Administration of mesenchymal stem cells in diabetic kidney disease: mechanisms, signaling pathways, and preclinical evidence.

Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes. Currently, the prevalence and mortality of DKD are increasing annually. However, with no effective drugs to prevent its occurrence and development, the primary therapeutic option is to control blood sugar and blood pressure. Therefore, new and effective drugs/methods are imperative to prevent the development of DKD in patients with diabetes. Mesenchymal stem cells (MSCs) with multi-differentiation potential and paracrine function have received extensive attention as a new treatment option for DKD. However, their role and mechanism in the treatment of DKD remain unclear, and clinical applications are still being explored. Given this, we here provide an unbiased review of recent advances in MSCs for the treatment of DKD in the last decade from the perspectives of the pathogenesis of DKD, biological characteristics of MSCs, and different molecular and signaling pathways. Furthermore, we summarize information on combination therapy strategies using MSCs. Finally, we discuss the challenges and prospects for clinical application.

Molecular dynamics based improvement of the solubilizing self-cleavable tag Zbasic-ΔI-CM application in the preparation of recombinant proteins in Escherichia coli.

Zbasic-ΔI-CM is a novel intein-based self-cleavable tag we developed to accelerate the soluble expression of recombinant proteins in Escherichia coli (E. coli). Previously we found that intein activity could be interfered by its flanking exteins, and thus reducing the production efficiency and final yield. In this work, we used CXC-chemokine 9 (CXCL9) as a model C-extein, which fusion with Zbasic-ΔI-CM showed high intein activity. When the fusion protein got soluble expression, CXCL9 was released immediately and purified directly from cell lysis supernatant. The results demonstrated that Zbasic-ΔI-CM tag had successfully mediated the efficient production of high-quality CXCL9 with reduced time and resources consumption in comparison with inclusion bodies expression. Molecular dynamics simulations suggested that the improved cleavage activity of Zbasic-ΔI-CM upon fusion with CXCL9 may be due to the higher dynamics of the first half loop and stabilization of the second half loop of intein. Our results proved that the self-cleavable Zbasic-ΔI-CM mediated soluble expression could be a feasible process for cytokines like CXCL9, thus of attractive potentials for production of therapeutic proteins using E. coli expression system.

A general platform for efficient extracellular expression and purification of Fab from Escherichia coli.

Antigen-binding fragments (Fabs) are an important part of monoclonal antibody (mAb) therapeutics and can be cost-effectively produced using an Escherichia coli (E. coli) expression system. However, Fabs tend to form undesirable aggregates when expressed in the cytoplasm of E. coli, substantially reducing the yield of correctly folded proteins. To solve this problem, in this study, we used five Fab fragments targeting IGF1R, Her2, VEGF, RANKL, and PD-1 to develop a novel system employing the alkaline phosphatase (phoA) promoter and the heat-stable enterotoxin II (STII) leader sequence to facilitate the efficient expression and extracellular secretion of Fabs. Following phosphate starvation, all five Fab fragments were expressed in BL21(DE3), were largely secreted into the culture medium, and then, were further purified by affinity chromatography specific to the constant region of the light chain. The purified Fab products were evaluated and were found to have high purity, antigen-binding affinity, and in vitro bioactivity. The mechanism experiments revealed that (1) BL21(DE3) had significantly higher productivity than the K-12 strains investigated; (2) the secretion ability of the PhoA promoter was superior to that of the T7 promoter; and (3) signal peptide, STII, showed higher extracellular secretion efficiency than pelB. Our findings strongly suggested that the phoA-STII-facilitated extracellular production platform is highly promising for application in the manufacturing of Fab fragments for both academic and industrial purposes.

FFNT25 ameliorates unilateral ureteral obstruction-induced renal fibrosis.

Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) patients who progress to end-stage renal disease (ESRD). With the increasing incidence of CKD, it is of importance to develop effective therapies that blunt development of renal fibrosis. FFNT25 is a newly developed molecular compound that could be used to prevent fibrosis. In this study, we administered FFNT25 to rats following unilateral ureteral obstruction (UUO) to investigate its anti-fibrosis mechanism. Thirty-two Sprague-Dawley rats were randomly divided into four groups: (1) control (normal rats), (2) sham-operated, (3) UUO-operated + vehicle, and (4) UUO-operated + FFNT25. Two weeks after UUO, the rats were gavaged with either FFNT25 (20.6 mg/kg/day) or vehicle for two weeks. Serum, urine, and kidney samples were collected at the end of the study. FFNT25 reduced levels of renal fibrosis and decreased mRNA and protein levels of extracellular matrix (ECM) markers α-smooth muscle actin (α-SMA) and plasminogen activator inhibitor-1 (PAI-1) following UUO compared to vehicle treatment (n = 8, p<.05). The current results indicate that FFNT25 can affect both the production and degradation of collagen fibers to reduce fibrosis.

Rapid development of stable transgene CHO cell lines by CRISPR/Cas9-mediated site-specific integration into C12orf35.

