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Bone defects are highly prevalent diseases caused by trauma, tumors, inflammation, congenital malformations and endocrine abnormalities. Ideally effective and side effect free approach to dealing with bone defects remains a clinical conundrum. Klotho is an important protein, which plays an essential role in regulating aging and mineral ion homeostasis. More recently, research revealed the function of Klotho in regulating skeleton development and regeneration. Klotho has been identified in mesenchymal stem cells, osteoblasts, osteocytes and osteoclasts in different skeleton regions. The specific function and regulatory mechanisms of Klotho in long bone and craniofacial bone vary due to their different embryonic development, ossification and cell types, which remain unclear and without conclusion. Moreover, studies have confirmed that Klotho is a multifunctional protein that can inhibit inflammation, resist cancer and regulate the endocrine system, which may further accentuate the potential of Klotho to be the ideal molecule in inducing bone restoration clinically. Besides, as an endogenous protein, Klotho has a promising potential for clinical therapy without side effects. In the current review, we summarized the specific function of Klotho in long bone and craniofacial skeleton from phenotype to cellular alternation and signaling pathway. Moreover, we illustrated the possible future clinical application for Klotho. Further research on Klotho might help to solve the existing clinical difficulties in bone healing and increase the life quality of patients with bone injury and the elderly. [ABSTRACT FROM AUTHOR]

Objective To observe the ameliorating effect of intragastric administration of Klotho protein on cerebral ischemia-reperfusion injury (CIRI) in rats with acute cerebral infarction (ACI) and to explore its mechanism. Methods Fifty SD male rats were divided into the sham operation group, model group, low-dose Klotho group, medium-dose Klotho group and high-dose Klotho group, with 10 rats in each group. CIRI models after ACI were established in the model group, low-dose Klotho group, medium-dose Klotho group and high-dose Klotho group. In the sham operation group, only carotid artery vessel separation and wound suture were performed, and carotid artery clamping was not performed. After being fed for 24 h, the rats in the low-dose, medium-dose and high-dose Klotho groups were treated with 25，50 and 100 mg/kg Klotho protein, respectively, and the rats in the model group and sham operation group were treated with equal volume of normal saline. All rats in the five groups were treated once a day, for 14 days. Longa scoring method and balance beam scoring method were used to evaluate the neurological scores of rats in each group. Cerebral tissues of rats in each group were taken after decapitation. Hematoxylin staining method was used to measure the apoptosis rate of cerebral cortex neurons of rats, and receptor-interacting protein kinase 1（RIP1) and RIP3 proteins in cerebral cortex tissues of rats were detected by Western blotting. The inflammatory mediators interleukin (IL) -1β, tumor necrosis factor (TNF) -α and IL-6 were detected by enzyme-linked immunoassay, MDA was detected by TBA, SOD was detected by enzyme-linked immunoassay, and GSH-Px was detected by ultraviolet colorimetry. Results The the neurological score and cerebral cortical neuron apoptosis rate of rats in the sham operation group were lower than those in the other groups (all P<0. 05), and those in the model group were higher than those in the other groups (all P<0. 05), and those in the high-dose Klotho group were higher than those in the low-dose Klotho group and medium-dose Klotho group (all P<0. 05), and those in the mediumdose Klotho group were higher than those in the low-dose Klotho group (all P<0. 05) . The relative expression levels of RIP1 and RIP3 proteins and the expression levels of IL-1β, TNF-α, IL-6 and MDA in the cerebral cortex of rats in the sham operation group were lower than those in the other groups, while the expression levels of SOD and GSH-Px were higher than those in the other groups (all P<0. 05) . The relative expression levels of RIP1 and RIP3 proteins and the expression levels of IL-1β, TNF-α, IL-6 and MDA in cerebral cortex of rats in the model group were higher than those in the other groups, while the expression levels of SOD and GSH-Px were lower than those in the other groups (all P<0. 05) . The relative expression levels of RIP1 and RIP3 proteins and the expression levels of IL-1β, TNF-α, IL-6 and MDA in the cerebral cortex of rats in the high-dose Klotho group were lower than those in the low-dose Klotho group and medium-dose Klotho group, while the expression levels of SOD and GSH-Px were higher than those of the low-dose and medium-dose Klotho groups (all P<0. 05) . The relative expression levels of RIP1 and RIP3 protein and the expression levels of IL-1β, TNF-α, IL-6 and MDA in cerebral cortex of rats in the medium-dose Klotho group were lower than those in the low-dose Klotho group, while the expression levels of SOD and GSH-Px were higher than those in the low-dose Klotho group (all P< 0. 05) . Conclusion Gastric administration of 100 mg/kg Klotho protein can alleviate CIRI in ACI rats, and its mechanism may be related to inhibiting the expression of RIP1 and RIP3 proteins in cerebral cortex and inhibiting the inflammatory response and oxidative stress response at the site of brain injury. [ABSTRACT FROM AUTHOR]

Neuropsychiatric disorders are mainly concerned with the behavioural, emotional and cognition symptoms that may be due to disturbed cerebral functions or extracerebral disease. Klotho protein is an antiaging protein that is mostly associated with cognitive changes in these disorders and thus this meta-analysis is conducted in order to find Klotho proteins association with these disorders. We searched related topics in pubmed, by using the key word i.e. Klotho and related disorder from neuropsychiatry e.g. Klotho levels and schizophrenia, Klotho levels and parkinsonism etc. Total 82 studies were found till 9th February 2021 after extensive search and 10 studies were selected for further analysis. The meta-analysis of studies was performed using the Random effect model. The forest plot represented each study in the meta-analysis, so as to make the comparison of SMD value across studies. The meta-analysis outcome demonstrated that overall schizophrenia had higher klotho levels as compared with bipolar disorder, psychosocial stress, parkinsonism, multiple sclerosis, depression, Alzheimer's disease, and healthy controls, followed by MS. The meta-analysis also found that bipolar disorder and Alzheimer's disease were associated with low klotho levels as compared to schizophrenia. The results indicate a significant association of the klotho levels and schizophrenia. Further studies are needed to characterize the potential biological roles of klotho levels in psychiatric disorders. [ABSTRACT FROM AUTHOR]

Bone defects are highly prevalent diseases caused by trauma, tumors, inflammation, congenital malformations and endocrine abnormalities. Ideally effective and side effect free approach to dealing with bone defects remains a clinical conundrum. Klotho is an important protein, which plays an essential role in regulating aging and mineral ion homeostasis. More recently, research revealed the function of Klotho in regulating skeleton development and regeneration. Klotho has been identified in mesenchymal stem cells, osteoblasts, osteocytes and osteoclasts in different skeleton regions. The specific function and regulatory mechanisms of Klotho in long bone and craniofacial bone vary due to their different embryonic development, ossification and cell types, which remain unclear and without conclusion. Moreover, studies have confirmed that Klotho is a multifunctional protein that can inhibit inflammation, resist cancer and regulate the endocrine system, which may further accentuate the potential of Klotho to be the ideal molecule in inducing bone restoration clinically. Besides, as an endogenous protein, Klotho has a promising potential for clinical therapy without side effects. In the current review, we summarized the specific function of Klotho in long bone and craniofacial skeleton from phenotype to cellular alternation and signaling pathway. Moreover, we illustrated the possible future clinical application for Klotho. Further research on Klotho might help to solve the existing clinical difficulties in bone healing and increase the life quality of patients with bone injury and the elderly.

Objective: To investigating the relationship between α-Klotho and FGF-23 with bone biochemical markers and bone density findings in extremely aged individuals. Methods: A total of 55 individuals with a mean age of 85.6 years were subjected to clinical, biochemical, and bone mineral density analyses and the enzyme-linked immunosorbent assay-based detection of α-Klotho and FGF-23. The mean, standard deviation, median, and interquartile ranges of the sample values were determined, and Spearman's test for association assessments was used for statistical analysis. Results: The study participants expressed median FGF-23 and α-Klotho levels of 69.81 RU/mL (51.43 RU/mL) and 733.43 pg/mL (360.83 pg/mL), respectively. The majority of the participants possessed osteopenia (54.5%) and a vitamin D deficiency (57%). The 25-hydroxyvitamin D concentrations ranged between 7.1 and 47.5ng/mL, with a median of 18.1ng/mL. Conclusion: No substantial associations were discovered between α-Klotho and FGF-23 levels and bone density in the study participants.

Chronic heart failure (CHF) is a global medical, social, and economic problem. It is a syndrome caused by imbalanced neurohumoral regulation of the cardiovascular system, which is accompanied by impaired systolic and/or diastolic function of the heart. Currently, the search and study of new biological markers that can help in the early diagnosis of CHF, serve as a laboratory tool for assessing treatment effectiveness, or be used as prognostic markers and risk stratification criteria are ongoing. Researchers focused on studying the role of Klotho protein, fibroblast growth factor 23 (FGF23), and sclerostin in patients with CHF. Klotho expression decreases as the body ages, and impaired production has been reported in various aging-related diseases. The FGF23 / Klotho axis plays a key regulatory role in cardiovascular pathology. Laboratory, clinical, and genetic studies have suggested that sclerostin is associated with heart disease, although available data are not entirely consistent. Clinical work conducted on the study of the Klotho protein, FGF-23, and sclerostin indicates the potentially important diagnostic and prognostic significance of their analysis in patients with CHF. Thus, more studies of the issues related to serial testing of these biological markers, including in the aspect of the multibiomarker model, are needed.

