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Graphical abstract Highlights • This study is aimed to establish a scientific basis for the anti-urolithiatic property of Terminalia arjuna. • Aqueous extract of T. arjuna bark was evaluated against oxalate injured renal tubular epithelial cells using in vitro model system. • The aqueous extract significantly improved the cell viability in a dose dependent manner. • The aqueous extract effectively attenuated the retention of CaOx crystals to apical surface of renal cells. • The aqueous extract substantially diminished oxalate induced apoptotic death. Abstract Previous studies have shown that hyperoxaluria is concomitant with the formation of CaOx crystals and the subsequent propensity of these crystals towards renal cells greatly increases the risk for the development of urolithiasis. Despite advances in surgical management, recurrence of stones and side effects of present day treatment persists and in the light of this a cost-effective substitute from natural sources such as phytotherapy is being sought. The present study was designed to investigate the antiurolithiatic efficacy of a single plant preparation comprising of an aqueous extract (AE) of the bark of Terminalia arjuna (T. arjuna) on oxalate injured cells. The authors used an in vitro model system comprising of a normal epithelial cell line (NRK-52E) which was exposed to 2 mM oxalate for 48 h, following which the cytoprotective potential of AE on cell viability, CaOx crystal adherence and apoptotic changes were evaluated. The results revealed that co-treatment with T. arjuna AE to cells exposed to 2 mM oxalate for 48 h, rendered protection from oxalate triggered damage. On treatment with different concentrations of the T. arjuna AE, the cell viability increased in a concentration dependent manner. Moreover, the extract prevented the interaction of the CaOx crystals to the cell surface and reduced the number of apoptotic cells. The current data suggests that T. arjuna bark aqueous extract could be a potential phytotherapeutic treatment against urolithiasis based on its ability to diminish oxalate induced morphological changes, apoptosis and death of renal cells thereby leading to cell survival. [ABSTRACT FROM AUTHOR]

Data collected from large-scale studies has shown that the incidence of prostate cancer globally is on the rise, which could be attributed to an overall increase in lifespan. So, the question is how has modern science with all its new technologies and clinical breakthroughs mitigated or managed this disease? The answer is not a simple one as prostate cancer exhibits various subtypes, each with its unique characteristics or signatures which creates challenges in treatment. To understand the complexity of prostate cancer these signatures must be deciphered. Molecular studies of prostate cancer samples have identified certain genetic and epigenetic alterations, which are instrumental in tumorigenesis. Some of these candidates include the androgen receptor (AR), various oncogenes, tumor suppressor genes, and the tumor microenvironment, which serve as major drivers that lead to cancer progression. These aberrant genes and their products can give an insight into prostate cancer development and progression by acting as potent markers to guide future therapeutic approaches. Thus, understanding the complexity of prostate cancer is crucial for targeting specific markers and tailoring treatments accordingly. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims Kidney stone formation is a highly prevalent disease, affecting 8–10% of the human population worldwide. Proteins are the major constituents of human kidney stone's organic matrix and considered to play critical role in the pathogenesis of disease but their mechanism of modulation still needs to be explicated. Therefore, in this study we investigated the effect of human kidney stone matrix proteins on the calcium oxalate monohydrate (COM) mediated cellular injury. Main methods The renal epithelial cells (MDCK) were exposed to 200 μg/ml COM crystals to induce injury. The effect of proteins isolated from human kidney stone was studied on COM injured cells. The alterations in cell-crystal interactions were examined by phase contrast, polarizing, fluorescence and scanning electron microscopy. Moreover, its effect on the extent of COM induced cell injury, was quantified by flow cytometric analysis. Key findings Our study indicated the antilithiatic potential of human kidney stone proteins on COM injured MDCK cells. Flow cytometric analysis and fluorescence imaging ascertained that matrix proteins decreased the extent of apoptotic injury caused by COM crystals on MDCK cells. Moreover, the electron microscopic studies of MDCK cells revealed that matrix proteins caused significant dissolution of COM crystals, indicating cytoprotection against the impact of calcium oxalate injury. Significance The present study gives insights into the mechanism implied by urinary proteins to restrain the pathogenesis of kidney stone disease. This will provide a better understanding of the formation of kidney stones which can be useful for the proper management of the disease. [ABSTRACT FROM AUTHOR]

