Search Results (33)

Kidney stone disease is a common urinary system disorder with a continuously rising global incidence, posing a major public health challenge. As a classic traditional Chinese medicine for the treatment of kidney stones, Lysimachia christinae Hance (LCH) has not yet been fully elucidated in terms of its pharmacological mechanism. In this study, a rat model of calcium oxalate kidney stones and a calcium oxalate monohydrate (COM)-induced injury model of human renal tubular epithelial (HK-2) cells were established. Combined with transcriptomic analysis and experimental verification, the therapeutic effect and underlying molecular mechanism of LCH against kidney stones were systematically explored. Results demonstrated that LCH extract significantly reduced serum levels of blood urea nitrogen (BUN) and creatinine (Cr), as well as renal tissue levels of kidney injury molecule-1 (KIM-1) and cystatin-C (Cys-C) in rats with calcium oxalate crystal-induced renal injury, and diminished calcium oxalate crystal deposition and adhesion in rat renal tissues as well as HK-2 cells, thus exerting a robust renoprotective effect. Mechanistically, transcriptome sequencing indicated that the anti-nephrolithiasis effect of LCH was closely related to the inhibition of oxidative stress and ferroptosis. LCH extract reversed CaOx crystal-induced upregulation of NADPH oxidase 2 (NOX2) and downregulation of superoxide dismutase 2 (SOD2), reduced intracellular oxygen species (ROS) levels, downregulated the expression of transferrin receptor 1 (TFR1) and acyl-CoA synthetase long-chain family member 4 (ACSL4) while upregulating that of ferritin heavy chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), and diminished intracellular iron accumulation, thereby effectively ameliorating crystal-mediated renal injury. The present study demonstrates that the therapeutic effect of LCH on kidney stones is closely related to the regulation of the NOX2/ROS signaling axis and ferroptosis, providing novel theoretical evidence for its clinical application. Full article

Pesticide exposure is a plausible but incompletely characterized contributor to kidney injury. This review integrates current clinical, epidemiologic, experimental, and mechanistic evidence on pesticide-related nephrotoxicity, focusing on glyphosate-based herbicides, paraquat, organophosphate insecticides, and atrazine. A structured search of PubMed and Web of Science identified English-language studies published between January 2015 and February 2026. Of 635 records screened, 61 human studies were retained for full-text evaluation, and relevant animal, in vitro, and regulatory sources were additionally reviewed for mechanistic interpretation. Across pesticide classes, the proximal tubule emerged as the most consistent renal target, although downstream pathways differed, including oxidative stress, mitochondrial dysfunction, transporter disruption, endoplasmic reticulum stress, inflammation, apoptosis, ferroptotic signaling, and fibrotic remodeling. Human evidence was strongest for acute kidney injury following severe poisoning, whereas associations between chronic occupational or environmental exposure and chronic kidney disease or end-stage renal disease were more limited and heterogeneous. Biomarkers including kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), β₂-microglobulin, cystatin C, interleukin-18 (IL-18), cytochrome c, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) often detected early tubular stress before abnormalities appeared in conventional renal indices. Overall, pesticide nephrotoxicity is best conceptualized as a spectrum of mechanism-specific tubular injury signatures, supporting a shift toward biomarker-informed early detection, improved hazard identification, and more mechanistically grounded risk assessment. Full article

Due to the limitations of conventional antibiotics, antimicrobial peptides (AMPs) have emerged as promising therapeutic alternatives for the prevention and treatment of oral infections. This study systematically evaluated in vitro evidence regarding the antimicrobial and anti-biofilm activity of natural AMPs against oral pathogens. A systematic search using the PICOT strategy was conducted in PubMed, EMBASE, and Scopus, retrieving 7711 articles. After title and abstract screening, 109 studies were selected for full-text analysis, resulting in 26 articles that met the eligibility criteria. Among the AMPs evaluated, nisin (n = 15) and LL-37 (n = 5) were the most frequently investigated, while other peptides included lactoferrin, lactoferricin, melittin, lysozyme, histatin-5, cystatin C, chromogranin A, parasin-1, protamine, AmyI-1-18, and DCD-1L. Natural AMPs of human and animal origin demonstrated antimicrobial activity against bacteria associated with oral infections, particularly Streptococcus mutans and Enterococcus faecalis. These peptides were tested in different formulations, including solutions, incorporation into dental materials and polymers, and application in sonodynamic antimicrobial therapy. Overall, the findings indicate that natural AMPs represent a promising class of biomolecules for controlling oral biofilms; however, further clinical studies are required to validate their long-term efficacy and safety. Full article