成纤维细胞生长因子23（fibroblast growth factor 23，FGF23）-Klotho内分泌轴参与磷酸盐代谢，研究提示该内分泌轴与卒中的发病机制密切相关。FGF23、Klotho水平均与卒中的发病及预后有关。FGF23-Klotho内分泌轴参与调节血管壁炎症反应，并可能参与高血压、胰岛素抵抗、脂代谢及肥胖等卒中危险因素的病理过程。本文介绍FGF23-Klotho内分泌轴对卒中的影响及可能机制的相关研究进展，以期为临床治疗和预防卒中带来新的思路。 Abstract: Fibroblast growth factor 23 (FGF23) -Klotho endocrine axis is involved in phosphate metabolism, and is closely related to the pathogenesis of stroke. FGF23 and Klotho levels are associated with the incidence and prognosis of stroke. The FGF23-Klotho endocrine axis is involved in the regulation of vascular inflammation and may be involved in the pathological process of stroke risk factors such as hypertension, insulin resistance, lipid metabolism and obesity. In this paper, the influence and mechanism of FGF23-Klotho endocrine axis on stroke were reviewed in order to bring new ideas for clinical treatment and prevention of stroke.

Objective To investigate the effect of sodium hydrosulfide (NaHS) on renal ischemia-reperfusion (I/R) injury in rats, and the relationship between its mechanism and Klotho protein. Methods We selected 18 male SD rats and randomly divided them into the sham group, I/R group, and NaHS intervention group (I/R + NaHS group), with 6 rats in each group. In the I/R group, we removed the right kidney, and then used non-invasive arterial clips to clamp the left renal pedicle to simulate the state of acute renal ischemia, and released the arterial clip after 45 minutes of clamping to simulate the state of renal reperfusion. After the acute renal ischemia model was established in the NaHS intervention group, NaHS was injected into the left renal artery, followed by reperfusion. The sham operation group was not clamped. After 24 h of reperfusion, blood samples were collected from each group, and serum renal function indexes such as urea ni- trogen (BUN) and creatinine (Scr) were detected by colorimetry. Renal tissue samples were taken from each group, and the histopathological changes of kidney were observed by HE staining, the content of SOD and MDA in renal tissues were detected by colorimetry, and the expression levels of Klotho and Nrf2 protein in renal tissues were detected by Western blotting. Results Compared with the sham group, serum creatinine and urea nitrogen increased, renal tubular injury was aggravated, SOD activity decreased, MDA content increased, the expression of Klotho protein in the renal tissues de- creased, and the expression of Nrf2 proteion increased in the I/R group (P<0.05 or P<0.01). Compared with the I/R group, the serum levels of creainine and urea nitrogen decreased, renal tubular injury was alleviated, SOD activity in- creased, MDA content decreased, the Klotho protein expression increased, and the Nrf2 protein expression decreased in the I/R + NaHS group （P<0. 05 or P<0. 01）. Conclusion NaHS can alleviate renal I/R injury in rats with acute renal ischemia， and its mechanism may be related to up-regulating Klotho protein expression and reducing oxidative stress. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mild cognitive impairment (MCI) is a mild memory or cognitive impairment. OBJECTIVE: To explore the relationship between serum klotho (K1) protein and insulin-like growth factor-1 and mild cognitive impairment in the elderly in order to provide accurate and appropriate indicators for clinical diagnosis and treatment of MCI. METHODS: This randomized stratified study adopted a multistage cluster sampling method. 161 elderly patients with mild cognitive impairment were included as the MCI group, and 161 healthy people matched with the MCI group in gender, age and education were selected as the control group. RESULTS: The levels of serum K1 protein and insulin-like growth factor-1 in the MCI group were lower than those in the control group (P < 0.05). Both IGF-1 and K1 had predictive value for MCI (P < 0.05). The area under the curve (AUC) of IGF-1 for predicting MCI was 0.859 (95% CI: 0.790 ∼ 0.929), and the AUC of K1 for predicting MCI was 0.793 (95% CI: 0.694 ∼ 0.892). The value of joint prediction of the two indicators was the highest, with an AUC of 0.939 (95% CI: 0.896–0.993). CONCLUSION: High serum K1 and insulin-like growth factor-1 are the protective factors of cognitive impairment in MCI patients. Both IGF-1 and serum K1 proteins have predictive value for MCI, and the combination of the two indicators has the highest predictive value. [ABSTRACT FROM AUTHOR]

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To assess the correlation between serum fibroblast growth factor 23 (FGF-23)/Klotho levels and end-stage renal disease (ESRD) in middle-aged and elderly patients combined with low bone mineral density (BMD). The BMD of the lumbar vertebrae and femoral neck of 87 patients with ESRD was measured using a dual-energy X-ray bone densitometer during hospitalisation and the patients were divided into a normal bone mass group and a low bone mass group. Haemoglobin, albumin, urea nitrogen, uric acid, creatinine, low-density lipoprotein cholesterol, alkaline phosphatase, blood calcium, blood phosphorus and full parathyroid hormone were detected using an automatic biochemical analyser. The levels of serum FGF-23, Klotho and activated vitamin D in the patients with ESRD were measured via an enzyme-linked immunosorbent assay. Older age and decreased serum creatinine levels and serum Klotho levels were associated with low bone mass. There were significantly more men in normal bone mass group (n=49, 74.24%) than in low bone mass group (n=8, 38.10%). The correlation analysis showed that BMD was negatively correlated with age but positively correlated with serum Klotho. The binary logistic regression analysis indicated that old age and the decrease in serum Klotho level were independent risk factors of a low BMD (all p<0.05). In conclusion, serum Klotho is closely related to BMD changes in middle-aged and elderly patients with ESRD. A high Klotho level is a protective factor and is expected to be a marker in reducing bone mineral metabolism disorders and improving the prognosis of patients with ESRD. [ABSTRACT FROM AUTHOR]

Purpose: End-stage renal disease patients on chronic hemodialysis (HD) have a shortened life expectancy compared to the general population. The aim of this study was to evaluate a possible link between three new and emerging factors in renal pathophysiology: Klotho protein, telomere length in peripheral blood mononuclear cells (TL) and redox status parameters before HD (bHD) and after HD (aHD), and to test mortality prediction capability of these emerging parameters in a population of HD patients. Methods: The study included 130 adult patients with average age 66 (54–72), on HD (3 times per week; 4–5 h per session). Klotho level, TL, routine laboratory parameters, dialysis adequacy and redox status parameters: advanced oxidation protein products (AOPP), prooxidant–antioxidant balance (PAB), superoxide anion (O2.−), malondialdehyde (MDA), ischemia-modified albumin (IMA), total sulfhydryl group content (SHG), and superoxide dismutase (SOD) were determined. Results: Klotho concentration was significantly higher aHD; 68.2 (22.6–152.9) vs. bHD 64.2 (25.5–119.8) (p = 0.027). The observed increase in TL was not statistically significant. AOPP, PAB, SHG, and SOD activity were significantly increased aHD (p > 0.001). The patients with the highest mortality risk score (MRS) had significantly higher PAB bHD (p = 0.002). Significantly lower O2.− (p < 0.001), SHG content (p = 0.072), and IMA (p = 0.002) aHD were found in patients with the lowest MRS values. Principal component analysis revealed redox balance-Klotho factor as a significant predictor of high mortality risk (p = 0.014). Conclusion: Decreased Klotho and TL attrition as well as redox status disturbance could be connected with higher mortality rate in HD patients. [ABSTRACT FROM AUTHOR]

