Optical coherence elastography under homolateral parallel acoustic radiation force excitation for ocular elasticity quantification.

Alteration in the elastic properties of biological tissues may indicate changes in the structure and components. Acoustic radiation force optical coherence elastography (ARF-OCE) can assess the elastic properties of the ocular tissues non-invasively. However, coupling the ultrasound beam and the optical beam remains challenging. In this Letter, we proposed an OCE method incorporating homolateral parallel ARF excitation for measuring the elasticity of the ocular tissues. An acoustic-optic coupling unit was established to reflect the ultrasound beam while transmitting the light beam. The ARF excited the ocular tissue in the direction parallel to the light beam from the same side of the light beam. We demonstrated the method on the agar phantoms, the porcine cornea, and the porcine retina. The results show that the ARF-OCE method can measure the elasticity of the cornea and the retina, resulting in higher detection sensitivity and a more extensive scanning range.

Peripherally targeted analgesia via AAV-mediated sensory neuron-specific inhibition of multiple pronociceptive sodium channels.

This study reports that targeting intrinsically disordered regions of NaV1.7 protein facilitates discovery of sodium channel inhibitory peptide aptamers (NaViPA) for adeno-associated virus (AAV)-mediated, sensory neuron-specific analgesia. A multipronged inhibition of INa1.7, INa1.6, INa1.3, and INa1.1. but not INa1.5 and INa1.8 was found for a prototype, named NaViPA1, which was derived from the NaV1.7 intracellular loop 1 and is conserved among the TTXs NaV subtypes. NaViPA1 expression in primary sensory neurons (PSNs) of dorsal root ganglia (DRG) produced significant inhibition of TTXs INa but not TTXr INa. DRG injection of AAV6-encoded NaViPA1 significantly attenuated evoked and spontaneous pain behaviors in both male and female rats with neuropathic pain induced by tibial nerve injury (TNI). Whole-cell current clamp of the PSNs showed that NaViPA1 expression normalized PSN excitability in TNI rats, suggesting that NaViPA1 attenuated pain by reversal of injury-induced neuronal hypersensitivity. Immunohistochemistry revealed efficient NaViPA1 expression restricted in PSNs and their central and peripheral terminals, indicating PSN-restricted AAV biodistribution. Inhibition of sodium channels by NaViPA1 was replicated in the human iPSC-derived sensory neurons. These results summate that NaViPA1 is a promising analgesic lead that, combined with AAV-mediated PSN-specific block of multiple TTXs NaVs, has potential as peripheral nerve-restricted analgesic therapeutics.

Establishment and Verification of an Artificial Intelligence Prediction Model for Children With Sepsis.

BACKGROUND: Early identification of high-risk groups of children with sepsis is beneficial to reduce sepsis mortality. This article used artificial intelligence (AI) technology to predict the risk of death effectively and quickly in children with sepsis in the pediatric intensive care unit (PICU). STUDY DESIGN: This retrospective observational study was conducted in the PICUs of the First Affiliated Hospital of Sun Yat-sen University from December 2016 to June 2019 and Shenzhen Children's Hospital from January 2019 to July 2020. The children were divided into a death group and a survival group. Different machine language (ML) models were used to predict the risk of death in children with sepsis. RESULTS: A total of 671 children with sepsis were enrolled. The accuracy (ACC) of the artificial neural network model was better than that of support vector machine, logical regression analysis, Bayesian, K nearest neighbor method and decision tree models, with a training set ACC of 0.99 and a test set ACC of 0.96. CONCLUSIONS: The AI model can be used to predict the risk of death due to sepsis in children in the PICU, and the artificial neural network model is better than other AI models in predicting mortality risk.

Redox-neutral α-functionalization of pyrrolidines: facile access to α-aryl-substituted pyrrolidines.

α-Aryl-substituted pyrrolidine moiety is found in many natural alkaloids. Starting from pyrrolidine, we were able to synthesize α-aryl-substituted pyrrolidines in one step using quinone monoacetal as the oxidizing agent and DABCO as the base. We also discovered the reaction condition needed to efficiently remove the N-aryl moiety from the α-arylated product. When the above reaction was carried out without the addition of an aryl nucleophile, the reaction of pyrrolidine and quinone monoacetal in 2,2,2-trifluoroethanol afforded octahydro-dipyrroloquinoline in high yield, which has the same skeleton as that of natural product incargranine B.