Urinary glycoproteins such as Tamm Horsfall Protein (THP) and Osteopontin (OPN) are well established key regulators of renal stone formation. Additionally, recent revelations have highlighted the influence of Endoplasmic Reticulum (ER) and mitochondria of crucial importance in nephrolithiasis. However, till date conclusive approach highlighting the influence of ER stress on urinary glycoproteins and chaperone in nephrolithiasis remains elusive. Therefore, the present study was focussed on deciphering the possible effect of 4-PBA mitigating ER stress on urinary glycoproteins and calnexin (chaperone) with emphasis on interlinking calcium homeostasis in hyperoxaluric rats. Post 9 days of treatment, animals were sacrificed, and renal tissues were investigated for urinary glycoproteins, calnexin, calcium homeostasis, ER environment, redox status, and mitochondrial linkage. 4-PBA appreciably reversed the altered levels of THP, OPN, and calnexin observed along with curtailing the disrupted calcium homeostasis when assessed for SERCA activity and intra-cellular calcium levels. Additionally, significant improvement in the perturbed ER environment as verified by escalated ER stress markers, disturbed protein folding-aggregation-degradation (congo red assay) pathway, and redox status was found post 4-PBA intervention. Interestingly, linkage of ER stress and mitochondria was established under hyperoxaluric conditions when assessed for protein levels of VDAC1 and GRP75. 4-PBA treatment resulted in rectifying the repercussions of ER-mitochondrial caused distress when assessed for protein folding/aggregation/degradation events along with disturbed calcium homeostasis. The present study advocates the necessity to adopt a holistic vision towards hyperoxaluria with emphasis on glycoproteins and ER environment. [Display omitted] • Hyperoxaluric conditions affect the protein folding capacity. • 4-PBA rectified the levels of Tamm Horsfall Protein, Osteopontin, and Calnexin. • 4-PBA rescued the disrupted ER-Mitochondrial functioning, and calcium homeostasis. • Establishment of inter-linkage between GRP78, Ca2+ Channels/Pump, VDAC-1 and GRP75. • Inhibiting Endoplasmic Reticulum stress curtailed the progression of hyperoxaluria. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Many medicinal plants have been employed during ages to treat urinary stones though the rationale behind their use is not well established. Recently, we have successfully purified an anticalcifying protein from the seeds of Trachyspermum ammi (L.) Sprague ex Turril (Umbelliferae) using oxalate depletion assay and deciphered its inhibitory activity against calcium oxalate crystal growth. Aim: In this report, the antilithiatic activity of Trachyspermum ammi anticalcifying protein (TAP) was studied in urolithiatic rat model. Methodology: Urolithiasis was induced by exposure of 0.4% ethylene glycol (EG) and 1.0% ammonium chloride (NH4Cl) for 9 days. The efficacy of TAP was studied in another group given same dose of EG and NH4Cl in addition to 2mg/kg body weight of TAP. Further, we evaluated ability of TAP to inhibit the attachment of calcium oxalate (CaO x ) crystal in kidney tissue and studied the consequences of CaO x adhesion on renal functioning and tissue integrity. Results: The antilithiatic potential of TAP was confirmed by its ability to maintain renal functioning, reduce renal injury and decrease crystal excretion in urine and retention in renal tissues. Conclusions: Thus, the present investigation suggests the potential of TAP in preventing calcium oxalate deposition and forms the basis for the development of antilithiatic drug interventions against urolithiasis. [Copyright &y& Elsevier]

Abstract: Hyperoxaluria is a condition where excessive oxalate is present in the urine. Many reports have documented free radical generation followed by hyperoxaluria as a consequence of which calcium oxalate deposition occurs in the kidney tissue. The present in vivo study was designed to investigate the potential of N-acetylcysteine in modulating hyperoxaluric manifestation induced by sodium oxalate in the rat kidneys. Male wistar rats in one group were administered single dose of sodium oxalate (70mg/kg body weight) intraperitoneally to induce hyperoxaluric conditions and in the other group, rats were injected N-acetylcysteine (NAC) (200mg/kg body weight) intraperitoneally, half an hour after sodium oxalate dose. The treatment is for a period of 24h. N-acetylcysteine significantly reduced hyperoxaluria caused oxidative stress by reducing lipid peroxidation, restoring antioxidant enzymes activity in kidney tissue, followed by reduction in impairment of renal functioning. In addition, NAC administration reduced the number of calcium oxalate monohydrate (COM) crystals in the urine as observed under polarization microscope. Histological analysis depicted that NAC treatment decreased renal epithelial damage, inflammation and restored normal glomeruli morphology. Thus, it shows that use of an extraneous antioxidant may prove beneficial for combating the conditions of oxidative stress produced by hyperoxaluria. [Copyright &y& Elsevier]