Background: Although lithium (LC) is considered the successful drug used for the treatment of psychiatric disorders, it has many toxic effects on human organs, particularly the thyroid gland. Thyroid health has been associated with the content of selenium as a component of strong antioxidant, whereas thyroid dysfunctions such as goiter are associated with low selenium status. Aim of the work: The aim of the current study was to clarify the modulation role of Se over structural and functional affection of the thyroid gland after 30 days' use of LC. Accordingly, the effects of LC administration on the thyroid gland and to evaluation of selenium's role as a wellknown antioxidant in the protection of the gland against these hazardous effects were investigated. The effect of lithium carbonate, selenium and co-treatment with these two drugs on Klotho protein immunohistochemical expression in the thyroid gland was also, evaluated. Methods: Twenty-four adult male albino rats aged 3 months weighing 200-250 gm were used. The rats were equally divided into four groups (6 rats each): Group I as a control, Group II as selenium-treated rats (a dose of Se, 1 mg/kg with water), Group III as lithium carbonate (LC) treated rats (25 mg/kg of LC injected intraperitoneally, twice a day), and Group IV as LC +Se treated rats (Received the same dose of both LC + Se respectively). The rats were treated with LC and Se doses for 30 days. At the end of the experiment, the rats were weighed, and both blood and thyroid tissue samples were taken for hormonal, oxidative stress, histological, and immunohistochemical investigations using hematoxylin and eosin stain, PAS stain, and α-Klotho immunohistochemistry. Results: In LC-treated rats, a highly significant increase of MDA as a lipid peroxide marker of cellular oxidative stress and serum TSH while, a decrease of FT4 was recorded compared to control rats. Also, degenerative changes in the thyroid gland in the form of decreased or absent colloid and fusion of the disrupted follicles with mild or absent positive αKlotho immunoreactivity. LC+selenium treated group revealed a nearly normal appearance of thyroid gland architecture, improved thyroid function, and strong expression of α-Klotho immunoreactivity compared to non-treated LC-intoxicated rats. In addition, MDA as a lipid peroxide marker of cellular oxidative stress significantly reduced in the serum compared to LC-group, indicating the antioxidant activity of Se to protect the thyroid against the toxicity of LC. Moreover, control rats who received Se only as a protective agent showed preserved non-change in the thyroid texture and normal function without initiated MDA oxidative stress. Conclusion: LC had harmful effects on thyroid structure and function. Concomitant administration of selenium preserved to a great extent the thyroid gland architecture and function. The protective role of Se proceeds through suppression of cellular oxidative stress and promoting antioxidant activity of the thyroid gland which was evidenced by expression of Klotho immunostain. [ABSTRACT FROM AUTHOR]

The aim of the work was to evaluate the GABA neuroprotective properties and its structural analogues in old animals after seven months of hyperglycemia.Materials and methods. Diabetes mellitus was modeled in white outbred male rats (12 months old) by the administration of a streptozotocin (65 mg/kg) and nicotinamide (230 mg/kg) combination. After 6 months, the animals with a postprandial glycemia level between 11 and 18 mmol/l were selected for the study. After the groups had been formed, the animals were administrated with GABA and GABAergic compounds (Compositions МРВАand PPC), respectively, for 1 month, the control group animals were administrated with saline. After the treatment, an oral glucose tolerance test and a set of behavioral tests aimed at studying sensory-motor (Open Field, Adhesion test, Rotarod) and cognitive functions (New Object Recognition and Morris Water Maze), as well as the functional state evaluation of the endothelium were performed. Further on, sampling of blood and brain tissues for a biochemical and enzyme immunoassay (the level of glucagon-like peptide-1 (GLP-1) and TNF-α in serum and the level of Klotho protein, BDNF, Nrf2, NF-κB and malondialdehyd (MDA) in brain homogenates), as well as a morphological analysis of changes in CA1 and CA3 neurons of the hippocampus and somatosensory cortex, was carried out.Results. GABA and compositions with its derivatives had a pronounced neuroprotective effect in old animals with prolonged hyperglycemia. The hypoglycemic effect of the studied compositions was accompanied by an increase in the production of GLP-1. In the animals with DM, after 6 weeks of the test substances administration, higher rates of sensory-motor and cognitive functions and a less structural damage to the sensory-motor cortex and the brain hippocampus were recorded. These effects may be due to higher levels of the Klotho proteins, Nrf2 and BDNF, as well as lower levels of NF-κB, which may underlie the suppression of the oxidative stress, the reduction of MDA and inflammation (TNF-α).Conclusion. After 6 weeks of the administration, GABA and its compositions in old animals (19 months old) significantly improved sensory-motor and cognitive functions, reduced negative structural changes in the hippocampus and somatosensory cerebral cortex.

Introduction: Gamma-aminobutyric acid (GABA) and GABAergic compounds emerged as potential therapeutic agents for diabetes mellitus and its complications. GABA acts as an inhibitory neurotransmitter in the central nervous system and as an extracellular signaling molecule in pancreatic islets, exerting beneficial effects on insulin secretion, glucagon production, apoptosis, beta-cell survival, and regeneration. Aim: This study aimed to compare the efficacy of GABA and GABAergic compounds as pancreatic β-cell protective agents in aged rats (18 months) with prolonged hyperglycemia induced by streptozotocin-nicotinamide injection. Materials and Methods: Male outbred albino rats aged 12 months were intraperitoneally injected with streptozotocin (65 mg/kg) and nicotinamide (230 mg/kg). Over the next 6 months, the level of glycemia was monitored every 4 weeks. Further, rats with postprandial glycemia levels between 11 and 18 mmol/L were selected. The experimental groups were treated with GABA and GABAergic compounds (compositions 2 and 3) for 1 month, while the control group received saline. An oral glucose tolerance test (OGTT) was performed after treatment. Blood and samples of the pancreatic tissue (splenic part) were collected for enzyme-linked immunosorbent assay (GLP-1, TNF-α serum level and NF-κB, Nrf2, Klotho tissue homogenate level), immunohistochemistry (islet NF-κB, Nrf2 and Klotho protein expression) and immunofluorescence assays (islet insulin and glucagon expression). Results: The research findings demonstrate significant hypoglycemic effects of the studied GABA derivatives in aged rats with prolonged hyperglycemia. These GABA derivatives effects were accompanied with increased GLP-1 production and improved pancreatic β-cell function and mass. Furthermore, elevated levels of Klotho protein and Nrf2 transcription factor, along with the suppression of NF-κB transcription factor after treatment, may play a crucial role in the β-cellprotective effects of these GABA derivatives. Conclusion: Novel GABA derivatives exhibit significant pancreatic β-cell protective effects that may be mediated by enhanced GLP-1, Klotho protein, and Nrf2 transcription factor, and suppressed NF-κB transcription factor. These results highlight the potential of GABA derivatives as promising therapeutic agents for managing diabetes mellitus and its associated complications.

To discuss the expression of Klotho in placenta exosomes (Exo)of the patients with pre-eclampsia (PE)，and to clarify its effect on the oxidative stress in the vascular endothelial cells. Methods The clinical data of 40 pregnant women including 20 with normal pregnancy(NP) women (NP group) and 20 PE patients (PE group) were collected. The placenta Exo in peripheral blood of the patients in two groups were isolated， and the oe-Klotho and oe-NC plasmids were transfected into the human chorionic trophoblast cells(HTR-8/SVneo)， respectively， and were regarded as oe-Klotho group and oe-NC group.The expression levels of Klotho mRNA and protein in placenta Exo and the HTR8/SVneo cells in two groups were detected by real-time fluorescence quantitative PCR (RT-qPCR) method and Western blotting method. The human umbilical vein endothelial cells (HUVECs) with good growth status were taken and divided into PE-Exo group (co-cultured with placenta Exo from the patients with PE)，NP-Exo group (co-cultured with placenta Exo from the NP subjects)， oe-Klotho-Exo group (co-cultured with Exo from the HTR-8/SVneo cells transfected with oe-Klotho)， and oe-NC-Exo group (co-cultured with Exo from the HTR-8/SVneo cells transfected with oe-NC) according to the sources of Exo.The expression levels of exosomal marker proteins CD63， TSG101， and placenta Exo-specific marker PLAP protein were identified by transmission electron microscope (TEM) and Western blotting method； the levels of nitric oxide (NO)， reactive oxygen species (ROS)， and malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) in the HUVECs in various groups were detected by enzyme-linked immunosorbent assay (ELISA) method；the expression levels of endothelial nitric oxide synthase (eNOS) mRNA in the HUVECs in various groups was detected by RT-qPCR method；the expression levels of eNOS protein in the HUVECs in various groups were detected by Western blotting method. Results Compared with NP group， the systolic and diastolic blood pressures of the patients in PE group were increased (P<0.05)， the body weight of newborn and placenta weight were significantly decreased (P<0.05 or P<0.01). The TEM observation results showed that the placenta Exo derived from the subjects in both NP and PE groups being round or oval vesicular discoid structures with complete membrane and similar shape， with a diameter of 50—100 nm. The Exo from the subjects in both groups highly expressed Exo marker proteins CD63 and TSG101， and placental Exo-specific protein PLAP. The nanoparticle tracking analysis (NTA) results showed that the particle size of Exo was 50—200 nm， suggesting that the vesicles isolated from the peripheral blood were derived from placental Exo. The TEM， Western blotting， and NTA results confirmed that the vesicles from oe-NC group and oe-klotho group had typical Exo structures， molecular markers， and particle size characteristics. The Exo with green fluorescence expression could be observed in the HUVECs， suggesting that the placenta Exo could be taken up by the HUVECs. The ELISA results showed that compared with NP-Exo group， the level of NO and activity of SOD in PE-Exo group were significantly decreasd(P<0.05 or P<0.01)， and the levels of ROS and MDA were significantly increased(P<0.05 or P<0.01)； compared with oe-NC-Exo group， the level of NO and activity of SOD in the HUVECs in oe-Klotho-Exo group were increased (P<0.05)， and the levels of ROS and MDA were significantly decreased (P<0.05 or P<0.01). The RT-qPCR results showed that compared with NP group， the expression level of Klotho mRNA in placenta Exo of the patients in PE group was significantly decreased (P<0.01)，and the expression level of eNOS mRNA in the HUVECs was significantly decreased (P<0.01)； compared with oe-NC group， the expression level of Klotho mRNA in Exo in the trophoblast cells in oe-Klotho group was significantly increased (P<0.01)； compared with oe-NC-Exo group， the expression level of eNOS mRNA in the HUVECs in oe-Klotho-Exo group was significantly increased (P<0.01). The Western blotting results showed that compared with NP group， the expression level of Klotho protein in placenta Exo of the patients in PE group was significantly decreased (P<0.01)； compared with NP-Exo group， the expression level of eNOS protein in the HUVECs in PE-Exo group was significantly decreased (P<0.01)； compared with oe-NC group， the expression level of Klotho protein in Exo in the trophoblast cells in oe-Klotho group was significantly increased (P<0.01)； compared with oe-NC-Exo group， the expression level of eNOS protein in the HUVECs in oe-Klotho-Exo group was significantly increased (P<0.01). Conclusion The placenta Exo from the PE patients may inhibit the production of NO in the HUVECs and promote the oxidative stress to impair the endothelial cell function. The over-expression of Klotho in Exo in the trophoblast cells can reduce the production of NO and level of oxidative stress in the HUVECs. [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease (CKD) confront with cardiovascular disease (CVD) complications which can be ameliorated with exercise. The purpose of the current study was to determine the effect of resistance training on pathological cardiac hypertrophy and FGF23-Klotho axis-induced adverse cardiovascular outcomes in rat model of CKD. Thirty male Wistar rats (7–8 weeks old) were randomly divided into three groups of the 5/6 nephrectomy (5/6NX) with and without resistance training and control group. The resistance training protocol consisted of 3 sessions per week. The proposed blood factors (Klotho, FGF23, serum phosphorus, parathyroid hormone, serum calcium, and vitamin D) evaluated for three groups at the end of 8th week. After confirming the normal distribution of data through Kolmogorov–Smirnov test, data analysis was performed by one-way ANOVA and Bonferroni post hoc test (P > 0.05). The effect of resistance training was significantly different between 3 groups of study for hypertrophy (P = 0.036) and cardiac function (P = 0.004). There was also a significant difference for blood factors of Klotho (P = 0.000), FGF23 (P = 0.043), serum phosphorus (P = 0.00), and parathyroid (P = 0.00). Serum calcium (P = 0.06) and vitamin D status (P = 0.06) improved but the differences were not significant. Resistance training can prevent progression of pathological cardiac hypertrophy in patients with renal disease. In the process of this improvement, changes in FGF23 and Klotho were significant; however, the vitamin D and calcium have played a less important role. [ABSTRACT FROM AUTHOR]

