The GDF11 expression pattern and its effect on organ regeneration after acute injury in the elderly population are highly controversial topics. In our study, GDF11/8 expression increased after kidney ischemia-reperfusion injury (IRI), and the relatively lower level of GDF11/8 in the kidneys of aged mice was associated with a loss of proliferative capacity and a decline in renal repair, compared to young mice. In vivo, GDF11 supplementation in aged mice increased vimentin and Pax2 expression in the kidneys as well as the percentage of 5-ethynyl-2'-deoxyuridine (EdU)-positive proximal tubular epithelial cells. GDF11 improved the renal repair, recovery of renal function, and survival of elderly mice at 72 h after IRI. Moreover, the addition of recombinant GDF11 to primary renal epithelial cells increased proliferation, migration, and dedifferentiation by upregulating the ERK1/2 pathway in vitro. Our study indicates that GDF11/8 in the kidney decreases with age and that GDF11 can increase tubular cell dedifferentiation and proliferation as well as improve tubular regeneration after acute kidney injury (AKI) in old mice.

Triptolide (TP), an active constituent of Tripterygium wilfordii, possesses numerous pharmacological activities. However, its effects on cytochrome P450 enzymes (CYP450s) in rats remain unexplored.

Colorectal cancer (CRC) remains one of the most common cancers worldwide. Increasing evidence indicates that SPRY4 intronic transcript 1 (SPRY4-IT1) regulate cell growth, differentiation, apoptosis, and cancer progression. However, the expression and function of SPRY4-IT1 in the progression of CRC remains largely unknown. Here, we reported that SPRY4-IT1 was upregulated in CRC. Increased SPRY4-IT1 expression in CRC was associated with larger tumor size and higher clinical stage. In vitro experiments revealed that SPRY4-IT1 knockdown significantly inhibited CRC cell proliferation by causing G1 arrest and promoting apoptosis, whereas SPRY4-IT1 overexpression promoted cell proliferation. Further functional assays indicated that SPRY4-IT1 overexpression significantly promoted cell migration and invasion by regulate the epithelial-mesenchymal transition (EMT). Taken together, our study demonstrates that SPRY4-IT1 could act as a functional oncogene in CRC, as well as a potential therapeutic target to inhibit CRC metastasis.

Membranous nephropathy is a common cause of nephrotic syndrome in adults. Although many mechanisms have been proposed, whole proteomic research is still lacking. We analyzed the passive Heymann nephritis animal model using label-free quantitative proteome technology. Results showed 160 differential proteins between control and PHN model groups at days 14 and 21. The expression level of endoplasmic reticulum stress (ERS)-associated protein GRP78 and GRP94 protein was up-regulated on day 14 or 21, which was confirmed by Western blotting. The results also showed that the autophagy marker LC3 was up-regulated in the models. Furthermore, we used tunicamycin to induce ERS of podocytes in vitro to investigate the mechanism. Results of Western blotting revealed that the expression of GRP78, GRP94, and LC3 was up-regulated, while that of the cytoskeletal protein tubulin-β was down-regulated, and immunofluorescence displayed disordered distribution of tubulin-β. These suggest that ERS plays an important role in podocyte damage. Autophagy can repair the cytoskeleton damage caused by ERS as a protective mechanism. This provides an important basis for a thorough understanding of the mechanism of podocyte damage and the pathogenesis of membranous nephropathy.

Dietary restriction (DR) has multiple and essential effects in protecting against DNA damage in model organisms. Persistent DNA damage plays a central role in the process of aging. Senescence-associated secretory phenotype (SASP), as a product of cellular aging, can accelerate the process of cellular senescence as a feedback. In this study, we directly observed whether a DR of 30% for 6months in aged rats could retard SASP by delaying the progression of DNA damage and also found the specific mechanism. The results revealed that a 30% DR could significantly improve renal pathology and some metabolic characteristics. The biomarkers and products of DNA damage were decreased in the process of renal aging on a 30% DR. A series of SASP, notably cytokine, chemokine, and growth factor, were obviously reduced by DR during renal aging. The phosphorylation levels of NF-κB and IκBα in aged kidneys of DR group were markedly reduced. These findings suggest that a 30% DR for 6months can delay renal aging and reduce the accumulation of SASP by retarding the progression of DNA damage and decreasing the transcription activity of NF-κB, thus providing a target to delay renal aging.

