Serum ß-klotho is a potential biomarker for the progression of hepatitis B virus-related liver diseases.

INTRODUCTION: Hepatitis B virus (HBV) infection is a global epidemic that can lead to several liver diseases, seriously affecting people's health. This study aimed to investigate the clinical potential of serum ß-klotho (KLB) as a promising biomarker in HBV-related liver diseases. METHODOLOGY: This study enrolled 30 patients with chronic hepatitis B (CHB), 35 with HBV-related cirrhosis, 66 with HBV-related hepatocellular carcinoma (HCC), and 48 healthy individuals. ELISA measured the levels of serum KLB in the four groups. We then compared the differences in serum KLB levels among the groups and analyzed the relationship between serum KLB and routine clinical parameters. RESULTS: The concentrations of serum KLB levels were increased sequentially among the healthy subjects, the HBV-related CHB group, the HBV-related cirrhosis group, and the HBV-related HCC group (p < 0.05). Expression of KLB was positively correlated with alpha-fetoprotein (AFP), total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl-transferase, alkaline phosphatase, total bile acid, serum markers for liver fibrosis, ascites, cirrhosis, splenomegaly, and model for end-stage liver disease sodium, while negatively correlated with platelet count, albumin, and prothrombin activity (p < 0.05). In addition, serum KLB has better sensitivity in diagnosing HCC than AFP, and serum KLB combined with AFP has higher sensitivity and specificity than AFP alone in diagnosing HCC. CONCLUSIONS: Serum KLB level is associated with the severity of HBV-related liver diseases and has important diagnostic value for HCC. Therefore, it could be a predictive biomarker for monitoring disease progression.

Inverse association of the systemic immune-inflammation index with serum anti-ageing protein Klotho levels in individuals with osteoarthritis: A cross-sectional study.

BACKGROUND: The association between the systemic immune-inflammation index (SII) and the serum soluble-Klotho concentration (pg/ml) in osteoarthritis (OA) patients is unknown. This study aimed to investigate the relationship between the SII and serum soluble-Klotho levels in OA patients. METHODS: All study data were obtained from the National Health and Nutrition Examination Survey (NHANES) database (n = 1852 OA patients; age range = 40-79 years). The SII and serum Klotho measurement data are from the NHANES mobile examination centre. The SII values were divided into quartiles (Q1-4: 0.02-3.36, 3.36-4.78, 4.79-6.70, and 6.70-41.75). A multivariate linear regression model was constructed to evaluate the association between the SII and serum Klotho levels in OA patients; interaction tests were conducted to test the stability of the statistical results. RESULTS: Multivariate linear regression revealed a negative linear relationship between the SII and serum Klotho concentration in OA patients (ß = -6.05; 95% CI: -9.72, -2.39). Compared to Q1, Q4 was associated with lower serum Klotho concentrations (ß = -59.93; 95% CI: -96.57, -23.28). Compared with that of Q1, the ß value of Q2-Q4 showed a downwards trend as the SII increased (Ptrend <0.001). The stratified analysis results indicated that the SII had a greater sensitivity in predicting serum Klotho concentrations in OA patients aged 60-79 years (Pinteraction = 0.028). CONCLUSIONS: There was a significant negative linear correlation between the SII and serum Klotho concentration in OA patients. The SII can serve as a predictive indicator of serum Klotho concentrations in OA patients. Klotho may be a potential anti-inflammatory drug for OA treatment.

Klotho is highly expressed in the chief sites of regulated potassium secretion, and it is stimulated by potassium intake.

Klotho regulates many pathways in the aging process, but it remains unclear how it is physiologically regulated. Because Klotho is synthesized, cleaved, and released from the kidney; activates the chief urinary K+ secretion channel (ROMK) and stimulates urinary K+ secretion, we explored if Klotho protein is regulated by dietary K+ and the potassium-regulatory hormone, Aldosterone. Klotho protein along the nephron was evaluated in humans and in wild-type (WT) mice; and in mice lacking components of Aldosterone signaling, including the Aldosterone-Synthase KO (AS-KO) and the Mineralocorticoid-Receptor KO (MR-KO) mice. We found the specific cells of the distal nephron in humans and mice that are chief sites of regulated K+ secretion have the highest Klotho protein expression along the nephron. WT mice fed K+-rich diets increased Klotho expression in these cells. AS-KO mice exhibit normal Klotho under basal conditions but could not upregulate Klotho in response to high-K+ intake in the K+-secreting cells. Similarly, MR-KO mice exhibit decreased Klotho protein expression. Together, i) Klotho is highly expressed in the key sites of regulated K+ secretion in humans and mice, ii) In mice, K+-rich diets increase Klotho expression specifically in the potassium secretory cells of the distal nephron, iii) Aldosterone signaling is required for Klotho response to high K+ intake.