Dipeptidyl peptidase 4 inhibitors vs. metformin for new-onset dementia: a propensity score-matched cohort study.

BACKGROUND: Hypoglycemic pharmacotherapy interventions for alleviating the risk of dementia remains controversial, particularly about dipeptidyl peptidase 4 (DPP4) inhibitors versus metformin. Our objective was to investigate whether the initiation of DPP4 inhibitors, as opposed to metformin, was linked to a reduced risk of dementia. METHODS: We included individuals with type 2 diabetes over 40 years old who were new users of DPP4 inhibitors or metformin in the Chinese Renal Disease Data System (CRDS) database between 2009 and 2020. The study employed Kaplan-Meier and Cox regression for survival analysis and the Fine and Gray model for the competing risk of death. RESULTS: Following a 1:1 propensity score matching, the analysis included 3626 DPP4 inhibitor new users and an equal number of metformin new users. After adjusting for potential confounders, the utilization of DPP4 inhibitors was associated with a decreased risk of all-cause dementia compared to metformin (hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.45-0.89). Subgroup analysis revealed that the utilization of DPP4 inhibitors was associated with a reduced incidence of dementia in individuals who initiated drug therapy at the age of 60 years or older (HR 0.69, 95% CI 0.48-0.98), those without baseline macrovascular complications (HR 0.62, 95% CI 0.41-0.96), and those without baseline microvascular complications (HR 0.67, 95% CI 0.47-0.98). CONCLUSION: In this real-world study, we found that DPP4 inhibitors presented an association with a lower risk of dementia in individuals with type 2 diabetes than metformin, particularly in older people and those without diabetes-related comorbidities.

Phosphorescent acyclic cucurbituril solid supramolecular multicolour delayed fluorescence behaviour.

Organic photoluminescent macrocyclic hosts have been widely advanced in many fields. Phosphorescent hosts with the ability to bind organic guests have rarely been reported. Herein, acyclic cucurbituril modified with four carboxylic acids (ACB-COOH) is mined to present uncommon purely organic room-temperature phosphorescence (RTP) at 510 nm with a lifetime of 1.86 µs. Its RTP properties are significantly promoted with an extended lifetime up to 2.12 s and considerable quantum yield of 6.29% after assembly with a polyvinyl alcohol (PVA) matrix. By virtue of the intrinsic self-crimping configuration of ACB-COOH, organic guests, including fluorescence dyes (Rhodamine B (RhB) and Pyronin Y (PyY)) and a drug molecule (morphine (Mor)), could be fully encapsulated by ACB-COOH to attain energy transfer involving phosphorescent acyclic cucurbituril. Ultimately, as-prepared systems are successfully exploited to establish multicolor afterglow materials and visible sensing of morphine. As an expansion of phosphorescent acyclic cucurbituril, the host afterglow color can be readily regulated by attaching different aromatic sidewalls. This study develops the fabrication strategies and application scope of a supramolecular phosphorescent host and opens up a new direction for the manufacture of intelligent long-lived luminescent materials.

Alkaloids from Zanthoxylum nitidum and their anti-proliferative activity against A549 cells by regulating the EGFR/AKT/mTOR pathway.

Zanthoxylum nitidum is frequently used as a traditional Chinese medicine and food supplement. Our previous study revealed that its constituent compounds were able to inhibit cancer cell proliferation. In our continuous exploration of bioactive compounds in Z. nitidum, we isolated ten alkaloids (1-10), including one new natural compound (1), and nine known alkaloids (2-10), from an ethanolic extract of the whole plant. The chemical structures were elucidated based on a combination of comprehensive NMR and HRESIMS analyses. Compounds 5, 8 and 10 exhibited significant antiproliferative effects against A549 cancer cell lines. We further elucidated the underlying molecular mechanisms of the antiproliferative activity of compound 8 in A549 human lung cancer cells. Compound 8 was found to induce cell cycle arrest in the G0/G1 phase via p53 activation and CDK4/6 suppression. Compound 8 also effectively inhibited cell migration through the modulation of the epithelial-mesenchymal transition (EMT), as indicated by the expression of biomarkers, such as N-cadherin downregulation and E-cadherin upregulation. Compound 8 significantly suppressed the activation of the EGFR/AKT/mTOR signalling pathway in A549 cells. These results indicate that alkaloid 8 from Z. nitidum has potential to be a lead antiproliferative compound in cancer cells.