Introduction: Gamma-aminobutyric acid (GABA) and GABAergic compounds emerged as potential therapeutic agents for diabetes mellitus and its complications. GABA acts as an inhibitory neurotransmitter in the central nervous system and as an extracellular signaling molecule in pancreatic islets, exerting beneficial effects on insulin secretion, glucagon production, apoptosis, beta-cell survival, and regeneration. Aim: This study aimed to compare the efficacy of GABA and GABAergic compounds as pancreatic β-cell protective agents in aged rats (18 months) with prolonged hyperglycemia induced by streptozotocinnicotinamide injection. Materials and Methods: Male outbred albino rats aged 12 months were intraperitoneally injected with streptozotocin (65 mg/kg) and nicotinamide (230 mg/kg). Over the next 6 months, the level of glycemia was monitored every 4 weeks. Further, rats with postprandial glycemia levels between 11 and 18 mmol/L were selected. The experimental groups were treated with GABA and GABAergic compounds (compositions 2 and 3) for 1 month, while the control group received saline. An oral glucose tolerance test (OGTT) was performed after treatment. Blood and samples of the pancreatic tissue (splenic part) were collected for enzyme-linked immunosorbent assay (GLP-1, TNF-α serum level and NF-κB, Nrf2, Klotho tissue homogenate level), immunohistochemistry (islet NF-κB, Nrf2 and Klotho protein expression) and immunofluorescence assays (islet insulin and glucagon expression). Results: The research findings demonstrate significant hypoglycemic effects of the studied GABA derivatives in aged rats with prolonged hyperglycemia. These GABA derivatives effects were accompanied with increased GLP-1 production and improved pancreatic β-cell function and mass. Furthermore, elevated levels of Klotho protein and Nrf2 transcription factor, along with the suppression of NF-κB transcription factor after treatment, may play a crucial role in the β-cell protective effects of these GABA derivatives. Conclusion: Novel GABA derivatives exhibit significant pancreatic β-cell protective effects that may be mediated by enhanced GLP-1, Klotho protein, and Nrf2 transcription factor, and suppressed NF-κB transcription factor. These results highlight the potential of GABA derivatives as promising therapeutic agents for managing diabetes mellitus and its associated complications. [ABSTRACT FROM AUTHOR]

Copyright of Practical Pharmacy & Clinical Remedies is the property of Editorial Department of Practical Pharmacy & Clinical Remedies and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract A lack of angiogenesis is the key problem in the healing of diabetic foot ulcers. Stem cells have already been proven to have a high potential for angiogenesis. The most important aspects of stem cell therapy are improving the microenvironment, cell homing and continuous factor stimulation. We investigated the effect of Klotho protein to heal wounds by promoting the proliferation and migration of bone mesenchymal stem cells and endothelial cells in vitro. Based on the above study, we produced a compound material by using poly(lactic‐co‐glycolic acid) (PLGA), chitosan microspheres and gelatin through electro spining technology. The structure of the compound material, just like a sandwich, is that two pieces of PLGA nanofiber films clamped gelatin film which contained chitosan microspheres. In the in vitro release experiment, we could detect the release of Klotho after seven days in the compound material, but the release time was approximately 40 hours for the chitosan microspheres. After seeded bone mesenchymal stem cells (BMSCs) on the surface of the compound material, we observed morphologies of the chitosan microsphere, the PLGA nanofiber and BMSCs by scanning electron microscopy. The nanofiber mesh biological tissue materials could supply an appropriate microenvironment and cell factors for the survival of BMSCs. Compared with the control group, the biological tissue material seeded with BMSCs significantly promoted angiogenesis in the lower limb of diabetic C57BL/6J mice and accelerated diabetic foot wound healing. The compound biomaterial which could continuously stimulate BMSCs through releasing Klotho protein could accelerate wound healing in the diabetic foot and other ischemic ulcers.

Objective: To investigate the relationship between serum Klotho protein, visinin-like protein 1 (VILIP-1), high mobility group box 1 protein (HMGB1) and cognitive function and prognosis in patients with Alzheimer's disease (AD). Methods: 136 patients with AD who received treatment in our hospital from April 2019 to May 2021 were selected as the AD group, and another 150 healthy volunteers who underwent physical examination in our hospital during the same period were selected as the control group. The expression levels of serum Klotho protein, VILIP-1 and HMGB1 in the two groups were detected by enzyme-linked immunosorbent assay. The cognitive function in the two groups was assessed by the Mini-Mental State Examination Scale (MMSE), and the relationship between the above three indicators and MMSE score was analyzed by Pearson correlation. The patients with AD were divided into good prognosis group (n=74) and poor prognosis group (n=62) according to the prognosis at 1 year after treatment. Univariate and multivariate Logistic regression were used to analyze the risk factors of poor prognosis in patients with AD. Receiver operating characteristic (ROC) curve was used to evaluate the predictive efficacy of combined detection of serum Klotho protein, VILIP-1 and HMGB1 in patients with AD. Results: MMSE score and serum Klotho protein level in the AD group were significantly lower than those in the control group, while serum VILIP-1 and HMGB1 levels were significantly higher than those in the control group (all P<0.05). Pearson correlation results showed that serum Klotho protein level was significantly positively correlated with MMSE score (P<0.05), while serum VILIP-1 and HMGB1 levels were significantly negatively correlated with MMSE score (all p<0.05). Multivariate Logistic regression analysis showed that increased serum VILIP-1 and HMGB1 levels were independent risk factors for poor prognosis in patients with AD, while increased serum Klotho protein level was a protective factor (P<0.05). ROC curve showed that the area under the curve of Klotho protein, VILIP-1 and HMGB1 in the combined detection of patients with AD was 0.839, the sensitivity was 80.65%, and the specificity was 83.78%. Conclusion: The serum Klotho protein, VILIP-1 and HMGB1 expression levels are strongly correlated with the cognitive function and prognosis of patients with AD, and the above three indicators can be used to assist the prognosis assessment of patients with AD. [ABSTRACT FROM AUTHOR]