Serum klotho associated with thyroid hormone in adults: A population-based cross-sectional research.

BACKGROUND AND STUDY AIM: The klotho protein, a multifunctional protein, has been shown to be associated with a wide range of endocrine diseases and has been linked to thyroid tumourigenesis. However, the relationship between serum klotho levels and thyroid hormones remains poorly understood. This study aimed to explore the correlation between serum klotho levels and thyroid hormones. METHODS: Data was obtained from the NHANES cycles 2007-2008, 2009-2010, and 2011-2012. A total of 4674 participants were recruited for this study. Statistical analysis was using multiple linear regression analyses, and restricted cubic spline plots (RCS) to investigate the association between serum klotho levels and serum levels of thyroid hormones. RESULTS: In the unadjusted covariate model, ln(klotho) significantly positively correlated with tT3, tT4, fT3, tT4/fT4, and tT3/fT3 (all P<0.01) and negatively correlated with TSH, tT4/tT3, and fT4/fT3 (all P<0.05). Furthermore, tT3, tT4, fT3and tT3/fT3 (P < 0.05) were still significant in the adjusted model. And it is worth noting that there is an approximately L-shaped nonlinear relationship between ln(klotho) and fT3,tT3 with a cut-off point of 6.697 (P-non-linear < 0.05). The stratification analysis showed gender and iodine level differences in the relationship between serum Klotho levels and thyroid hormones. CONCLUSION: There is an L-shaped nonlinear relationship between ln(klotho) and fT3, tT3, suggesting that klotho could be involved in the physiological regulation of thyroid function.

Association between serum Klotho levels and hypothyroidism in older adults: NHANES 2007-2012.

Whether Klotho plays any role in hypothyroidism is unknown. This study aimed to determine the relationship between serum Klotho levels and hypothyroidism in older adults. From the 2007 to 2012 National Health and Nutrition Examination Survey (NHANES), 1444 older adults aged 65-79 were included in this cross-sectional study. Hypothyroidism was diagnosed using participants' reports of current medications and TSH tests. Klotho was measured using an enzyme-linked immunosorbent assay. The relationship between serum Klotho levels and hypothyroidism in older people was analyzed by one-way analysis of variance, multiple linear regression models, subgroup analyses, interaction tests, smoothed curve fitting, and threshold effects. A total of 209 (14.47%) participants were identified as having hypothyroidism. Serum Klotho (ln transformation) is independently and significantly negatively associated with the risk of hypothyroidism after complete adjustment for confounders (OR = 0.49, 95% CI 0.31-0.80; P = 0.0039). The results remained stable based on subgroup analyses and interaction tests. However, we observed an inverted U-shaped curve between the two using a smoothed curve fitting in the subgroups of 70 < age ≤ 75 years and females, with inflection points of 6.26 and 6.17, respectively. The results of our study indicate that serum Klotho levels negatively correlate with hypothyroidism among older adults.

Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program.

BACKGROUND: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of ß-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII. METHODS: This disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022. RESULTS: As of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and - 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died. CONCLUSIONS: To date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.

Impact of heparanase-2 (Hpa2) on cancer and inflammation: Advances and paradigms.