Human immunodeficiency virus (HIV) infection remains a major health burden in Sub-Saharan Africa, despite the widespread use of antiretroviral therapy (ART). Oxidative stress contributes to HIV-related comorbidities, including renal dysfunction. However, the role of oxidative stress in kidney impairment among people living with HIV (PLWH) is not fully understood. This cross-sectional study included PLWH on ART (n = 80), PLWH without ART (n = 27), and people not living with HIV (PNLWH) (n = 44). Oxidative stress was measured by serum malondialdehyde (MDA), superoxide dismutase (SOD) and total antioxidant capacity (TAC), while renal function was assessed using cystatin C-based estimated glomerular filtration rate (eGFR_cystC). Participants on ART were older (median 43 years) and had higher CD4+ T-cell counts compared to those not on ART. PLWH on ART showed significantly elevated MDA levels compared to PLWH without ART (p < 0.001) and PNLWH (p = 0.001). There was no difference in superoxide dismutase (SOD) and TAC levels among the groups (p = 0.177 and 0.888, respectively). Among PLWH, MDA was higher in those with reduced renal function (eGFR_cystC < 90) versus normal function (p < 0.05). In PLWH on ART, SOD activity was significantly lower in mild renal impairment (eGFR_cystC 60–89) compared to normal function (p = 0.017), but no difference was observed in the TAC levels (p = 0.883). In PLWH on ART, regression analyses indicated no independent association between MDA and renal function decline, while higher SOD activity independently predicted better renal function (adjusted β = 2.26, p = 0.042). Oxidative damage accompanied by the inability of the body’s primary antioxidant defenses may be present at the early onset of renal function decline in PLWH. Superoxide dismutase, as an antioxidant defence enzyme, may be a key contributor to renal health in PLWH on ART. Future studies with larger cohorts and longitudinal designs are needed to clarify these relationships emanating from this pilot study. Full article

Chronic kidney disease (CKD) is associated with heart failure and neurological disorders. Therefore, point-of-care (POC) detection of CKD is essential, allowing disease monitoring from home and alleviating healthcare professionals’ workload. Lateral flow immunoassays (LFIAs) facilitate POC testing for a renal function biomarker, serum Cystatin C (CysC). LF devices were fabricated and optimised by varying the diluted sample volume, the nitrocellulose (NC) membrane, bed volume, AuNPs’ OD value and volume, and assay formats of partial or full LF systems. Notably, 310 samples were analysed to satisfy the minimum sample size for statistical calculations. This allowed for a comparison between the LFIAs’ results and the general Roche standard assay results from the Southern Health and Social Care Trust. Bland–Altman plots indicated the LFIAs measured 0.51 mg/L lower than the Roche assays. With the 95% confidence interval, the Roche method might be 0.24 mg/L below the LFIAs’ results or 1.27 mg/L above the LFIAs’ results. In summary, the developed non-fluorescent LFIAs could detect clinical CysC values in agreement with Roche assays. Even though the developed LFIA had an increased bias in low CysC concentration (below 2 mg/L) detection, the developed LFIA can still alert patients at the early stages of renal function impairment. Full article

Kidney disorders significantly contribute to morbidity and mortality in sickle cell disease (SCD). Acute kidney injury (AKI), a major risk factor for chronic kidney disease (CKD), often arises from intravascular hemolysis, where plasma cell-free heme drives AKI through inflammatory and oxidative stress mechanisms. Hydroxyurea (HU), a well-established SCD-modifying therapy, improves clinical outcomes, but its effects on systemic heme and inflammatory mediators of kidney injury remain underexplored. This study evaluated HU’s impact on plasma heme, pro-inflammatory mediators, kidney injury, and renal histopathology in a sickle cell mouse model. Townes humanized sickle cell mice (HbSS) and non-sickle (HbAA) controls were treated with HU or vehicle for two weeks. HU significantly reduced total plasma heme, lactate dehydrogenase, and pro-inflammatory cytokines (CXCL10, VEGF-A, IFN-γ) in HbSS mice. HU reduced renal injury biomarkers (cystatin C, NGAL) and improved renal histopathology, evidenced by reduced vascular congestion, glomerulosclerosis, and tubular damage. Interestingly, HU did not alter the levels of kidney repair biomarkers (clusterin and EGF). These findings suggest that HU mitigates kidney injury by reducing the deleterious effects of circulating heme and inflammation, supporting its potential to slow or prevent progressive kidney injury in SCD. Full article