Objective To investigate the role of Klotho protein in acute renal injury and fibrosis induced by ischemiareperfusion (I/R) in rats. Methods Sixty healthy SD rats were randomly divided into the sham operation group (sham group), the renal ischemia-reperfusion group (I/R group) and the Klotho protein intervention group (I/R+Kl group), with 20 rats in each group. In the I/R group, the acute renal injury model of I/R was established by clamping the right renal pedicle for 40 min. In the sham group, the right renal artery was dissociated, but the right renal pedicle was not clamped. After exposure for 40 minutes, the abdominal cavity was sutured. The operation method of the I/R+Kl group was the same as that of the I/R group. Kiotho protein (0.01 mg/kg) was injected intraperitoneally. The blood and renal tissue samples were collected on the 1st, 7th, 14th and 28th days after successful modeling in the three groups, and blood creatinine (Scr) and blood urea nitrogen (BUN) were measured respectively. HE staining was used to observe the damage of renal tissue. Masson staining was used to observe the renal fibrosis. ELISA was used to detect levels of Klotho protein in blood and renal tissue. Western blot assay was used to detect the expression of Klotho protein in renal tissue. Results Compared with the sham group, levels of SCR and BUN were increased in the I/R group and the I/R+Kl group (P＜0.05). Compared with the I/R+Kl group, serum levels of SCR and BUN were increased in different time points in the I/R group (P＜0.05). HE staining showed extensive acute necrosis of renal tubules in the I/R group, and the injury was mild in the I/R+Kl group. Masson staining showed that mild fibrosis occurred in the I/R group on the 14th day, and the degree of fibrosis was more significant on the 28th day, while the degree of fibrosis was very mild in the I/R+Kl group (P < 0.05). ELISA results showed that compared with the Sham group at day 1, 14 and 28, levels of Klotho in blood and renal tissue decreased significantly in the I/R+Kl group and the I/R group, and the level of Klotho decreased in the I/R group than that of the I/R+Kl group (P＜0.05). Western blot results showed that compared with the Sham group, Klotho levels were decreased at all time points in the I/R group and the I/R+Kl group. while Klotho levels were higher in the I/R+Kl group than those in the I/R group (P＜0.05). Conclusion Klotho expression is down-regulated during renal I/R injury. Exogenous supplementation of Klotho protein can alleviate acute renal injury and fibrosis in rats with renal I/R injury and play a role in renal protection. [ABSTRACT FROM AUTHOR]

Background The serum soluble α-Klotho protein level may be associated with a lower risk and progression of multiple nervous system diseases. However, there are few reports concerning its dynamic changes and prognostic value in patients with craniocerebral injury. Objective To assess the dynamic changes of serum soluble α-Klotho protein level and associated prognostic value in patients with serious craniocerebral injury. Methods Participants were recruited from Shanxi Bethune Hospital from July 2019 to September 2020, including 103 cases of severe craniocerebral injury with surgical treatment and postoperative monitoring from the ICU (case group, including 74 survived and 29 decreased as of the 28th day posterior to admission) , and 50 physical examinees (healthy controls) . Clinical data of case group were collected. ELISA was used to measure the serum soluble α-Klotho protein level for all participants on the 1st, 3rd, 5th, and 7th days posterior to study enrollment. Results The mean levels of serum soluble α-Klotho protein measured at the four time points in case group were all higher than those of control group (P

Background: Anti-neutrophil cytoplasmic antibody-associated small-vessel vasculitis (AASV) is an autoimmune disease with unclear pathogenesis, which causes damage to multiple organs and systems, renal failure or even death. We aimed to explore the expression of serum soluble Klotho protein in patients with AASV-induced renal damage and influence on prognosis.

Сhronic kidney Disease (CKD) is the cause of both morbidity and mortality worldwide. In Ukraine, 12 % of the population is diagnosed with CKD. Significantly worsen the quality of life in patients with CKD progression of renal fibrosis and impaired mineral homeostasis. Early diagnosis and treatment are the main measures to prevent CKD progression and delay adverse effects. Deficiency of early, non-invasive biomarkers adversely affects the ability to rapidly detect and treat CKD. Proximal tubular lesions play an important role in the progression of CKD. There are new markers of kidney damage, such as uromodulin (UMOD), Klotho protein and post-translational modifications of fetuin A (FtA). Treatment of CKD in the early stages may improve renal function and/or slow the progression of CKD.

Cirrhosis is associated with increased risk for osteoporosis and osteopenia. This study aims to further investigate this relationship by examining if etiology and severity of cirrhosis are independent predictors of bone mineral density (BMD) loss. Furthermore we examined the serum levels of osteoprotegerin (OPG) and Klotho proteins that have been involved in bone metabolism. Seventy-four patients with cirrhosis of different etiology and 25 matched healthy controls were included in this study. Bone mineral densitometry at both lumbar spine and femoral neck was measured. Serum total OPG, Klotho protein and vitamin D levels were also determined. Comparisons were performed according to etiology and severity of cirrhosis. Decreased bone density was observed in cirrhotic patients compared to healthy controls with T = −1.46 and T = −1.37 in lumbar spine and femoral bone respectively compared to T = −0.396 and T = −0.672 in the control group. In the cirrhotic group, osteopenia was observed in 46% in lumbar spine and 51% in femoral bone whereas osteoporosis was observed in 20% in lumbar spine and 9% in femoral bone. Decreased bone density was confirmed, regardless of cirrhosis etiology or stage of liver function. Patients were found to have higher levels of OPG than the control group (136 pg/ml vs. 67 pg/ml, p < 0.001), but lower levels of Klotho protein (1051 pg/ml vs. 1842 pg/ml, p < 0.001) regardless etiology and severity of cirrhosis. High OPG levels were found to be associated with low femoral bone density. BMD is lower in cirrhotic patients regardless etiology and severity of liver disease with osteopenia and osteoporosis be present in 50% and 20%, respectively. Higher levels of OPG and lower levels of Klotho protein were observed in cirrhotic patients regardless etiology and severity in comparison to matched healthy group. [ABSTRACT FROM AUTHOR]

Purpose: Oxidative damage is important in calcium oxalate (CaOx) stone development but occurs via multiple pathways. Studies have shown that klotho plays an essential role in ameliorating oxidative damage. This study aims to explore the role of klotho in CaOx stones and whether the underlying mechanism is related to the regulation of Keap1-Nrf2-ARE signaling.Methods. Methods: The levels of GSH, SOD, CAT, MDA, and ROS were examined by ELISA. The klotho, Bcl-2, caspase-3, Keap1, Nrf2, HO-1, and NQO1 mRNA levels were measured by qRT‒PCR, and their protein levels were detected by Western blotting. Renal tissue apoptosis was examined by TUNEL staining, and crystal cell adherence and apoptosis in HKC cells were assessed based on the Ca2+ concentrations and by flow cytometry. The renal pathological changes and the adhesion of CaOx crystals in the kidneys were examined by hematoxylin–eosin and von Kossa staining, respectively.Results. Results: We constructed a CaOx kidney stone model in vitro. By regulating the klotho gene, klotho overexpression inhibited the CaOx‐induced promotion of crystal cell adherence and apoptosis in HKC cells, and these effects were reversed by klotho knockdown. Moreover, our in vivo assay demonstrated that klotho overexpression alleviated glyoxylate administration-induced renal oxidative damage, renal apoptosis, and crystal deposition in the kidneys of mice, and these effects were also associated with activation of the Keap1-Nrf2-ARE pathway.Conclusion. Conclusion: Klotho protein inhibits the oxidative stress response of HKC cells through the Keap1-Nrf2-ARE signaling pathway, reduces the apoptosis of and adhesion of CaOx crystals to HKC cells, and decreases the occurrence of CaOx kidney stones. Clinical trial registration: 20220304. [ABSTRACT FROM AUTHOR]

Ischaemia, followed by reperfusion, causes the generation of reactive oxygen species, overproduction of peroxynitrite, activation of matrix metalloproteinases (MMPs), and subsequently the degradation of heart contractile proteins in the cardiomyocytes. Klotho is a membrane-bound or soluble protein that regulates mineral metabolism and has antioxidative activity. This study aimed to examine the influence of Klotho protein on the MMP-mediated degradation of contractile proteins during ischaemia/reperfusion injury (IRI) to the cardiomyocytes. Human cardiac myocytes (HCM) underwent in vitro chemical IRI (with sodium cyanide and deoxyglucose), with or without the administration of recombinant Klotho protein. The expression of MMP genes, the expression and activity of MMP proteins, as well as the level of contractile proteins such as myosin light chain 1 (MLC1) and troponin I (TnI) in HCM were measured. Administration of Klotho protein resulted in a decreased activity of MMP-2 and reduced the release of MLC1 and TnI that followed in cells subjected to IRI. Thus, Klotho protein contributes to the inhibition of MMP-dependent degradation of contractile proteins and prevents injury to the cardiomyocytes during IRI. [ABSTRACT FROM AUTHOR]