HPSE2, the gene-encoding heparanase 2 (Hpa2), is mutated in urofacial syndrome (UFS), a rare autosomal recessive congenital disease attributed to peripheral neuropathy. Hpa2 lacks intrinsic heparan sulfate (HS)-degrading activity, the hallmark of heparanase (Hpa1), yet it exhibits a high affinity toward HS, thereby inhibiting Hpa1 enzymatic activity. Hpa2 regulates selected genes that promote normal differentiation, tissue homeostasis, and endoplasmic reticulum (ER) stress, resulting in antitumor, antiangiogenic, and anti-inflammatory effects. Importantly, stress conditions induce the expression of Hpa2, thus establishing a feedback loop, where Hpa2 enhances ER stress which, in turn, induces Hpa2 expression. In most cases, cancer patients who retain high levels of Hpa2 survive longer than patients bearing Hpa2-low tumors. Experimentally, overexpression of Hpa2 attenuates the growth of tumor xenografts, whereas Hpa2 gene silencing results in aggressive tumors. Studies applying conditional Hpa2 knockout (cHpa2-KO) mice revealed an essential involvement of Hpa2 contributed by the host in protecting against cancer and inflammation. This was best reflected by the distorted morphology of the Hpa2-null pancreas, including massive infiltration of immune cells, acinar to adipocyte trans-differentiation, and acinar to ductal metaplasia. Moreover, orthotopic inoculation of pancreatic ductal adenocarcinoma (PDAC) cells into the pancreas of Hpa2-null vs. wild-type mice yielded tumors that were by far more aggressive. Likewise, intravenous inoculation of cancer cells into cHpa2-KO mice resulted in a dramatically increased lung colonization reflecting the involvement of Hpa2 in restricting the formation of a premetastatic niche. Elucidating Hpa2 structure-activity-relationships is expected to support the development of Hpa2-based therapies against cancer and inflammation.

Curry-Odorants and Their Metabolites Transfer into Human Milk and Urine.

SCOPE: The excretion of dietary odorants into urine and milk is evaluated and the impact of possible influencing factors determined. Furthermore, the metabolic relevance of conjugates for the excretion into milk is investigated. METHODS AND RESULTS: Lactating mothers (n = 20) are given a standardized curry dish and donated one milk and urine sample each before and 1, 2, 3, 4.5, 6, and 8 h after the intervention. The concentrations of nine target odorants in these samples are determined. A significant transition is observed for linalool into milk, as well as for linalool, cuminaldehyde, cinnamaldehyde, and eugenol into urine. Maximum concentrations are reached within 1 h after the intervention in the case of milk and within 2-3 h in the case of urine. In addition, the impact of glucuronidase treatment on odorant concentrations is evaluated in a sample subset of twelve mothers. Linalool, eugenol, and vanillin concentrations increased 3-77-fold in milk samples after treatment with ß-glucuronidase. CONCLUSION: The transfer profiles of odorants into milk and urine differ qualitatively, quantitatively, and in temporal aspects. More substances are transferred into urine and the transfer needs a longer period compared with milk. Phase II metabolites are transferred into urine and milk.

Serum Klotho and insulin resistance: Insights from a cross-sectional analysis.

The prevalence of diabetes has surged globally, posing significant health and economic burdens. Insulin resistance underlies the initiation and development of type 2 diabetes. Klotho is a crucial endogenous antiaging factor, associated with atherosclerotic cardiovascular diseases, cancer, neurological disorders, and renal diseases. It additionally has a function in controlling glucose metabolism and holds promise as a new therapeutic target for diabetes. However, its relationship with insulin resistance remains unclear. This study utilizes the National Health and Nutrition Examination Survey (NHANES) 2007 to 2016 data to investigate the relationship between serum Klotho concentrations and insulin resistance. In this observational study, information from the NHANES spanning 2007 to 2016 was employed. The sample consisted of 6371 participants. Weighted linear regression model and chi-square tests were utilized to assess differences in continuous and categorical variables, respectively, among groups categorized by Klotho quartiles. The relationship between Klotho and HOMA-IR (homeostatic model assessment of insulin resistance) was studied using multiple linear regression. Smooth curve fitting was used to analyze nonlinear relationships and the inflection point was determined through a 2-stage linear regression method. After adjusting for multiple confounding factors, serum Klotho levels were found to be positively correlated with insulin resistance [0.90 (0.68, 1.13)]. This correlation is nonlinear and exhibits a saturation effect, with the inflection point identified at 1.24 pg/µL. When Klotho levels are below 1.24 pg/µL, for every unit increase in Klotho, HOMA-IR increases by 1.30 units. Conversely, when Klotho levels exceed 1.24 pg/µL, there is no correlation between HOMA-IR and Klotho. Subgroup analysis reveals that the relationship between HOMA-IR and Klotho varies depending on diabetes and body mass index (BMI). This positive correlation was most prominent in the obese nondiabetic population. There is a positive correlation between serum Klotho and insulin resistance.