The type-I, III nodal ring, type-I, III quadratic nodal point, and Dirac valley phonons in 2D kagome lattices M2C3(M = As, Bi, Cd, Hg, P, Sb, Zn).

Topological phases in kagome systems have garnered considerable interest since the introduction of the colloidal kagome lattice. Our study employs first-principle calculations and symmetry analysis to predict the existence of ideal type-I, III nodal rings (NRs), type-I, III quadratic nodal points (QNPs), and Dirac valley phonons (DVPs) in a collection of two-dimensional (2D) kagome lattices M2C3(M = As, Bi, Cd, Hg, P, Sb, Zn). Specifically, the Dirac valley points (DVPs) can be observed at two inequivalent valleys with Berry phases of +πand-π, connected by edge arcs along the zigzag and armchair directions. Additionally, the QNP is pinned at the Γ point, and two edge states emerge from its projections. Notably, these kagome lattices also exhibit ideal type-I and III nodal rings protected by time inversion and spatial inversion symmetries. Our work examines the various categories of nodal points and nodal ring phonons within the 2D kagome systems and presents a selection of ideal candidates for investigating topological phonons in bosonic systems.

Discovery of Urea Derivatives of Celastrol as Selective Peroxiredoxin 1 Inhibitors against Colorectal Cancer Cells.

Peroxiredoxin (PRDX1) is a tumor-overexpressed antioxidant enzyme for eliminating excessive reactive oxygen species (ROS) to protect tumor cells from oxidative damage. Herein, a series of celastrol urea derivatives were developed based on its cocrystal structure with PRDX1, with the aim of pursuing a PRDX1-specific inhibitor. Among them, derivative 15 displayed potent anti-PRDX1 activity (IC50 = 0.35 µM) and antiproliferative potency against colon cancer cells. It covalently bound to Cys-173 of PRDX1 (KD = 0.37 µM), which was secured by the cocrystal structure of PRDX1 with an analogue of 15 while exhibiting weak inhibitory effects on PRDX2-PRDX6 (IC50 > 50 µM), indicating excellent PRDX1 selectivity. Treatment with 15 dose-dependently decreased the mitochondria membrane potential of SW620 cells, probably due to ROS induced by PRDX1 inhibition, leading to cell apoptosis. In colorectal cancer cell xenograft model, it displayed potent antitumor efficacy with superior safety to celastrol. Collectively, 15 represents a promising PRDX1 selective inhibitor for the development of anticolorectal cancer agents.

Maximakinin reversed H2O2 induced oxidative damage in rat cardiac H9c2 cells through AMPK/Akt and AMPK/ERK1/2 signaling pathways.

Maximakinin (MK), a homolog of bradykinin (BK), is extracted from skin venom of the Chinese toad Bombina maxima. Although MK has a good antihypertensive effect, its effect on myocardial cells is unclear. This study investigates the protective effect of MK on hydrogen peroxide (H2O2)-induced oxidative damage in rat cardiac H9c2 cells and explores its mechanism of action. A 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide (MTT) assay was selected to detect the effect of MK on H9c2 cell viability, while flow cytometry was used to investigate the influence of MK and H2O2 on intracellular reactive oxygen species (ROS) levels. Protein expression changes were detected by western blot. In addition, specific protein inhibitors were applied to confirm the induction of ROS-related signaling pathways by MK. MTT assay results show that MK significantly reversed H2O2-induced cell growth inhibition. Flow cytometry Dichlorodihydrofluorescein diacetate (DCFH-DA) staining shows that MK significantly reversed H2O2-induced increases in intracellular ROS production in H9c2 cells. Moreover, the addition of specific protein inhibitors suggests that MK reverses H2O2-induced oxidative damage by activating AMP-activated protein kinase (AMPK)/protein kinase B (Akt) and AMPK/extracellular-regulated kinase 1/2 (ERK1/2) pathways. Finally, an inhibitor of bradykinin B2 receptors (B2Rs), HOE-140, was applied to investigate potential targets of MK in H9c2 cells. HOE-140 significantly blocked induction of AMPK/Akt and AMPK/ERK1/2 pathways by MK, suggesting a potentially important role for B2Rs in MK reversing H2O2-induced oxidative damage. Above all, MK protects against oxidative damage by inhibiting H2O2-induced ROS production in H9c2 cells. The protective mechanism of MK may be achieved by activation of B2Rs to activate downstream AMPK/Akt and AMPK/ERK1/2 pathways.