A lack of angiogenesis is the key problem in the healing of diabetic foot ulcers. Stem cells have already been proven to have a high potential for angiogenesis. The most important aspects of stem cell therapy are improving the microenvironment, cell homing and continuous factor stimulation. We investigated the effect of Klotho protein to heal wounds by promoting the proliferation and migration of bone mesenchymal stem cells and endothelial cells in vitro. Based on the above study, we produced a compound material by using poly(lactic‐co‐glycolic acid) (PLGA), chitosan microspheres and gelatin through electro spining technology. The structure of the compound material, just like a sandwich, is that two pieces of PLGA nanofiber films clamped gelatin film which contained chitosan microspheres. In the in vitro release experiment, we could detect the release of Klotho after seven days in the compound material, but the release time was approximately 40 hours for the chitosan microspheres. After seeded bone mesenchymal stem cells (BMSCs) on the surface of the compound material, we observed morphologies of the chitosan microsphere, the PLGA nanofiber and BMSCs by scanning electron microscopy. The nanofiber mesh biological tissue materials could supply an appropriate microenvironment and cell factors for the survival of BMSCs. Compared with the control group, the biological tissue material seeded with BMSCs significantly promoted angiogenesis in the lower limb of diabetic C57BL/6J mice and accelerated diabetic foot wound healing. The compound biomaterial which could continuously stimulate BMSCs through releasing Klotho protein could accelerate wound healing in the diabetic foot and other ischemic ulcers. [ABSTRACT FROM AUTHOR]

Dongdong Huang,1 Saibin Wang2 1Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, Zhejiang, People’s Republic of China; 2Department of Respiratory Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua Municipal Central Hospital, Jinhua, 321000, Zhejiang, People’s Republic of ChinaCorrespondence: Saibin WangDepartment of Respiratory Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua Municipal Central Hospital, Jinhua, 321000, Zhejiang Province, People’s Republic of ChinaTel +86 579 82552278Fax +86 579 82325006Email saibinwang@hotmail.comPurpose: Sleep duration is associated with aging. However, the relationship between sleep duration and the concentration of the protein klotho in the serum remains unknown in the general population of the United States. Hence, this study aimed at exploring the association between them.Methods: Participants whose data included klotho protein and sleep duration variables in the National Health and Nutrition Examination Survey data from 2007 to 2016 were utilized for this analysis.Results: Sleep duration was non-linearly associated with the level of klotho protein in the serum, with a negative association between sleep duration and serum klotho concentration after adjusting for confounding variables (β = − 7.6; 95% CI: − 11.3, − 4.0; P < 0.001). The conversion of the sleep duration from a continuous variable to a categorical variable (tertile: T1: < 5.5 hours; T2: 5.5– 7.5 hours; T3: > 7.5 hours) revealed that the serum klotho of the participants in the highest tertile (> 7.5 hours) was 21.9 pg/mL lower (95% CI: − 38.6, − 5.2; P = 0.01) than those in the lowest tertile (< 5.5 hours).Conclusion: Our results revealed that people who sleep more than 7.5 hours per night have decreased levels of the anti-aging protein klotho in their serum, thus being more at risk of aging-related syndromes.Keywords: klotho protein, sleep duration, aging, NHANES

Klotho, an anti-aging protein, plays a vital role in diverse biological functions, such as regulating calcium and vitamin D levels, preventing chronic fibrosis, acting as an antioxidant and anti-inflammatory agent, safeguarding against cardiovascular and neurodegenerative conditions, as well as exerting anti-apoptotic, anti-senescence effects. Additionally, it contributes to metabolic processes associated with diabetes and exhibits anti-cancer properties. This protein is commonly expressed in organs, such as kidneys, brain, pancreas, parathyroid glands, ovaries, and testes. Recent research has highlighted its significance in human fertility. This narrative review provides insight into the involvement of Klotho protein in male and female fertility, as well as its potential role in managing human infertility in the future. In this study, a search was conducted on literature spanning from November 1997 to June 2024 across multiple databases, including PUBMED, SCOPUS, and Google Scholar, focusing on Klotho proteins. The search utilized keywords, such as "discovery of Klotho proteins," "Biological functions of Klotho," "Klotho in female fertility," "Klotho and PCOS," "Klotho and cryopreservation," and "Klotho in male infertility." Inclusion criteria comprised full-length original or review articles, as well as abstracts, discussing the role of Klotho protein in human fertility, published in English in various peer-reviewed journals. Exclusion criteria involved articles published in languages other than English. Hence, due to its anti-aging characteristics, Klotho protein presents potential roles in male and female fertility and holds promising prospects for reproductive medicine. Further, it holds the potential to become a valuable asset in addressing infertility concerns for both males and females., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction. The clinical course and outcome in patients with comorbid pathology has a number of features that require further investigation. The investigation of biomarkers is important in this area as any change in their levels reflects the severity of pathogenetic changes and has prognostic value. Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) are one of the most frequently reported comorbid pathologies. This is due to a large number of common interrelated links of pathogenesis and risk factors.The aim of the study. To study and analyze, in a comparative aspect, the level of Klotho protein in patients with MI and patients with MI and COPD, in relation to the number of stenosis of coronary arteries (CA) according to coronary angiography.Materials and methods. 110 patients were examined, divided into two groups: the main group - patients with MI on the background of COPD (n = 60) and the comparison group – patients with MI (n = 50). Somatically healthy individuals (n = 30) were examined as a control group. Determination of Klotho protein level in plasma samples was carried out by enzyme-linked immunosorbent assayResults. It was found that in patients with MI and COPD, the level of Klotho protein was statistically significantly lower than in the control group and in patients with MI. The relationship between the Klotho protein level and lipid profile parameters was revealed in both patients with MI and patients with MI and COPD, with a greater strength of relationships in patients with comorbid pathology. It was also found that in the group of patients with comorbid pathology in individuals with lesions of one, two, three or more CA, the Klotho level was statistically significantly lower than in patients with MI with the corresponding number of affected CA.Conclusions. The results obtained prove the promise and the need for further study of the pathogenetic role of the Klotho protein level in patients with comorbid pathology.

Objective: To investigate the value of serum uromodulin (UMOD), heparin-binding protein (HBP), Klotho protein combined with Acute physiology and chronic health evaluation system Ⅱ (APACHE Ⅱ) score in predicting the 28-day prognosis in patients with sepsis complicated with acute kidney injury (AKI) . Methods: 120 patients with sepsis complicated with AKI who were diagnosed and treated in our hospital from January 2018 to January 2020 were selected as the research object. According to the survival within 28 days, they were divided into survival group (86 cases) and death group (34 cases) . Enzyme linked immunosorbent assay was used to detect the expression levels of serum UMOD, HBP and Klotho proteins in each group. The expression of serum UMOD, HBP, Klotho protein and APACHE Ⅱ score difference in patients with AKI at different stages were compared. Multivariate Logistic regression analysis was used to analyze the risk factors affecting the 28 day prognosis of patients with sepsis complicated with AKI. The receiver operating characteristic (ROC) curve was used to analyze the value of serum UMOD, HBP, Klotho protein and APACHE Ⅱ score alone and in combination in predicting the 28 day prognosis of patients with sepsis complicated with AKI. Results: Compared with the survival group, the serum UMOD and Klotho in the death group were lower, and the procalcitonin (PCT), high-sensitivity C-reactive protein (hs-CRP), HBP and APACHE Ⅱ scores were higher (all P<0.05) . There were significant differences in the serum UMOD, HBP, Klotho and APACHE Ⅱ scores in patients with different AKI stages (all P<0.05) . Multivariate Logistic regression analysis showed that UMOD <62.43 mg/mL and HBP > 30.14 μg/L, Klotho ≤ 180.37 ng/L and APACHE Ⅱ score > 16.00 scores were the risk factors affecting the prognosis of 28 day death. The area under the curve of the combined prediction of serum UMOD, HBP, Klotho and APACHE Ⅱ score for 28 day death in patients with sepsis complicated with AKI was 0.897 (0.842 ～ 0.939), which was significantly higher than that of the single detection of serum UMOD [0.724 (0.674 ～ 0.765) ], HBP [0.666 (0.622 ～ 0.710) ], Klotho [0.767 (0.731 ～ 0.804) ] and APACHE Ⅱscore [0.840 (0.802 ～ 0.878) ]. Conclusions: Serum UMOD and Klotho decrease, HBP level increases and APACHE Ⅱ score is higher in patients with sepsis complicated with AKI, which are related to the severity of sepsis complicated with AKI. The combination of the four can help to predict 28 days death of sepsis complicated with AKI. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The aim of the work is to study the Klotho protein concentration in the oral fluid of patients exposed to work-related harmful factors and to reveal correlations with the content of bone tissue and vitamin D metabolism markers. Materials and methods. The study group consisted of 126 patients with generalized periodontitis of initial (n = 8), I (n = 32), II (n = 68) and III (n = 18) degree of severity, chronic course, working in hazardous conditions of the “Dniprospetsstal” plant in Zaporizhzhia. The comparison group consisted of 32 periodontitis patients of initial (n = 5), I (n = 10), II (n = 11) and III (n = 6) degree of severity without exposure to work-related harmful factors. The control group included 20 otherwise healthy individuals aged 19–25 years without signs of periodontal diseases. The levels of vitamin D, VDBP, MMP-8 and osteocalcin were determined by enzyme-linked immunosorbent assays, the concentration of soluble Klotho was detected by the enzyme-linked ImmunoChem-2100 immunosorbent assay. Results. It was found, that in the study group of patients working in hazardous work-related conditions, the decrease in oral fluid Klotho protein concentration was greater, than in the comparison group of patients with periodontal diseases, but not exposed to work-related hazardous conditions. The indicator of Klotho protein is an early marker of the periodontal disease progression and varies inversely with the severity of periodontitis, starting in the early stages of the disease. The correlation coefficient between the level of Klotho protein and the degree of the disease severity in the comparison group patients was γ = -0.957, P < 0.05 and γ = -0.906, P < 0.05 – in the study group. In the patients with periodontal diseases, there was a decrease in the Klotho protein concentration with a parallel increase in the marker of bone tissue destruction - MMP-8, and a decrease in the marker of remodeling – osteocalcin, as compared to the controls. The decrease in Klotho protein concentration occurred with vitamin D deficiency and worsened with the vitamin D-binding protein reduction. Conclusions. The Klotho protein is the early, sensitive and specific diagnostic biomarker in dental diseases, and its measurement can be used as a predictor of inflammatory periodontal disease and its complications. The Klotho protein is one of the main regulators of bone metabolic processes.