Cognitive Impairment Related to Chronic Kidney Disease Is Associated with a Decreased Abundance of Membrane-Bound Klotho in the Cerebral Cortex.

Cognitive impairment (CI) is a complication of chronic kidney disease (CKD) that is frequently observed among patients. The aim of this study was to evaluate the potential crosstalk between changes in cognitive function and the levels of Klotho in the brain cortex in an experimental model of CKD. To induce renal damage, Wistar rats received a diet containing 0.25% adenine for six weeks, while the control group was fed a standard diet. The animals underwent different tests for the assessment of cognitive function. At sacrifice, changes in the parameters of mineral metabolism and the expression of Klotho in the kidney and frontal cortex were evaluated. The animals with CKD exhibited impaired behavior in the cognitive tests in comparison with the rats with normal renal function. At sacrifice, CKD-associated mineral disorder was confirmed by the presence of the expected disturbances in the plasma phosphorus, PTH, and both intact and c-terminal FGF23, along with a reduced abundance of renal Klotho. Interestingly, a marked and significant decrease in Klotho was observed in the cerebral cortex of the animals with renal dysfunction. In sum, the loss in cerebral Klotho observed in experimental CKD may contribute to the cognitive dysfunction frequently observed among patients. Although further studies are required, Klotho might have a relevant role in the development of CKD-associated CI and represent a potential target in the management of this complication.

Quantitative Estimation of Promoter Activity in Cannabis sativa Using Agroinfiltration-Based Transient Gene Expression.

To properly assess promoter activity, which is critical for understanding biosynthetic pathways in different plant species, we use agroinfiltration-based transient gene expression assay. We compare the activity of several known promoters in Nicotiana benthamiana with their activity in Cannabis sativa (both hemp and medicinal cannabis), which has attracted much attention in recent years for its industrial, medicinal, and recreational properties. Here we describe an optimized protocol for transient expression in Cannabis combined with a ratiometric GUS reporter system that allows more accurate evaluation of promoter activity and reduces the effects of variable infiltration efficiency.

The Effect of Propofol on the Hippocampus in Chronic Cerebral Hypoxia in a Rat Model Through Klotho Regulation.

BACKGROUND/AIM: Chronic cerebral hypoxia often leads to brain damage and inflammation. Propofol is suggested to have neuroprotective effects under anaesthesia. MATERIALS AND METHODS: This study used rat models with carotid artery coarctation or closure. Four groups of rats were compared: a control group, a propofol-treated group, a group with bilateral common carotid artery blockage (BCAO), and a BCAO group treated with propofol post-surgery. RESULTS: The Morris water maze test indicated cognitive impairment in BCAO rats, which also showed hippocampal structure changes, oxidative stress markers alteration, and reduced Klotho expression. Propofol treatment post-BCAO surgery improved these outcomes, suggesting its potential in mitigating chronic cerebral hypoxia effects. CONCLUSION: Propofol may increase klotho levels and reduce apoptosis and inflammation linked to oxidative stress in cognitively impaired mice.

Tumoral acidosis promotes adipose tissue depletion by fostering adipocyte lipolysis.

OBJECTIVE: Tumour progression drives profound alterations in host metabolism, such as adipose tissue depletion, an early event of cancer cachexia. As fatty acid consumption by cancer cells increases upon acidosis of the tumour microenvironment, we reasoned that fatty acids derived from distant adipose lipolysis may sustain tumour fatty acid craving, leading to the adipose tissue loss observed in cancer cachexia. METHODS: To evaluate the pro-lipolytic capacities of acid-exposed cancer cells, primary mouse adipocytes from subcutaneous and visceral adipose tissue were exposed to pH-matched conditioned medium from human and murine acid-exposed cancer cells (pH 6.5), compared to naive cancer cells (pH 7.4). To further address the role of tumoral acidosis on adipose tissue loss, a pH-low insertion peptide was injected into tumour-bearing mice, and tumoral acidosis was neutralised with a sodium bicarbonate buffer. Prolipolytic mediators were identified by transcriptomic approaches and validated on murine and human adipocytes. RESULTS: Here, we reveal that acid-exposed cancer cells promote lipolysis from subcutaneous and visceral adipocytes and that dampening acidosis in vivo inhibits adipose tissue depletion. We further found a set of well-known prolipolytic factors enhanced upon acidosis adaptation and unravelled a role for ß-glucuronidase (GUSB) as a promising new actor in adipocyte lipolysis. CONCLUSIONS: Tumoral acidosis promotes the mobilization of fatty acids derived from adipocytes via the release of soluble factors by cancer cells. Our work paves the way for therapeutic approaches aimed at tackling cachexia by targeting the tumour acidic compartment.