Objective: To assess the effectiveness and safety of the total glucosides of paeony (TGP) on the treatment of primary Sjögren's syndrome (pSS) by conducting a meta-analysis. Methods: Eight databases were searched from their inception to December 10, 2018 for randomized controlled trials (RCTs). The Revman 5.3 software was used for this meta-analysis. Results: Nine RCTs which included 770 participants were identified. Pooled results showed that significant difference in Schirmer's test (P < 0.00001) comparing TGP with placebo (PBO). However, the pooled results displayed significant differences in salivary flow rate, Schirmer's test, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), serum γ-globulin, immunoglobulin G (IgG), IgA, IgM, and effective rate (P ≤ 0.01) in the co-administration of TGP with immunosuppressant (IS) compared with IS alone. Subgroup analyses revealed both heterogeneities in ESR and serum γ-globulin were eliminated, showing combined intervention of TGP + IS being more advantageous than single usage of IS (P < 0.00001). However, the advantage varied among three subgroups and showed a gradual weakening over time. Furthermore, our results showed statistical significance in Schirmer's test (P = 0.0006), when hydroxychloroquine (HCQ) was jointly applied, but not in the case of combined TGP with methotrexate (MTX) (P = 0.41). For the safety analysis, the most common adverse events (AEs) were diarrhea or gastrointestinal discomfort, and no severe AEs were reported in TGP group. Meanwhile, six trials showed statistically insignificant differences between TGP + IS and IS in AEs (P = 0.76). Conclusions: Improving the lacrimal gland secretion (Schirmer's test) is the prominent function of TGP compared with PBO. TGP + IS can improve the clinical symptoms, such as lacrimal and salivary gland secretion function (Schirmer's test, salivary flow rate), inflammatory indices (ESR, CRP, and RF) and immunoglobulins (γ-globulin, IgG, IgA, and IgM) on the basis of IS monotherapy. In addition, TGP has an acceptable safety profile and AEs were not increased when TGP combined with IS in pSS. Therefore, TGP can be considered to be a potentially valid and safe drug for the treatment of pSS in the clinic. In view of the limitations of the included trials, the potential beneficial effectiveness and safety of TGP need additional high-quality, multi-center, and large-scale RCTs to assess its use in pSS treatment.

TSC2-PKD1 contiguous gene deletion syndrome is characterized by tuberous sclerosis complex and polycystic kidney disease. We obtained peripheral blood mononuclear cells from a patient with TSC2-PKD1 contiguous gene deletion syndrome. We performed reprogramming using non-integrative episomal vectors to obtain human induced pluripotent stem cells (iPSCs). The obtained iPSCs had a normal karyotype and expressed human ES cell-specific cell surface markers and genes; in teratomas, iPSCs differentiated into derivatives of all three germ layers. The iPSCs can be used to study pathogenesis of TSC2-PKD1 contiguous gene deletion syndrome and serve as a potential therapeutic target.

To systematically analyze the existing intelligent rehabilitation mobile applications (APPs) related to distal radius fracture (DRF) and evaluate their features and characteristics, so as to help doctors and patients to make evidence-based choice for appropriate intelligent-assisted rehabilitation.

We established an exogenous biological renal support model through the generation of parabiotic mice. At 72 hours after ischemia reperfusion injury (IRI), the aged mice that received exogenous biological renal support showed significantly higher levels of renal cell proliferation and dedifferentiation, lower levels of renal tubular injury, improved renal function, and a lower mortality than those that did not receive exogenous biological renal support. Using the Quantibody Mouse Cytokine Antibody Array, we found that aged IRI mice that received exogenous biological renal support had an up-regulation of multiple inflammatory related cytokines compared to the group that did not receive exogenous biological renal support. We suggest that the exogenous biological renal support might promote renal tubular epithelial cell proliferation and dedifferentiation and improve the prognosis of aged IRI mice. Exogenous biological renal support may play an important role in the amelioration of renal IRI by regulating the expression of multiple cytokines.