Background and Aims: Klotho protein is a substance effective in increasing life expectancy. Moreover, it prevents muscle atrophy, osteoporosis, and cardiovascular disease. Therefore, the present aimed to assess changes in the expression of klotho protein and insulin-like growth factor 1 (IGF-1) genes in the muscles of aged Wistar rats after eight weeks of resistance training. Materials and Methods: The present experimental study was connected on 16 Wistar male rats, aged 20 months, which were assigned to two groups of resistance training group and control. Resistance training was performed three sessions a week over eight weeks. After dissecting the rats, the soleus and flexor hallucis longus muscles of the rats were extracted to measure the expression of klotho protein and (IGF-1) genes using the real-time polymerase chain reaction technique. Results: After the resistance training program, Klotho protein in the fast-twitch muscle tissue of the trained rats did not show a significant difference, compared to that in the control group. Furthermore, IGF-1 in the fast-twitch and slow-twitch muscles of the training group did not display a marked difference, compared to that in the control group. Conclusion: As evidenced by the obtained results, the values of klotho protein and IGF-1 did not improve after a period of resistance training. It can be argued that resistance training should be conducted in longer periods and with different intensities, which should be scrutinized in future research.

Low levels of the Klotho protein are associated with accelerated tissue aging, including arterial stiffness, in patients with cardiovascular and renal diseases. However, this association has not been examined in a diverse cohort. We aimed to investigate the association between serum Klotho protein levels and pulse pressure, as an indicator of arterial stiffness, in a cohort representative of the US population. We used the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016. Association between pulse pressure and Klotho levels as a continuous variable and in quartiles were examined using survey weight-adjusted linear regression models. Multivariable models were adjusted for age, gender, race, BMI, hypertension, diabetes, smoking, alcohol use, total cholesterol, and estimated GFR. Of the 13,362 participants, 3954(29.6%) were > 65 years, 5792(43%) were Caucasian, and 6773(50.7%) had hypertension. Mean(SD) Klotho was 0.85(0.31) ng/mL and pulse pressure was 55.8(18.5) mmHg. In unadjusted and adjusted models, each ng/mL increase in Klotho was associated with a 3.88 mmHg (95%CI = −5.19,−2.57; P < 0.001) and 1.63 mmHg (95%CI = −3.01,−0.24; P = 0.02) decrease in pulse pressure, respectively. Similarly, participants in the highest quartile of Klotho had lower pulse pressure than those in the lowest quartile (−3.05 mmHg; 95%CI = −4.05,−2.05; P < 0.001), and this difference remained significant in adjusted models (−1.10 mmHg; 95%CI = −2.20,−0.01; P = 0.05). In this large diverse cohort, we found an inverse and independent association between serum Klotho levels and pulse pressure suggesting that Klotho is associated with arterial stiffness. The mechanisms underlying this association need further study. • Low levels of serum Klotho protein are associated with accelerated aging of several tissues. • We examined the association between the serum soluble Klotho protein levels and pulse pressure. • An inverse relationship between soluble serum Klotho levels and pulse pressure was observed independent of confounders. [ABSTRACT FROM AUTHOR]

Сhronic kidney Disease (CKD) is the cause of both morbidity and mortality worldwide. In Ukraine, 12 % of the population is diagnosed with CKD. Significantly worsen the quality of life in patients with CKD progression of renal fibrosis and impaired mineral homeostasis. Early diagnosis and treatment are the main measures to prevent CKD progression and delay adverse effects. Deficiency of early, non-invasive biomarkers adversely affects the ability to rapidly detect and treat CKD. Proximal tubular lesions play an important role in the progression of CKD. There are new markers of kidney damage, such as uromodulin (UMOD), Klotho protein and post-translational modifications of fetuin A (FtA). Treatment of CKD in the early stages may improve renal function and/or slow the progression of CKD. [ABSTRACT FROM AUTHOR]

ObjectiveUsing a newly released National Health and Nutrition Examination Survey (NHANES) data of serum Klotho, this study aimed to explore the relationship between Klotho and specific cardiovascular diseases (CVD), as well as the mediation effect of renal function, among middle-aged and older individuals within the general population.MethodsThis nationally representative cross-sectional study analyzed data from the 2007–2016 NHANES. A total of 13,765 participants, who aged 40 years or older, from the general population were examined. Klotho were divided into four groups based on median and interquartile range. The associations among Klotho (exposure), congestive heart failure (CHF; outcome), and renal function markers [estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), uric acid (UA), and urine albumin-to-creatinine ratio (UACR); mediators] were investigated using mediation analysis.ResultsIn comparison to the lowest quartile, Klotho in the highest quartile was independently associated with the prevalence of CHF (OR 0.59; 95% CI 0.46–0.77, p for trend = 0.001), but not with other individual CVDs. Klotho had a significant direct effect on the prevalence of CHF (all p < 0.001), while eGFR, BUN, UA, and UACR partly mediated the indirect effect of Klotho on the prevalence of CHF (all p < 0.05), explaining 19.51, 6.98, 13.93, and 0.71% of the association between Klotho and CHF, respectively. Additionally, restricted cubic spline regression demonstrated a linear association and negative correlation between Klotho level and CHF.ConclusionThese findings suggest that Klotho is closely linked to CHF and renal function may be a key mediator of this association.

This study evaluated the mechanistic sequel of aldehyde dehyrogenase (ALDH2) and Klotho protein in cyclophosphamide (CP)‐induced cardiotoxicity in rats and the protective effect of astaxanthin (AST) against that sequel. A total of 40 male Wistar albino rats were divided into four groups of 10 animals each: Group 1 was injected intraperitoneally (i.p.) with normal saline for 10 successive days. Group 2 was injected with normal saline for 5 days before and after a single dose of CP (200 mg/kg, i.p.). Group 3 received AST (50 mg/kg/day, i.p.) for 10 days. Group 4 received CP as group 2 and AST as group 3. After the last dose of the treatment protocol, serum was separated to measure cardiotoxicity indices and the left ventricle was then dissected for mRNA and protein expression studies and histopathological examinations. Treatment with CP significantly increased serum lactate dehydrogenase (LDH), creatine kinase isoenzyme MB (CK‐MB), and troponin, while significantly decreased soluble α Klotho protein and caused histopathological lesions in cardiac tissues. In cardiac tissues, CP significantly decreased gene expression of ALDH2, Klotho protein, mTOR, IGF, AKT, AMPK, BCL2, but significantly increased expression of BAX and caspase‐8. Interestingly, administration of AST in combination with CP completely reversed all the biochemical, histopathological and gene expression changes induced by CP to the control values. The current study suggests that inhibition of ALDH2, Klotho protein, mTOR, and AMPK signals in cardiac tissues may contribute to CP‐induced acute cardiomyopathy. AST supplementation attenuates CP‐induced cardiotoxicity by modulating ALDH2 and Klotho protein expression in heart tissues, along with its downstream apoptosis effector markers. [ABSTRACT FROM AUTHOR]

Purpose of the study was to determine the quantitative content of Klotho protein in the blood of men with coronary heart disease in comparison with the control group and its association with the blood lipid profile. Material and methods. The study included 178 men, including 115 people aged 50-65 years (I age group) and 63 people over 80 years (II age group). The main group included 98 men with coronary heart disease, the average age was 61.1±11.4 years, the control group consisted of 80 men without coronary heart disease, and the average age was 68.1 ± 14.4 years. Klotho protein serum concentration was measured by ELISA. Results. Klotho’s protein level tends to decrease in people with coronary heart disease, its lower level is associated with an increased relative risk of coronary heart disease. In men with coronary heart disease, Kloto protein tends to increase with age, and men without coronary heart disease, on the contrary, decrease. In patients with coronary heart disease, an increase in Klotho protein in the blood is associated with an increase in the level of HDL-C and a decrease in the atherogenic coefficient. Conclusion. Thus, it can be assumed that Klotho protein in men with coronary heart disease exhibits anti-atherogenic properties.