Heparanase promotes the onset and progression of atherosclerosis in apolipoprotein E gene knockout mice.

BACKGROUND AND AIMS: Atherosclerosis is the primary underlying cause of myocardial infarction and stroke, which are the major causes of death globally. Heparanase (Hpse) is a pro-inflammatory extracellular matrix degrading enzyme that has been implicated in atherogenesis. However, to date the precise roles of Hpse in atherosclerosis and its mechanisms of action are not well defined. This study aims to provide new insights into the contribution of Hpse in different stages of atherosclerosis in vivo. METHODS: We generated Hpse gene-deficient mice on the atherosclerosis-prone apolipoprotein E gene knockout (ApoE-/-) background to investigate the impact of Hpse gene deficiency on the initiation and progression of atherosclerosis after 6 and 14 weeks high-fat diet feeding, respectively. Atherosclerotic lesion development, blood serum profiles, lesion composition and aortic immune cell populations were evaluated. RESULTS: Hpse-deficient mice exhibited significantly reduced atherosclerotic lesion burden in the aortic sinus and aorta at both time-points, independent of changes in plasma cholesterol levels. A significant reduction in the necrotic core size and an increase in smooth muscle cell content were also observed in advanced atherosclerotic plaques of Hpse-deficient mice. Additionally, Hpse deficiency reduced circulating and aortic levels of VCAM-1 at the initiation and progression stages of disease and circulating MCP-1 levels in the initiation but not progression stage. Moreover, the aortic levels of total leukocytes and dendritic cells in Hpse-deficient ApoE-/- mice were significantly decreased compared to control ApoE-/-mice at both disease stages. CONCLUSIONS: This study identifies Hpse as a key pro-inflammatory enzyme driving the initiation and progression of atherosclerosis and highlighting the potential of Hpse inhibitors as novel anti-inflammatory treatments for cardiovascular disease.

Patients With Coronary Microvascular Dysfunction Have Less Circulating α-Klotho.

BACKGROUND: Coronary microvascular dysfunction (CMD) represents an early functional characteristic of coronary vascular aging. Klotho (α-klotho) is a circulating protein inversely linked to physiological aging. We examined low klotho as a potential marker for vascular aging in patients with CMD and no coronary artery disease. METHODS AND RESULTS: Patients undergoing nonurgent angiogram for chest pain who had no coronary artery disease underwent invasive coronary microvascular and endothelial function testing. CMD was defined by ≤50% increase in coronary blood flow (percentage change in coronary blood flow) in response to intracoronary acetylcholine or coronary flow reserve ≤2. Fresh arterial whole blood was used to analyze circulating endothelial progenitor cells with flow cytometry. Stored arterial plasma was used for klotho analysis by ELISA. Participants with CMD (n=62) were compared with those without CMD (n=36). Those with CMD were age 55±10 years (versus 51±11 years; P=0.07) and 73% women (versus 81%; P=0.38). Traditional risk factors for coronary artery disease were similar between groups. Patients with CMD had less klotho (0.88±1.50 versus 1.75±2.38 ng/mL; P=0.03), and the odds of low klotho in CMD were significant in a logistic regression model after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 0.80 [95% CI, 0.636-0.996]; P=0.05). Higher klotho was associated with higher numbers of endothelial progenitor cells with vascular regenerative potential (CD34+ and CD34+CD133+KDR+). Among a subgroup of patients with atherosclerotic cardiovascular disease risk <5% (n=58), CMD remained associated with lower klotho (OR, 0.80 [95% CI, 0.636-0.996]; P=0.047). CONCLUSIONS: Klotho may be a biomarker for CMD and may be a therapeutic target for groups of patients without significant traditional cardiovascular risk.

[Clinical study on growth impairment induced by oral glucocorticoids based on FGF23/Klotho homeostasis observations]. / 基于FGF23/Klothoç¨³æ€è§‚å¯Ÿå£æœç³–çš®è´¨æ¿€ç´ è‡´ç”Ÿé•¿éšœç¢çš„ä¸´åºŠç ”ç©¶.