In individuals with type 2 diabetes mellitus (T2DM), elevated levels of both plasma and urinary cystatin C (Cys-C) contribute to increased oxidation, which in turn accelerates the oxidation of low-density lipoprotein (LDL). This process may worsen the development of atherosclerosis and cardiovascular disease by promoting endothelial dysfunction and inflammation. Despite its potential significance, the relationship between Cys-C and oxidized LDL (ox-LDL) in T2DM remains poorly understood. This study investigated the relationship between plasma and urinary Cys-C and ox-LDL levels in T2DM patients. The cohort included 57 patients with T2DM (mean age 61.14 ± 9.99 years; HbA1c 8.66 ± 1.60% and BMI 35.15 ± 6.65 kg/m²). Notably, 95% of the patients had hypertension, 82% had dyslipidemia, 59% had an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², 14% had coronary artery disease (CAD), and 5% had a history of stroke. Plasma and urinary Cys-C and ox-LDL levels were measured using ELISA. Adipokine and cytokine levels were measured using the multiplex^® MAP Human Adipokine Magnetic Bead Panels. Spearman’s correlation analysis revealed a significant positive correlation of plasma and urinary Cys-C with ox-LDL (r = 0.569, p = 0.0001 and r = 0.485, p = 0.0001, respectively). Multivariable regression analysis indicated that both plasma and urinary Cys-C were independently associated with ox-LDL, after adjusting for confounding factors (β = 0.057, p = 0.0001 and β = 0.486, p = 0.003, respectively). Stepwise linear regression identified TNFα and adiponectin as the strongest predictors of the relationship between urinary Cys-C and ox-LDL (β = 0.382, p = 0.0001; r² = 0.64), while adiponectin alone was the best predictor of the plasma Cys-C and ox-LDL association (β = 0.051, p = 0.005; r² = 0.46). Furthermore, adiponectin partly mediated the relationship between plasma Cys-C and ox-LDL, explaining 18% of the variance in this association. In contrast, TNFα partly mediated the relationship between urinary Cys-C and ox-LDL, accounting for 28% of the variance. This study emphasizes the complex interaction between Cys-C and ox-LDL in T2DM. It highlights the need for additional research involving larger patient cohorts to improve our understanding of the therapeutic potential of plasma and urinary Cys-C in conjunction with ox-LDL for managing complications associated with T2DM. Full article

Sepsis-associated acute kidney injury (SA-AKI) is defined as the development of AKI in the context of a potentially life-threatening organ dysfunction attributed to an abnormal immune response to infection. SA-AKI has been associated with increased mortality when compared to sepsis or AKI alone. Therefore, its early recognition is of the utmost importance in terms of its morbidity and mortality rates. The aim of this review is to shed light on the pathophysiological pathways implicated in SA-AKI as well as its diagnostics and therapeutics. In this review, we will elucidate upon serum and urinary biomarkers, such as creatinine, cystatin, neutrophil gelatinase-associated lipocalin (NGAL), proenkephalin A 119–159, interleukin-6, interleukin-8 and interleukin-18, soluble toll-like receptor 2 (sTLR2), chemokine ligand 2 (CCL2) and chemokine C-C-motif 14 (CCL14). In addition, the role of RNA omics as well as machine learning programs for the timely diagnosis of SA-AKI will be further discussed. Moreover, regarding SA-AKI treatment, we will elaborate upon potential therapeutic agents that are being studied, based on the pathophysiology of SA-AKI, in humans and in animal models. Full article