Objective To investigate the association of serum klotho level with renal function deterioration and whether serum klotho level can be used as a predictor of progression of chronic kidney disease (CKD) into renal end point events. Methods We examined serum klotho protein level using ELISA in 261 patients with primary chronic kidney disease stages 3~5 hospitalized in our department between March and November 2015. Kaplan-Meier survival analysis was used to compare the survival time of the patients with low (< 469.26 pg/mL), medium (469.26-844.55 pg/mL) and high (≥844.55 pg/mL) levels of klotho; Cox regression analysis was performed to assess the risk factors associated with the outcomes of the patients. Results During a mean follow-up for 42.7 months, 190 (72.80%) out of the 261 patients with CKD developed renal end point events. Serum klotho level showed a significant positive correlation with estimated glomerular filtration rate (eGFR) of the patients (r=0.567, P < 0.001). The patients with different serum klotho levels had significant differences in serum levels of calcium, phosphorus, parathyroid hormone (PTH) and hemoglobin (P < 0.001). Kaplan-Meier survival analysis showed that a low serum level of klotho was associated with a shorter time for CKD to progress into renal end point events. Cox regression analysis revealed that compared with the patients with a high level of klotho, the patients with low and medium serum levels of klotho had significantly increased risks for developing renal end point events by 3.3 and 1.1 folds, respectively; after adjustment for multiple factors, the risk for renal end point events was still high in low klotho level group (2.401 times that in high klotho level group). Conclusion We confirm that serum klotho level is closely related to the occurrence of renal end point events in CKD patients, and serum klotho level is a predictor of the renal function progression in CKD patients.

Background: Early diagnosis of acute kidney injury (AKI) after cardiac surgery is based on serum creatinine which is neither a specific nor a sensitive biomarker. In our study, we investigated the role of serum Klotho in early prediction of AKI after cardiac surgery using cardiopulmonary bypass (CPB). Methods: The included patients were classified into three groups according to AKI stages using KDIGO criteria. The measurements of creatinine and Klotho levels in serum were performed before surgery, at the end of CPB, 2 hours after the end of CPB, 24 hours and 48 hours postoperatively. Results: Seventy-eight patients were included in the study. A significant increase of creatinine levels (p

Ischaemia, followed by reperfusion, causes the generation of reactive oxygen species, overproduction of peroxynitrite, activation of matrix metalloproteinases (MMPs), and subsequently the degradation of heart contractile proteins in the cardiomyocytes. Klotho is a membrane-bound or soluble protein that regulates mineral metabolism and has antioxidative activity. This study aimed to examine the influence of Klotho protein on the MMP-mediated degradation of contractile proteins during ischaemia/reperfusion injury (IRI) to the cardiomyocytes. Human cardiac myocytes (HCM) underwent in vitro chemical IRI (with sodium cyanide and deoxyglucose), with or without the administration of recombinant Klotho protein. The expression of MMP genes, the expression and activity of MMP proteins, as well as the level of contractile proteins such as myosin light chain 1 (MLC1) and troponin I (TnI) in HCM were measured. Administration of Klotho protein resulted in a decreased activity of MMP-2 and reduced the release of MLC1 and TnI that followed in cells subjected to IRI. Thus, Klotho protein contributes to the inhibition of MMP-dependent degradation of contractile proteins and prevents injury to the cardiomyocytes during IRI.

Objective: To explore the correlation between serum Klotho protein, fibroblast growth factor-23 (FGF-23), retinol binding protein 4 (RBP4), tumor necrosis factor like weak apoptosis inducing factor (TWEAK) levels and renal function in patients with chronic kidney disease at different stages(CKD). Methods: 80 cases of patients with CKD who were diagnosed and treated in our hospital from February 2018 to February 2020 were selected as the CKD group, and 80 healthy patients who underwent physical examination in our hospital during the same period were selected as the control group. Serum levels of Klotho protein, FGF-23, RBP4, TWEAK and the renal function indexes in the control group, CKD group and patients with different CKD stages were measured and compared, the correlation between serum levels of Klotho protein, FGF-23, RBP4, TWEAK and renal function indexes were analyzed by Pearson correlation. Results: Compared with the control group, the serum levels of Klotho protein, TWEAK and glomerular filtration rate (GFR) were significantly reduced in the CKD group, while the levels of serum FGF-23, RBP4, serum creatinine, 24 urine protein and serum urea nitrogen were significantly increased (P<0.05). Serum levels of Klotho protein, TWEAK and glomerular filtration rate in the Ⅰ~Ⅱ stage patients was highest, followed by Ⅲ ~ Ⅳ period patients, Ⅴ period in patients were the lowest (P<0.05). And the Serum level of FGF-23, RBP4 24 urinary protein, serum creatinine, serum urea nitrogen in the stage Ⅰ~Ⅱ patients were the lowest, followed by Ⅲ ~ Ⅳ period patients, patients with Ⅴ period were the highest(P<0.05). The levels of serum Klotho protein and TWEAK were negatively correlated with the levels of serum creatinine, 24 urine protein quantification and serum urea nitrogen, and positively correlated with glomerular filtration rate (P<0.05). The levels of FGF-23 and RBP4 were positively correlated with the levels of serum creatinine, 24 urine protein quantification and serum urea nitrogen, and negatively correlated with glomerular filtration rate (P<0.05). Conclusion: In CKD patients, the levels of serum Klotho protein, TWEAK and renal function decreased, the levels of FGF-23 and RBP4 increased significantly, and the levels of serum Klotho protein, TWEAK, FGF-23 and RBP4 are related to the renal function and the CKD stage. [ABSTRACT FROM AUTHOR]

Recently, the Klotho protein (Klotho) has received substantial attention as protective factor against cardiovascular complications of chronic kidney disease (CKD). However, the direct effect and mechanism of Klotho on endothelial cells injury are not well‐known. In this study, we incubated human vein umbilical endothelial cells (HUVECs) with uremic toxin indoxyl sulfate (IS) to mimic CKD internal environment and investigated the direct effect of Klotho on the HUVECs injury induced by IS and to explore the mechanism in this process. We found IS inhibited cell viability, increased endoplasmic reticulum stress, and mediated apoptosis of HUVECs. Treatment with Klotho significantly attenuated IS‐induced above effects. Furthermore, Klotho alleviated the IS toxic effect on HUVECs via promoting AMP‐activated protein kinase (AMPK) α1 phosphorylation instead of directly upregulating AMPKα1, which could be partly blocked by AMPK pathway inhibitor‐Compound C. In addition, Klotho also inhibited intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1) expression induced by IS. Altogether, these results indicated that Klotho can protect HUVECs from IS‐induced injury by alleviating AMPKα1‐mediated endoplasmic reticulum stress. Indoxyl sulfate (IS) injured human vein umbilical endothelial cells (HUVECs) and increased endoplasmic reticulum stress and mediated apoptosis of HUVECs. Klotho attenuated IS‐induced above effects via promoting AMP‐activated protein kinase (AMPK) α1 phosphorylation instead of directly upregulating AMPKα1. [ABSTRACT FROM AUTHOR]

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Objective: To study the relationship between serum levels of osteosclerotin(Sclerostin), osteopontin(OPN), Klotho protein, bone morphogenetic protein(BMP)-7 and vascular calcification in maintenance hemodialysis patients. Methods: 109 cases of maintenance hemodialysis patients treated in our hospital from April 2018 to April 2020 were selected, the calcification of the patients was divided into calcification group(48 cases) and non calcification group(61 cases) accordding to the CT examine, and 50 healthy subjects were selected as the control group. Serum levels of sclerostin, OPN, Klotho protein and BMP-7 were detected and compared in each group. To analyze the influencing factors of vascular calcification in maintenance hemodialysis patients. Results: Serum levels of Sclerostin and OPN in calcification group and non calcification group were higher than those in control group and the above indexes in calcification group were higher than those in non-calcification group(P<0.05). The levels of serum Klotho protein and BMP-7 in the calcification group and non calcification group were lower than those in the control group, and the levels of above indicators in the calcification group were lower than those in the non calcification group(P<0.05). Univariate analysis showed that vascular calcification in maintenance hemodialysis patients was related to serum Sclerostin, OPN, Klotho protein and BMP-7(P<0.05). Multivariate Logistic regression analysis showed that serum Sclerostin, OPN, Klotho protein and BMP-7 were the influencing factors of vascular calcification in maintenance hemodialysis patients(P<0.05). Conclusion: Maintenance hemodialysis patients are usually accompanied by increased serum levels of Sclerostin and OPN, decreased levels of Klotho protein and BMP-7, and serum Sclerostin, OPN, Klotho protein and BMP-7 are the influencing factors of their vascular calcification. In clinical work, targeted intervention should be carried out in combination with the above factors to prevent the occurrence of vascular calcification in such patients. [ABSTRACT FROM AUTHOR]