In the Indian traditional system of medicine, Bergenia ligulata (Wall.) Engl. has been used for treatment of urolithiasis. Its efficacious nature has led to its incorporation in various commercial herbal formulations such as Cystone and Neeri which are prescribed for kidney related ailments. To assess whether ethanolic extract of B. ligulata can mitigate the cascade of inflammatory responses that cause oxidative stress and ultimately cell death in renal epithelial cells exposed to hyperoxaluric conditions. Bioactivity guided fractionation using solvents of varying polarities was employed to evaluate the potential of the extracts of B. ligulata to inhibit the crystallization process. Modulation of crystal morphology was visualized through Scanning electron microscopy (SEM) analysis. Cell death was assessed using flow cytometry based assays. Alteration in the inflammatory mediators was evaluated using real time PCR and immunocytochemistry. Phytochemical characterization of the ethanolic extract was carried out using FTIR, LC-MS and GC-MS. Bioactivity guided fractionation for the assessment of antilithiatic activity revealed dose dependent inhibition of nucleation and aggregation process of calcium oxalate crystals in the presence of various extracts, however ethanolic extract showed maximum inhibition and was chosen for further experiments. Studies on renal epithelial NRK-52E cells showed, cytoprotective efficacy of B. ligulata extract against oxalate injury. SEM anaysis further revealed the potential of the extract to modulate the crystal structure and adhesion to renal cell surface. Exposure of the renal cells to the extract led to conversion of the calcium oxalate monohydrate (COM) crystals to the less injurious calcium oxalate dihydrate (COD) form. Expression analysis for oxidative stress and inflammatory biomarkers in NRK-52E cells revealed up-regulation of Mitogen activated protein kinase (MAPK), Osteopontin (OPN) and Nuclear factor- ĸB (NF-ĸB), in response to calcium oxalate insult; which was drastically reduced in the presence of B. ligulata extract. Flow cytometric evaluation pointed to caspase 3 mediated apoptotic cell death in oxalate injured cells, which was attenuated by B. ligulata extract. Considering the complex multifactorial etiology of urolithiasis, ethanolic extract from B. ligulata can be a promising option for the management of kidney stones, as it has the potential to limit inflammation and the subsequent cell death. [Display omitted] [ABSTRACT FROM AUTHOR]

Increased levels of urinary oxalate also known as hyperoxaluria, increase the likelihood of kidney stone formation through enhanced calcium oxalate (CaOx) crystallization. The management of lithiatic renal pathology requires investigations at the initial macromolecular stages. Hence, the current study was designed to unravel the protein make-up of human kidney stones and its impact on renal cells' altered proteome, induced as the consequence of CaOx injury. CaOx kidney stones were collected from patients; stones were pooled for entire cohort, followed by protein extraction. Immunocytochemistry, RT-PCR and flow-cytometric analysis revealed the promising antilithiatic activity of kidney stone matrix proteins. The iTRAQ analysis of renal cells showed up-regulation of 12 proteins and down-regulation of 41 proteins due to CaOx insult, however, this differential expression was normalized in the presence of kidney stone matrix proteins. Protein network analysis revealed involvement of up-regulated proteins in apoptosis, calcium-binding, inflammatory and stress response pathways. Moreover, seven novel antilithiatic proteins were identified from human kidney stones' matrix: Tenascin-X-isoform2, CCDC-144A, LIM domain kinase-1, Serine/Arginine receptor matrix protein-2, mitochondrial peptide methionine sulfoxide reductase, volume-regulated anion channel subunit-LRRC8A and BMPR2. In silico analysis concluded that these proteins exert antilithiatic potential through crystal binding, thereby inhibiting the crystal-cell interaction, a pre-requisite to initiate inflammatory response. Thus, the outcomes of this study provide insights into the molecular events of CaOx induced renal toxicity and subsequent progression into nephrolithiasis. • The human kidney stone matrix proteins have an important role in modulating various processes of CaOx crystallization • We identified seven novel proteins from the matrix of CaOx kidney stones with promising activity against crystallization • Kidney stone matrix proteins normalized the differential expression of various proteins in COM treated renal cells [ABSTRACT FROM AUTHOR]