Mesangial cell (MC) proliferation is a key pathological feature in a number of common human renal diseases, including mesangial proliferative nephritis and diabetic nephropathies. Knowledge of MC responses to pathological stimuli is crucial to the understanding of these disease processes. We previously determined that Krϋppel-like factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, was required for inhibition of MC proliferation. In the present study, we investigated the direct target gene and the underlying mechanism by which KLF15 regulated mesangial proliferation. First, we screened small ubiquitin-related modifier 1 (SUMO1) as the direct transcriptional target of KLF15 and validated this finding with ChIP-PCR and luciferase assays. Furthermore, we demonstrated that overexpressing KLF15 or SUMO1 enhanced the stability of P53, which blocked the cell cycle of human renal MCs (HRMCs) and therefore abolished cell proliferation. Conversely, knockdown of SUMO1 in HRMCs, even those overexpressed with KLF15, could not inhibit HRMC proliferation rates and increase SUMOylation of P53. Finally, the results showed that the levels of SUMOylated P53 in the kidney cortices of anti-Thy 1 model rats were decreased during proliferation periods. These findings reveal the critical mechanism by which KLF15 targets SUMO1 to mediate the proliferation of MCs.

Background: Rhabdomyolysis (RM) is a clinical syndrome characterized by breakdown of skeletal muscle fibers and release of their contents into the circulation. Myoglobin-induced acute kidney injury (AKI) is one of the most severe complications of RM. Based on our previous research, exogenous biological renal support alleviates renal ischemia-reperfusion injury in elderly mice. This study aimed to determine whether exogenous biological renal support promotes renal recovery from RM-induced AKI and to preliminarily explore the mechanisms involved. Methods: A parabiosis animal model was established to investigate the effects of exogenous biological renal support on RM-induced AKI. Mice were divided into three groups: the control group (in which mice were injected with sterile saline), the RM group (in which mice were injected with 8 mL/kg glycerol), and the parabiosis + RM group (in which recipient mice were injected with glycerol 3 weeks after parabiosis model establishment). Blood samples and kidney tissue were collected for further processing 48 h after RM induction. Bioinformatics analysis was conducted via Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, functional enrichment analysis, and clustering analysis. Results: No mice died within 48 h after the procedure. Exogenous biological renal support attenuated the histological and functional deterioration in mice with RM-induced AKI. Bioinformatics analysis identified key pathways and proteins involved in this process. We further demonstrated that exogenous biological renal support ameliorated AKI through multiple mechanisms, including by suppressing the complement system; attenuating oxidative stress, inflammation, and cell death; and increasing proliferation. Conclusions: Exogenous biological renal support provided by parabiosis can improve renal function in RM-induced AKI by suppressing the complement system; decreasing oxidative stress, inflammation, and cell death; and promoting tubular cell proliferation. Our study provides basic research evidence for the use of bioartificial kidneys to treat RM-induced AKI.

In vivo fluorescence imaging in the second near-infrared window (NIR-II) has been considered as a promising technique for visualizing mammals. However, the definition of the NIR-II region and the mechanism accounting for the excellent performance still need to be perfected. Herein, we simulate the photon propagation in the NIR region (to 2340 nm), confirm the positive contribution of moderate light absorption by water in intravital imaging and perfect the NIR-II window as 900-1880 nm, where 1400-1500 and 1700-1880 nm are defined as NIR-IIx and NIR-IIc regions, respectively. Moreover, 2080-2340 nm is newly proposed as the third near-infrared (NIR-III) window, which is believed to provide the best imaging quality. The wide-field fluorescence microscopy in the brain is performed around the NIR-IIx region, with excellent optical sectioning strength and the largest imaging depth of intravital NIR-II fluorescence microscopy to date. We also propose 1400 nm long-pass detection in off-peak NIR-II imaging whose performance exceeds that of NIR-IIb imaging, using bright fluorophores with short emission wavelength.