Post-COVID-19 Pandemic Rebound of Macrolide-Resistant Mycoplasma pneumoniae Infection: A Descriptive Study.

The rebound characteristics of respiratory infections after lifting pandemic control measures were uncertain. From January to November 2023, patients presenting at a teaching hospital were tested for common respiratory viruses and Mycoplasma pneumoniae using a combination of antigen, nucleic acid amplification, and targeted next-generation sequencing (tNGS) tests. The number and rate of positive tests per month, clinical and microbiological characteristics were analyzed. A rapid rebound of SARS-CoV-2 was followed by a slower rebound of M. pneumoniae, with an interval of 5 months between their peaks. The hospitalization rate was higher, with infections caused by respiratory viruses compared to M. pneumoniae. Though the pediatric hospitalization rate of respiratory viruses (66.1%) was higher than that of M. pneumoniae (34.0%), the 4094 cases of M. pneumoniae within 6 months posed a huge burden on healthcare services. Multivariate analysis revealed that M. pneumoniae-infected adults had more fatigue, comorbidities, and higher serum C-reactive protein, whereas children had a higher incidence of other respiratory pathogens detected by tNGS or pathogen-specific PCR, fever, and were more likely to be female. A total of 85% of M. pneumoniae-positive specimens had mutations detected at the 23rRNA gene, with 99.7% showing A2063G mutation. Days to defervescence were longer in those not treated by effective antibiotics and those requiring a change in antibiotic treatment. A delayed but significant rebound of M. pneumoniae was observed after the complete relaxation of pandemic control measures. No unusual, unexplained, or unresponsive cases of respiratory infections which warrant further investigation were identified.

Correction: Noureddine et al. Impact of the Renin-Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives. Int. J. Mol. Sci. 2020, 21, 4268.

The authors would like to make the following correction to the publication dealing with Reference #3 [...].

Cerebrovascular Dysfunction in Alzheimer's Disease and Transgenic Rodent Models.

Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementia (ADRD) are the primary causes of dementia that has a devastating effect on the quality of life and is a tremendous economic burden on the healthcare system. The accumulation of extracellular beta-amyloid (Aß) plaques and intracellular hyperphosphorylated tau-containing neurofibrillary tangles (NFTs) in the brain are the hallmarks of AD. They are also thought to be the underlying cause of inflammation, neurodegeneration, brain atrophy, and cognitive impairments that accompany AD. The discovery of APP, PS1, and PS2 mutations that increase Aß production in families with early onset familial AD led to the development of numerous transgenic rodent models of AD. These models have provided new insight into the role of Aß in AD; however, they do not fully replicate AD pathology in patients. Familial AD patients with mutations that elevate the production of Aß represent only a small fraction of dementia patients. In contrast, those with late-onset sporadic AD constitute the majority of cases. This observation, along with the failure of previous clinical trials targeting Aß or Tau and the modest success of recent trials using Aß monoclonal antibodies, has led to a reappraisal of the view that Aß accumulation is the sole factor in the pathogenesis of AD. More recent studies have established that cerebral vascular dysfunction is one of the earliest changes seen in AD, and 67% of the candidate genes linked to AD are expressed in the cerebral vasculature. Thus, there is an increasing appreciation of the vascular contribution to AD, and the National Institute on Aging (NIA) and the Alzheimer's Disease Foundation recently prioritized it as a focused research area. This review summarizes the strengths and limitations of the most commonly used transgenic AD animal models and current views about the contribution of Aß accumulation versus cerebrovascular dysfunction in the pathogenesis of AD.

Gene Rearrangements in the Mitochondrial Genome of Gonatopsis borealis and Onychoteuthis compacta Reveal Their Phylogenetic Implications for Oegopsida.

The complete mitochondrial genome provides crucial information for comprehending gene rearrangement, molecular evolution, and phylogenetic analysis. Here, we have determined the complete mitogenome sequence of Gonatopsis borealis and Onychoteuthis compacta for the first time. Their genome sizes were 20,148 bp and 20,491 bp, respectively, including 18 protein-coding genes, COI-COIII, ATP6, and ATP8 are duplicated, 23 transfer RNA genes, and 2 ribosomal RNA (rRNA) genes (12S and 16S rRNA). Specifically, the overall A+T content is 70.69% and 72.67%. It shows a significant AT bias. The whole mitogenomes indicate positive AT skew (0.070 and 0.062). Furthermore, the gene order has been rearranged within Oegopsida. The tandem duplication random loss model was determined as most likely to explain the observed gene rearrangements. Phylogenetic analysis was performed, and the result tree was found to be consistent with the morphological identification classification. Estimation of divergence time for 35 species showed that the main differentiation of Oegopsida occurred in 140.70 Mya. These results will help to better understand the gene rearrangements and evolution of G. borealis and O. compacta and lay a foundation for further phylogeny genetic studies of Oegopsida.