Cystatin F (CstF) is a protease inhibitor of cysteine cathepsins, including those involved in activating the perforin/granzyme cytotoxic pathways. It is targeted at the endolysosomal pathway but can also be secreted to the extracellular milieu or endocytosed by bystander cells. CstF was shown to be significantly increased in tuberculous pleurisy, and during HIV coinfection, pleural fluids display high viral loads. In human macrophages, our previous results revealed a strong upregulation of CstF in phagocytes activated by interferon γ or after infection with Mycobacterium tuberculosis (Mtb). CstF manipulation using RNA silencing led to increased proteolytic activity of lysosomal cathepsins, improving Mtb intracellular killing. In the present work, we investigate the impact of CstF depletion in macrophages during the coinfection of Mtb-infected phagocytes with lymphocytes infected with HIV. The results indicate that decreasing the CstF released by phagocytes increases the major pro-granzyme convertase cathepsin C of cytotoxic immune cells from peripheral blood-derived lymphocytes. Consequently, an observed augmentation of the granzyme B cytolytic activity leads to a significant reduction in viral replication in HIV-infected CD4⁺ T-lymphocytes. Ultimately, this knowledge can be crucial for developing new therapeutic approaches to control both pathogens based on manipulating CstF. Full article

A phospholipid bilayer is a typical structure that serves crucial functions in various cells and organelles. However, it is not unusual for it to take part in pathological processes. The cell membrane may be a binding target for amyloid-forming proteins, becoming a factor modulating the oligomerization process leading to amyloid deposition—a hallmark of amyloidogenic diseases—e.g., Alzheimer’s disease. The information on the mechanisms governing the oligomerization influenced by the protein–membrane interactions is scarce. Therefore, our study aims to describe the interactions between DPPA, a cell membrane mimetic, and amyloidogenic protein human cystatin C. Circular dichroism spectroscopy and differential scanning calorimetry were used to monitor (i) the secondary structure of the human cystatin C and (ii) the phase transition temperature of the DPPA, during the protein–membrane interactions. NMR techniques were used to determine the protein fragments responsible for the interactions, and molecular dynamics simulations were applied to provide a molecular structure representing the interaction. The obtained data indicate that the protein interacts with DPPA, submerging itself into the bilayer via the AS region. Additionally, the interaction increases the content of α-helix within the protein’s secondary structure and stabilizes the whole molecule against denaturation. Full article

Cystatin C, ammonia, and bicarbonate have been described to be biomarkers of sepsis and inflammation in humans. The saliva of pigs can be used to detect a wide range of pathogens but also many biomarkers that can be analyzed to evaluate different conditions such as stress (i.e., cortisol and alpha amylase), immune system (i.e., ADA, S100 proteins), inflammation (i.e., acute phase proteins), redox status (i.e., various antioxidants and oxidants), and general metabolism or the status of different organs and tissues. However, there is a lack of assays for the possible measurement and use of cystatin C, ammonia, and bicarbonate in saliva as biomarkers of sepsis or inflammation in pigs. The objective of this study was to validate commercially available automated assays for the measurement of cystatin C, ammonia, and bicarbonate in the saliva of pigs, having the advantage of using a noninvasive sample that is easy to collect. The assays were precise and accurate, and the recommended storage condition for the saliva samples was −80 °C. In addition, cystatin and ammonia showed significant increases in the saliva of pigs with S. suis infection, whereas bicarbonate decreased. Further studies would be recommended to increase knowledge about the possible potential applications of the measurements of these three analytes in the saliva of pigs as biomarkers to evaluate the animals’ health and welfare. Full article

A high incidence of cholangiocarcinoma (bile duct cancer) has been observed in Thailand. This usually rare cancer has been associated with infection with the human liver fluke, Opisthorchis viverrini. Secretions of the parasite that interact with the host are thought to be a major component of its pathogenicity and proteolysis is a key biological activity of the secreted molecules. In this study, we present a molecular analysis of cysteine proteinase inhibitors (cystatins) of Opisthorchis viverrini. Six cDNA coding sequences of Opisthorchis viverrini cystatins, OvCys1–6, were cloned from the adult stage of the parasite using RT-PCR. Based on their sequences, OvCys1 and OvCys2 are classified as type 1 cystatins, while OvCys3–6 are classified as type 2 cystatins, with each containing a signal peptide and only one C-terminal disulfide bond. Their C-terminal region sequences are diverse compared with other cystatin members. Cystatins OvCys1, 3 and 4 were found in crude worm extracts and excretory-secretory (ES) products from the adult parasite using Western blot detection, while the other isoforms were not. Thus, OvCys1, 3 and 4 were selected for inhibition analysis and immune reactivity with Opisthorchis viverrini-infected hamster sera. OvCys1, 3, and 4 inhibited mammalian cathepsin L more effectively than cathepsin B. The pH range for their full activity was very wide (pH 3–9) and they were heat stable for at least 3 h. Unlike Fasciola gigantica cystatins, they showed no immune reactivity with infected hamster sera based on indirect ELISA. Our findings suggest that Opisthorchis viverrini cystatins are not major antigenic components in the ES product of this parasite and that other effects of Opisthorchis viverrini cystatins should be investigated. Full article