OBJECTIVES: To observe the correlation between growth impairment induced by long-term oral glucocorticoids (GC) therapy and the ratio of FGF23/Klotho in children with primary nephrotic syndrome (PNS). METHODS: A prospective study was conducted on 56 children with GC-sensitive PNS who had discontinued GC therapy for more than 3 months and revisited the Department of Pediatrics of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine between June 2022 and December 2022. After monitoring qualitative and quantitative urine protein levels upon admission, the children with proteinuria relapse were treated with GC (GC group; n=29), while those without relapse did not receive GC treatment (non-GC group; n=27). In addition, 29 healthy children aged 3 to prepuberty were selected as the control group. Height, bone age, growth rate, and the FGF23/Klotho ratio were compared among the groups. The correlations of the FGF23/Klotho ratio with height, bone age, and growth rate were analyzed. RESULTS: The FGF23/Klotho ratio in the GC group was significantly higher than that in the non-GC group after 1 month of GC therapy (P<0.05), and the height and bone age growth rates within 6 months were lower than those in the non-GC group (P<0.05). Correlation analysis showed significant negative correlations between the FGF23/Klotho ratio after 1 month of treatment and the growth rates of height and bone age within 6 months in children with PNS (r=-0.356 and -0.436, respectively; P<0.05). CONCLUSIONS: The disturbance in FGF23/Klotho homeostasis is one of the mechanisms underlying the growth impairment caused by long-term oral GC therapy.

Obesity aggravates acute kidney injury resulting from ischemia and reperfusion in mice.

In critically ill patients, overweight and obesity are associated with acute respiratory distress syndrome and acute kidney injury (AKI). However, the effect of obesity on ischemia-reperfusion injury (IRI)-induced AKI is unknown. We hypothesized that obesity would aggravate renal IRI in mice. We fed mice a standard or high-fat diet for eight weeks. The mice were divided into four groups and submitted to sham surgery or IRI: obese, normal, normal + IRI, obese, and obese + IRI. All studies were performed 48 h after the procedures. Serum glucose, cholesterol, and creatinine clearance did not differ among the groups. Survival and urinary osmolality were lower in the obese + IRI group than in the normal + IRI group, whereas urinary neutrophil gelatinase-associated lipocalin levels, tubular injury scores, and caspase 3 expression were higher. Proliferating cell nuclear antigen expression was highest in the obese + IRI group, as were the levels of oxidative stress (urinary levels of thiobarbituric acid-reactive substances and renal heme oxygenase-1 protein expression), whereas renal Klotho protein expression was lowest in that group. Expression of glutathione peroxidase 4 and peroxiredoxin 6, proteins that induce lipid peroxidation, a hallmark of ferroptosis, was lower in the obese + IRI group. Notably, among the mice not induced to AKI, macrophage infiltration was greater in the obese group. In conclusion, greater oxidative stress and ferroptosis might aggravate IRI in obese individuals, and Klotho could be a therapeutic target in those with AKI.

Oral-Gut-Estrobolome Axis May Exert a Selective Impact on Oral Cancer.

A subset of bacterial species that holds genes encoding for ß-glucuronidase and ß-galactosidase, enzymes involved in the metabolism of conjugated estrogens, is called the "estrobolome." There is an emerging interest embracing this concept, as it may exert a selective impact on a number of pathologies, including oral cancer. Although the estrobolome bacteria are typically part of the gut microbiota, recent experimental pieces of evidence have suggested a crosstalk among oral and gut microbiota. In fact, several oral bacterial species are well represented also in the gut microbiota, and these microbes can effectively induce the estrobolome activation. The main pathways used for activating the estrobolome are based on the induction of the expression patterns for 2 bacterial enzymes: ß-glucuronidase and aromatase, both involved in the increase of estrogen released in the bloodstream and consequently in the salivary compartment. Mechanistically, high estrogen availability in saliva is responsible for an increase in oral cancer risk for different reasons: briefly, 1) estrogens directly exert biological and metabolic effects on oral mucosa cells; 2) they can modulate the pathological profile of some bacteria, somewhere associated with neoplastic processes (i.e., Fusobacterium spp., Parvimonas ssp.); and 3) some oral bacteria are able to convert estrogens into carcinogenic metabolites, such as 4-hydroxyestrone and 16α-hydroxyestrone (16α-OHE), and can also promote local and systemic inflammation. Nowadays, only a small number of scientific studies have taken into consideration the potential correlations among oral dysbiosis, alterations of the gut estrobolome, and some hormone-dependent cancers: this lack of attention on such a promising topic could be a bias affecting the full understanding of the pathogenesis of several estrogen-related oral pathologies. In our article, we have speculated on the activity of an oral-gut-estrobolome axis, capable of synergizing these 2 important microbiotas, shedding light on a pilot hypothesis requiring further research.