Diisoprenyl Cyclohexene-Type Meroterpenoids with Cytotoxic Activity from a Mangrove Endophytic Fungus Aspergillus sp. GXNU-Y85.

Five new diisoprenyl cyclohexene-type meroterpenoids, aspergienynes J-N (1-5), along with three known analogues (6-8), were obtained from the mangrove endophytic fungal strain Aspergillus sp. GXNU-Y85. The chemical structures, including their absolute configurations, were established via spectroscopic data and comparison of experimental and calculated ECD spectra. Cytotoxicity assay results indicated that compound 8 had strong cytotoxicity against HeLa cancer cells, and its IC50 value was 11.8 µM. In addition, flow cytometry analysis revealed that the cytotoxicity of 8 was due to the induction of G1 cell cycle arrest and apoptosis in HeLa cells.

MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity.

Rationale: Renal fibrosis, with no therapeutic approaches, is a common pathological feature in various chronic kidney diseases (CKD). Tubular cell injury plays a pivotal role in renal fibrosis. Commonly, injured tubular cells exhibit significant lipid accumulation. However, the underlying mechanisms remain poorly understood. Methods: 2-arachidonoylglycerol (2-AG) levels in CKD patients and CKD model specimens were measured using mass spectrometry. 2-AG-loaded nanoparticles were infused into unilateral ureteral obstruction (UUO) mice. Lipid accumulation and renal fibrosis were tested. Furthermore, monoacylglycerol lipase (MAGL), the hydrolyzing enzyme of 2-AG, was assessed in CKD patients and models. Tubular cell-specific MAGL knock-in mice were generated. Moreover, MAGL recombination protein was also administered to unilateral ischemia reperfusion injury (UIRI) mice. Besides, a series of methods including RNA sequencing, metabolomics, primary cell culture, lipid staining, etc. were used. Results: 2-AG was increased in the serum or kidneys from CKD patients and models. Supplement of 2-AG further induced lipid accumulation and fibrogenesis through cannabinoid receptor type 2 (CB2)/ß-catenin signaling. ß-catenin knockout blocked 2-AG/CB2-induced fatty acid ß-oxidation (FAO) deficiency and lipid accumulation. Remarkably, MAGL significantly decreased in CKD, aligning with lipid accumulation and fibrosis. Specific transgene of MAGL in tubular cells significantly preserved FAO, inhibited lipid-mediated toxicity in tubular cells, and finally retarded fibrogenesis. Additionally, supplementation of MAGL in UIRI mice also preserved FAO function, inhibited lipid accumulation, and protected against renal fibrosis. Conclusion: MAGL is a potential diagnostic marker for kidney function decline, and also serves as a new therapeutic target for renal fibrosis through ameliorating lipotoxicity.

Feasibility and Tolerability of Anlotinib Plus PD-1 Blockades for Patients with Treatment-Refractory Metastatic Colorectal Cancer: A Retrospective Exploratory Study.

Objective: Therapeutic regimens are relatively scarce among patients with treatment-refractory metastatic colorectal cancer (CRC). This study aimed to determine the feasibility and tolerability of anlotinib plus PD-1 blockades in patients with treatment-refractory metastatic CRC retrospectively. Methods: A total of 68 patients with previously treated metastatic CRC who received anlotinib plus PD-1 blockades in clinical practice were included in this study retrospectively. Demographic and clinical characteristics of the patients, therapeutic outcomes and safety profile during administration were collected and briefly analyzed. All subjects were followed up regularly. Therapeutic outcomes, including drug response and prognosis, were presented, and a safety profile was depicted to illustrate the adverse reactions. Results: A total of 68 patients with treatment-refractory metastatic CRC who received anlotinib plus PD-1 blockades in clinical practice were included in the final analysis. Best therapeutic response during treatment indicated that partial response was observed in 11 patients, stable disease was noted in 41 patients, and progressive disease was found in 16 patients, producing an objective response rate of 16.2% (95% CI: 8.4%-27.1%) and a disease control rate of 76.5% (95% CI: 64.6%-85.9%). Prognostic analysis suggested that the median progression-free survival (PFS) of the 68 patients was 5.3 months (95% CI: 3.01-7.59), and the median overall survival (OS) was 12.5 months (95% CI: 9.40-15.60). Of the 11 patients who responded, the median duration of response was 6.7 months (95% CI: 2.89-10.53). Safety profile during treatment showed that patients experienced adverse reactions regardless of grade, and grade ≥3 adverse reactions were found in 61 patients (89.7%) and 41 patients (60.3%), respectively. Common adverse reactions were hypertension, myelosuppression (including leukopenia, neutropenia, thrombocytopenia, and anemia), fatigue, and hand-foot syndrome. Conclusion: Anlotinib plus PD-1 blockades demonstrated encouraging efficacy and acceptable safety profile in patients with treatment-refractory metastatic CRC preliminarily in clinical practice. This conclusion should be confirmed in prospective clinical trials.