To investigate the levels of serum oxytocin (OT) in children with autism spectrum disorder (ASD) and explore the association between OT levels and gut microbiota relative abundances, we recruited 39 children with ASD children-mother dyads and 44 healthy controls. Serum OT levels were determined via enzyme-linked immunosorbent assay and gut microbiota abundances were determined by 16S rRNA sequencing. We found that the OT level of ASD was lower than the healthy control group overall (P < 0.05). Furthermore, we present preliminary evidence of gut microbiome dysbiosis observed among children with ASD to lower levels of OT based on correlational analysis between serum OT and specific gut microbiota abundances (P < 0.05). We also found sex-related differences in serum OT levels and GIS index (P < 0.05). However, the generalizability of findings relevant to females with ASD require further validation in future studies involving larger sample sizes and balanced sex distributions due to the small number of females involved in this study. Nonetheless, these new findings further our understanding of the effects of low serum OT levels among individuals with ASD, which provides preliminary evidence in hopes of guiding future study design or mechanistic studies. The findings of the present study may be suggestive of potential ASD subtypes based on ASD severity and gut microbiome composition that may facilitate the prediction of the therapeutic responses of OT among those with ASD.

Background: Roxadustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), has been used to treat anemia in patients with chronic kidney disease (CKD). However, its safety and efficacy remain controversial. Methods: The PubMed, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials, and Clinical Trial Registries databases were searched for relevant studies published up to April 2021. We identified randomized controlled trials (RCTs) comparing roxadustat with placebo or erythropoiesis-stimulating agents (ESAs) in anemia patients with CKD with or without dialysis. Results: Eleven studies including 6,631 patients met the inclusion criteria. In non-dialysis-dependent (NDD-) and dialysis-dependent (DD-) CKD patients, the total adverse events were not significantly different between the roxadustat and control (placebo for NDD-CKD patients and ESA for DD-CKD patients) groups [relative risk (RR) = 1.02, 95% confidence interval (CI) = 1.00, 1.04, P = 0.08, and RR = 1.22, 95% CI = 0.91, 1.64, P = 0.18, respectively], and the trial sequential analysis (TSA) confirmed the result in the NDD-CKD groups. No significant differences in hyperkalemia and infection incidences were found between roxadustat and placebo in the DD-CKD groups. The pooled results showed that roxadustat significantly increased the hemoglobin response rate compared with placebo in the NDD-CKD group and had an effect similar to that of ESA in the DD-CKD group. However, iron metabolism parameters did not seem to be obviously optimized by roxadustat. Conclusion: Roxadustat can be safely used in CKD patients. Oral roxadustat was more effective than placebo as a therapy for anemia in NDD-CKD patients and non-inferior to ESA in correcting anemia in DD-CKD patients. However, additional clinical trials are still needed to further prove whether roxadustat can optimize iron metabolism.

