaryocyte dysplasia/hyperplasia determines the release of inflammatory cytokines that, in turn, stimulate stromal cells and induce bone marrow fibrosis. The pathogenic mechanism and the cells responsible for progression to bone marrow fibrosis in PMF are not completely understood. This review article aims to provide an overview of the crucial role of megakaryocytes in myelofibrosis by discussing the role and the altered secretion of megakaryocyte-derived soluble factors, enzymes and extracellular matrices that are known to induce bone marrow fibrosis.

Anti-Tubular Basement Membrane Antibody Nephritis Manifesting in a Patient With Chronic Lymphocytic Leukemia: A Very Rare Case Report.

Anti-tubular basement membrane (anti-TBM) antibody nephritis is a rare type of tubulointerstitial nephritis associated with progressive decline in kidney function. It is characterized histopathologically by tubular atrophy and dilation, interstitial fibrosis, lymphocyte and macrophage-predominant cellular infiltration, and linear deposition of IgG and complement along the tubular basement membrane. We herein present a case of a 69-year-old male who was recently diagnosed with chronic lymphocytic leukemia (CLL) and was referred for evaluation of kidney failure, ultimately diagnosed as anti-TBM

Advances in Extracellular Matrix-Associated Diagnostics and Therapeutics.

The extracellular matrix (ECM) is the common denominator of more than 50 chronic diseases. Some of these chronic pathologies lead to enhanced tissue formation and deposition, whereas others are associated with increased tissue degradation, and some exhibit a combination of both, leading to severe tissue alterations. To develop effective therapies for diseases affecting the lung, liver, kidney, skin, intestine, musculoskeletal system, heart, and solid tumors, we need to modulate the ECM's composition to restore its organization and function. Across diverse organ diseases, there are common denom

Targeting strategies for bone diseases: signaling pathways and clinical studies.

Since the proposal of Paul Ehrlich's magic bullet concept over 100 years ago, tremendous advances have occurred in targeted therapy. From the initial selective antibody, antitoxin to targeted drug delivery that emerged in the past decades, more precise therapeutic efficacy is realized in specific pathological sites of clinical diseases. As a highly pyknotic mineralized tissue with lessened blood flow, bone is characterized by a complex remodeling and homeostatic regulation mechanism, which makes drug therapy for skeletal diseases more challenging than other tissues. Bone-targeted therapy has b

Selective JAK2/ABL dual inhibition therapy effectively eliminates TKI-insensitive CML stem/progenitor cells.

Polymyalgia rheumatica (PMR) is a common disorder in the elderly population. The diagnosis is based upon recognition of a clinical syndrome, consisting of pain and stiffness in the shoulder and pelvic girdle, muscle tenderness of the upper and lower limbs and nonspecific somatic complaints. In addition, in most cases the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration are highly elevated. Although PMR and giant cell arteritis (GCA) are commonly regarded as two clinical variations of the same disease, their clinical picture is quite different. Whilst in PMR the m

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… Gene encoding collagen Type IV (COL1A1) was investigated in 2008 (Zhao et al. 2008 ). The results of this study show that expression of COL1A1 on mRNA levels is significantly higher in patients with ICTEV than in healthy patients. …

Biological implant-associated granulomatous inflammation resulting in secondary hypercalcemia and azotemia in a dog.

Implant associated granulomatous inflammation causing hypercalcemia can occur following use of commercial xenogeneic pericardial tissue patches in dogs. Removal of the implant can result in resolution of the hypercalcemia, suggesting a causal relationship between the tissue reaction to a xenogeneic implant and development of hypercalcemia.

Mesenchymal stem cells: A new therapeutic tool for chronic kidney disease.

Chronic kidney disease (CKD) has a major impact on public health, which could progress to end-stage kidney disease (ESRD) and consume many medical resources. Currently, the treatment for CKD has many flaws, so more effective treatment tools are urgently required for CKD. Mesenchymal stem cells (MSCs) are primitive cells with self-renewal and proliferation capacity and differentiation potential. Extensive preclinical and clinical data has shown that cell-based therapies using MSCs can modulate immunity, inhibit inflammatory factors, and improve renal function in CKD, suggesting that MSCs have t

High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer.

Mounting evidence indicates that vitamin C has the potential to be a potent anti-cancer agent when administered intravenously and in high doses (high-dose IVC). Early phase clinical trials have confirmed safety and indicated efficacy of IVC in eradicating tumour cells of various cancer types. In recent years, the multi-targeting effects of vitamin C were unravelled, demonstrating a role as cancer-specific, pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator, reversing epithelial-to-mesenchymal transition, inhibiting hypoxia and oncogenic kinase signalling and b

SOX9 Induces Orbital Fibroblast Activation in Thyroid Eye Disease Via MAPK/ERK1/2 Pathway.

PurposeTo evaluate the expression of sry-box transcription factor 9 (SOX9) in orbital fibroblasts (OFs) of thyroid eye disease (TED) and to find its potential role and underlying mechanism in orbital fibrosis.MethodsOFs were cultured from orbital connective tissues obtained from patients with TED (n = 10) and healthy controls (n = 6). SOX9 was depleted by small interfering RNA or overexpressed through lentivirus transduction in OFs. Fibroblast contractile activity was measured by collagen gel contraction assay and proliferation was examined by EdU assay. Transcriptomic changes were assessed by

Exosomes for angiogenesis induction in ischemic disorders.

Ischaemic disorders are leading causes of morbidity and mortality worldwide. While the current therapeutic approaches have improved life expectancy and quality of life, they are unable to "cure" ischemic diseases and instate regeneration of damaged tissues. Exosomes are a class of extracellular vesicles with an average size of 100-150 nm, secreted by many cell types and considered a potent factor of cells for paracrine effects. Since exosomes contain multiple bioactive components such as growth factors, molecular intermediates of different intracellular pathways, microRNAs and nucleic acids, t