Association of accelerometer-measured physical activity and its change with progression to chronic kidney disease in adults with type 2 diabetes and overweight/obesity.

OBJECTIVE: To examine the long-term association of objectively measured moderate-to-vigorous physical activity (MVPA) and its longitudinal changes with progression to chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) and overweight/obesity. METHODS: This study included 1746 participants in the Look AHEAD trial with baseline estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2. MVPA was measured at baseline, year 1, year 4 and year 8 using an RT3 accelerometer. The outcome was progression to CKD, defined as eGFR<60 mL/min per 1.73 m2 with a drop of ≥30% or end-stage kidney disease. Cox hazards models were fitted to examine the association between MVPA and outcomes. RESULTS: Over a median follow-up of 12.0 years, 567 participants experienced progression to CKD. Overall, there was a linear inverse association of cumulative average total MVPA (per 100 min/week higher amount, HR: 0.91; 95% CI: 0.86 to 0.96) and MVPA accumulated in bouts of ≥10 min (per 100 minutes/week higher amount, HR: 0.81; 95% CI: 0.72 to 0.91) with progression to CKD. Moreover, an increase in total MVPA from baseline to year 4 (the fourth quartile, ≥63.2 min/week) was associated with a 33% lower risk of progression to CKD compared with the largest MVPA reduction (the first quartile, <-198.3 min/week). A lower risk of progression to CKD was also observed for increases in MVPA accumulated in bouts of both <10 min and ≥10 min. CONCLUSIONS: Longer MVPA time and increases in MVPA was associated with a reduced risk of progression to CKD in adults with overweight/obesity and T2D.

Klotho-derived peptide 1 inhibits cellular senescence in the fibrotic kidney by restoring Klotho expression via posttranscriptional regulation.

Background: Klotho deficiency is a common feature of premature aging and chronic kidney disease (CKD). As such, restoring Klotho expression could be a logic strategy for protecting against various nephropathies. In this study, we demonstrate that KP1, a Klotho-derived peptide, inhibits cellular senescence by restoring endogenous Klotho expression. Methods: The effects of KP1 on cellular senescence and Klotho expression were assessed in mouse models of CKD. RNA-sequencing was employed to identify the microRNA involved in regulating Klotho by KP1. Gain- or loss-of-function approaches were used to assess the role of miR-223-3p and IncRNA-TUG1 in regulating Klotho and cellular senescence. Results: KP1 inhibited senescence markers p21, p16 and γ-H2AX in tubular epithelial cells of diseased kidneys, which was associated with its restoration of Klotho expression at the posttranscriptional level. Profiling of kidney microRNAs by RNA sequencing identified miR-223-3p that bound to Klotho mRNA and inhibited its protein expression. Overexpression of miR-223-3p inhibited Klotho and induced p21, p16 and γ-H2AX, which were negated by KP1. Conversely, inhibition of miR-223-3p restored Klotho expression, inhibited cellular senescence. Furthermore, miR-223-3p interacted with lncRNA-TUG1 and inhibited its expression. Knockdown of lncRNA-TUG1 increased miR-223-3p, aggravated Klotho loss and worsened cellular senescence, whereas KP1 mitigated all these changes. Conclusion: These studies demonstrate that KP1 inhibits cellular senescence and induces Klotho expression via posttranscriptional regulation mediated by miR-223-3p and lncRNA-TUG1. By restoring endogenous Klotho, KP1 elicits a broad spectrum of protective actions and could serve as a promising therapeutic agent for fibrotic kidney disorders.