Africa, particularly sub-Sharan Africa (SSA), faces major challenges in respect to chronic kidney disease (CKD). There is a rising prevalence due to the combined effects of hypertension, diabetes, and human immunodeficiency virus (HIV) (and the interaction between them) and the effect of apolipoprotein L1 (APOL1) variants on the susceptibility to CKD. Epidemiological data on the prevalence of CKD are of low-to-medium quality, and reliable data are urgently needed for health planning. Furthermore, there are important deficiencies in creatinine-based equations in underestimating the prevalence of CKD in Africa, and evidence suggests that cystatin C based equations are more reliable. There is a changing spectrum of HIV related CKD with the greater availability of antiretroviral treatment. Major clinical trials using SGLT2 inhibitors have signalled a major advance in the treatment of CKD, especially in relation to type 2 diabetes, but the affordability, availability, and relevance to the African population is not established. The importance of the effects of hypertension in pregnancy and pregnancy related acute kidney injury on CKD and the newer concept of CKD of unknown cause (CKDu) are highlighted. Hypertension remains a dominant cause of CKD in Africa, and newer information suggests that the most appropriate treatment to control blood pressure and thus prevent CKD is the combination of either amlodipine plus a thiazide diuretic or angiotensin converting enzyme (ACE) inhibitor. Full article

The golden age of antibiotics for tuberculosis (TB) is marked by its success in the 1950s of the last century. However, TB is not under control, and the rise in antibiotic resistance worldwide is a major threat to global health care. Understanding the complex interactions between TB bacilli and their host can inform the rational design of better TB therapeutics, including vaccines, new antibiotics, and host-directed therapies. We recently demonstrated that the modulation of cystatin C in human macrophages via RNA silencing improved the anti-mycobacterial immune responses to Mycobacterium tuberculosis infection. Available in vitro transfection methods are not suitable for the clinical translation of host-cell RNA silencing. To overcome this limitation, we developed different RNA delivery systems (DSs) that target human macrophages. Human peripheral blood-derived macrophages and THP1 cells are difficult to transfect using available methods. In this work, a new potential nanomedicine based on chitosan (CS-DS) was efficiently developed to carry a siRNA-targeting cystatin C to the infected macrophage models. Consequently, an effective impact on the intracellular survival/replication of TB bacilli, including drug-resistant clinical strains, was observed. Altogether, these results suggest the potential use of CS-DS in adjunctive therapy for TB in combination or not with antibiotics. Full article

The impact of malaria-associated acute kidney injury (MAKI), one of the strongest predictors of death in children with severe malaria (SM), has been largely underestimated and research in this area has been neglected. Consequently, a standard experimental mouse model to research this pathology is still lacking. The purpose of this study was to develop an in vivo model that resembles the pathology in MAKI patients. In this study, unilateral nephrectomies were performed on wild-type mice prior to infection with Plasmodium berghei NK65. The removal of one kidney has shown to be an effective approach to replicating the most common findings in humans with MAKI. Infection of nephrectomized mice, compared to their non-nephrectomized counterparts, resulted in the development of kidney injury, evident by histopathological analysis and elevated levels of acute kidney injury (AKI) biomarkers, including urinary neutrophil gelatinase-associated lipocalin, serum Cystatin C, and blood urea nitrogen. Establishment of this in vivo model of MAKI is critical to the scientific community, as it can be used to elucidate the molecular pathways implicated in MAKI, delineate the development of the disease, identify biomarkers for early diagnosis and prognosis, and test potential adjunctive therapies. Full article