Bright anti-Stokes fluorescence (ASF) in the first near-infrared spectral region (NIR-I, 800 nm-900 nm) under the excitation of a 915 nm continuous wave (CW) laser, is observed in Indocyanine Green (ICG), a dye approved by the Food and Drug Administration for clinical use. The dependence of fluorescence intensity on excitation light power and temperature, together with fluorescence lifetime measurement, establish this ASF to be originated from absorption from a thermally excited vibrational level (hot-band absorption), as shown in our experiments, which is stronger than the upconversion fluorescence from widely-used rare-earth ion doped nanoparticles. To test the utility of this ASF NIR-I probe for advanced bioimaging, we successively apply it for biothermal sensing, cerebral blood vessel tomography and blood stream velocimetry. Moreover, in combination with L1057 nanoparticles, which absorb the ASF of ICG and emit beyond 1100 nm, these two probes generate multi-mode images in two fluorescent channels under the excitation of a single 915 nm CW laser. One channel is used to monitor two overlapping organs, urinary system & blood vessel of a live mouse, while the other shows urinary system only. Using in intraoperative real-time monitoring, such multi-mode imaging method can be beneficial for visual guiding in anatomy of the urinary system to avoid any accidental injury to the surrounding blood vessels during surgery.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with unclear mechanisms of pathogenesis. Gastrointestinal microbiome alterations were found to correlate with ASD core symptoms, but its specific role in ASD pathogenesis has not been determined. In this study, we used a case-control strategy that simultaneously compared the ASD gastrointestinal microbiome with that from age-sex matched controls and first-degree relative controls, using a statistical framework accounting for confounders such as age. Enterobacteriaceae (including Escherichia/Shigella) and Phyllobacterium were significantly enriched in the ASD group, with their relative abundances all following a pattern of ASD > first degree relative control > healthy control, consistent with our hypothesis of living environment and shared microbial and immunological exposures as key drivers of ASD gastrointestinal microbiome dysbiosis. Using multivariable omnibus testing, we identified clinical factors including ADOS scores, dietary habits, and gastrointestinal symptoms that covary with overall microbiome structure within the ASD cohort. A microbiome-specific multivariate modeling approach (MaAsLin2) demonstrated microbial taxa, such as Lachnoclostridium and Tyzzerella, are significantly associated with ASD core symptoms measured by ADOS. Finally, we identified alterations in predicted biological functions, including tryptophan and tyrosine biosynthesis/metabolism potentially relevant to the pathophysiology of the gut-brain-axis. Overall, our results identified gastrointestinal microbiome signature changes in patients with ASD, highlighted associations between gastrointestinal microbiome and clinical characteristics related to the gut-brain axis and identified contributors to the heterogeneity of gastrointestinal microbiome within the ASD population.

Frailty and sarcopenia are prevalent in chronic kidney disease (CKD) populations and could increase the risk for adverse health outcomes. Few studies assess the correlation between frailty, sarcopenia and CKD in non-dialysis patients. Therefore, this study aimed to determine frailty-associated factors in elderly CKD stage I-IV patients, expected to early identify and intervene in the frailty of elderly CKD patients.

Dark-field microscopy offers several advantages, including high image contrast, minimal cell damage, and the absence of photobleaching of nanoprobes, which make it highly advantageous for cell imaging. The NIR-II window has emerged as a prominent research focus in optical imaging in recent years, with its low autofluorescence background in biological samples and high imaging SBR. In this study, we initially compared dark-field imaging results of colorectal cancer cells in both visible and NIR-II wavelengths, confirming the superior performance of NIR-II imaging. Subsequently, we synthesized gold nanorods with localized surface plasmon resonance (LSPR) absorption peaks in the NIR-II window. After bio-compatible modification, we non-specifically labeled colorectal cancer cells for NIR-II dark-field scattering imaging. The imaging results revealed a sixfold increase in SBR, especially in the 1425-1475 nm wavelength range. Finally, we applied this imaging system to perform dark-field imaging of cell nuclei in the NIR-II region and used GNRs for specific nuclear labeling in colorectal cancer cells. The resulting images exhibited higher SBR than non-specifically-labeled cell imaging, and the probe's labeling was precise, confirming the potential application of this system in photothermal therapy and drug delivery for cancer cells.

Mesangial cells play a prominent role in the development of inflammatory diseases and autoimmune disorders of the kidney. Mesangial cells perform the essential functions of helping to ensure that the glomerular structure is stable and regulating capillary flow, and activated mesangial cells acquire proinflammatory activities. We investigated whether activated mesangial cells display immune properties and control the development of T cell immunity.

The fluctuating position of an optically trapped cilium tip under untreated and Taxol-treated conditions was used to characterize mechanical properties of the cilium axoneme and its basal body by combining experimental, analytical, and computational tools. We provide, for the first time, evidence that the persistence length of a ciliary axoneme is length-dependent; longer cilia are stiffer than shorter cilia. We demonstrate that this apparent length dependence can be understood by a combination of modeling axonemal microtubules as anisotropic elastic shells and including actomyosin-driven stochastic basal body motion. Our results also demonstrate the possibility of using observable ciliary dynamics to probe interior cytoskeletal dynamics. It is hoped that our improved characterization of cilia will result in deeper understanding of the biological function of cellular flow sensing by this organelle.