Exploring Heparanase Levels in Tears: Insights From Herpes Simplex Virus-1 Keratitis Patients and Animal Studies.

Purpose: Heparanase (HPSE) cleaves heparan sulfate proteoglycans during herpes simplex virus-1 (HSV-1) infection, aiding in viral egress and disease progression. Its action has been well established in in vitro and in vivo models, but its relevance in human patients remains unclear. This study aimed to specifically evaluate tear HPSE levels of patients with herpes simplex keratitis (HSK) and to correlate these findings with a commonly used murine model. Methods: Tear samples from patient and mice samples were collected at LV Prasad Eye Institute, Hyderabad, India, and at the University of Illinois, Chicago, IL, respectively. Tears were collected from HSV-1 patients, bacterial/fungal keratitis cases, and healthy individuals. For in vivo study, C57BL/6 mice were infected with HSV-1 (McKrae strain) followed by tear fluid collection at various time points (0-10 days). Results: The HSV-1, bacterial keratitis, fungal keratitis, and healthy control groups each had 30 patients. There was a significant difference in HPSE expression in the HSV-1 infected eyes (1.55 ± 0.19 units/mL) compared to HSV-1 contralateral eyes (1.23 ± 0.13 units/mL; P = 0.82), bacterial keratitis eyes (0.87 ± 0.15 units/mL; P = 0.0078), fungal keratitis eyes (0.64 ± 0.09 units/mL; P < 0.00001), and normal controls (0.53 ± 0.06 units/mL; P < 0.00001). C57BL/6 mice tear HPSE expression in infected eyes was 0.66 to 5.57 ng heparan sulfate (HS) removed per minute when compared to non-infected eye (range, 0.70-3.67 ng HS removed per minute). Conclusions: To the best of our knowledge, this study is the first to report elevated HPSE levels in the tears of patients with different forms of HSV-1 keratitis, and it confirms similar findings in a murine model, providing a valuable basis for future in vivo and clinical research on HSV-1 ocular infection.

Clinical manifestations and genetic mutation analysis of patients with mucopolysaccharidosis type VII in China.

OBJECTIVE: This study aimed to explore the clinical and genetic features of Chinese patients with mucopolysaccharidosis type VII (MPS VII), thereby improving early detection, disease management, and patient outcomes. METHODS: A retrospective review of medical records for five patients presenting with coarse facial features, rib protrusion, chest deformities, and scoliosis was conducted. Exome sequencing was employed to identify causative genetic mutations. RESULTS: The study comprised five patients (four males, one female) with disease onset at six months of age (range: 0-1.5 years). Common symptoms included coarse facial features, skeletal abnormalities, delayed motor and language development, and intellectual disability. Approximately 80% of the patients exhibited multiple skeletal dysplasias, enlarged adenoids or tonsils, and snoring; 60% had hernias; 40% reported hearing loss and hepatosplenomegaly. Less frequent manifestations were short stature, valvular heart disease, non-immune hydrops fetalis, and corneal opacity. All patients demonstrated elevated urine glycosaminoglycans levels and absent ß-glucuronidase activity in leukocytes. Exome sequencing identified compound heterozygous mutations in the GUSB gene in all four tested patients, uncovering seven mutations in total, three of which were novel (c.189G > A, c.869C > T, and c.1745 T > C). Furthermore, prenatal diagnosis through chorionic villus sampling in subsequent pregnancies of one patient's mother revealed both fetuses had normal ß-glucuronidase activity and no disease-causing mutations in the GUSB gene. CONCLUSION: The study's patients all presented with classic symptoms of MPS VII due to ß-glucuronidase deficiency, with three new pathogenic mutations identified in the GUSB gene. Genetic counseling and prenatal testing were highlighted as crucial for disease prevention.