Chinese hamster ovary (CHO) cells are the most widely used mammalian hosts for recombinant protein production. However, by conventional random integration strategy, development of a high-expressing and stable recombinant CHO cell line has always been a difficult task due to the heterogenic insertion and its caused requirement of multiple rounds of selection. Site-specific integration of transgenes into CHO hot spots is an ideal strategy to overcome these challenges since it can generate isogenic cell lines with consistent productivity and stability. In this study, we investigated three sites with potential high transcriptional activities: C12orf35, HPRT, and GRIK1, to determine the possible transcriptional hot spots in CHO cells, and further construct a reliable site-specific integration strategy to develop recombinant cell lines efficiently. Genes encoding representative proteins mCherry and anti-PD1 monoclonal antibody were targeted into these three loci respectively through CRISPR/Cas9 technology. Stable cell lines were generated successfully after a single round of selection. In comparison with a random integration control, all the targeted integration cell lines showed higher productivity, among which C12orf35 locus was the most advantageous in both productivity and cell line stability. Binding affinity and N-glycan analysis of the antibody revealed that all batches of product were of similar quality independent on integrated sites. Deep sequencing demonstrated that there was low level of off-target mutations caused by CRISPR/Cas9, but none of them contributed to the development process of transgene cell lines. Our results demonstrated the feasibility of C12orf35 as the target site for exogenous gene integration, and strongly suggested that C12orf35 targeted integration mediated by CRISPR/Cas9 is a reliable strategy for the rapid development of recombinant CHO cell lines.

Long Noncoding RNA Small Nucleolar RNA Host Gene 1 (SNHG1) Promotes Renal Cell Carcinoma Progression and Metastasis by Negatively Regulating miR-137.

BACKGROUND Data on the expression of RCC tissues from the GEO database and patient survival data from TCGA were used to explore the prognostic significance of long noncoding RNA SNHG1. SNHG1 has been reported to participate in the development of several cancers, but, the underlying mechanism of SNHG1 in renal cell carcinoma (RCC) has not been reported. The purpose of our study was to investigate the potential function of SNHG1 in RCC. MATERIAL AND METHODS The expression of SNHG1 in 40 cases of RCC and adjacent normal tissues and 5 cell lines was detected by qRT-PCR. Cell proliferation, Transwell assay, and Western blotting assay were carried out to investigate the biological function of SNHG1. A rescue experiment was performed to verify that miR-137 can partly impede the effect of SNHG1 on renal cancer cells. RESULTS SNHG1 was identified to be overexpressed in RCC tissues and RCC cell lines. High levels of SNHG1 were correlated with poor prognosis of RCC patients. Knockdown of SNHG1 suppressed the proliferation, invasion, and EMT capacity in RCC. Moreover, miR-137 abrogated the effect of SNHG1 on RCC. CONCLUSIONS SNHG1 is significantly upregulated in RCC and renal cancer cell lines. Overexpression of SNHG1 participates in RCC tumorigenesis by regulating miR-137.

Genetic variants of nuclear factor erythroid-derived 2-like 2 associated with the complications in Han descents with type 2 diabetes mellitus of Northeast China.

The transcription factor nuclear factor erythroid 2-like 2 (NFE2L2) is essential for preventing type 2 diabetes mellitus (T2DM)-induced complications in animal models. This case and control study assessed genetic variants of NFE2L2 for associations with T2DM and its complications in Han Chinese volunteers. T2DM patients with (n = 214) or without (n = 236) complications, or healthy controls (n = 359), were genotyped for six NFE2L2 single nucleotide polymorphisms (SNPs: rs2364723, rs13001694, rs10497511, rs1806649, rs1962142 and rs6726395) with TaqMan Pre-Designed SNP Genotyping and Sequence System. Serum levels of heme oxygenase-1 (HMOX1) were determined through enzyme-linked immunosorbent assay. Informative data were obtained for 341 cases and 266 controls. Between T2DM patients and controls, the genotypic and allelic frequencies and haplotypes of the SNPs were similar. However, there was a significant difference in genotypic and allelic frequencies of rs2364723, rs10497511, rs1962142 and rs6726395 between T2DM patients with and without complications, including peripheral neuropathy, nephropathy, retinopathy, foot ulcers and microangiopathy. Furthermore, HMOX1 levels were significantly higher in T2DM patients with complications than in controls. Multiple logistic regression analysis, however, showed that only rs2364723 significantly reduced levels of serum HMOX1 in T2DM patients for the GG genotype carriers compared with participants with CG+CC genotype. The data suggest that although NFE2L2 rs2364723, rs10497511, rs1962142 and rs6726395 were not associated with T2DM risk, they were significantly associated with complications of T2DM. In addition, only for rs2364723 higher serum HMOX1 levels were found in the T2DM patients with CG+CC than those with GG genotype.

Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation.

Glomerulosclerosis and interstitial fibrosis represent the key events in development of diabetic nephropathy (DN), with connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1) and fibronectin 1 (FN-1) playing important roles in these pathogenic processes. To investigate whether the plant metabolite curcumin, which exerts epigenetic modulatory properties when applied as a pharmacological agent, may prevent DN via inhibition of the JNK pathway and epigenetic histone acetylation, diabetic and age-matched non-diabetic control mice were administered a 3-month course of curcumin analogue (C66), c-Jun N-terminal kinase inhibitor (JNKi, sp600125), or vehicle alone. At treatment end, half of the mice were sacrificed for analysis and the other half were maintained without treatment for an additional 3 months. Renal JNK phosphorylation was found to be significantly increased in the vehicle-treated diabetic mice, but not the C66- and JNKi-treated diabetic mice, at both the 3-month and 6-month time points. C66 and JNKi treatment also significantly prevented diabetes-induced renal fibrosis and dysfunction. Diabetes-related increases in histone acetylation, histone acetyl transferases' (HATs) activity, and the p300/CBP HAT expression were also significantly attenuated by C66 or JNKi treatment. Chromatin immunoprecipitation assays showed that C66 and JNKi treatments decreased H3-lysine9/14-acetylation (H3K9/14Ac) level and p300/CBP occupancy at the CTGF, PAI-1 and FN-1 gene promoters. Thus, C66 may significantly and persistently prevent renal injury and dysfunction in diabetic mice via down-regulation of diabetes-related JNK activation and consequent suppression of the diabetes-related increases in HAT activity, p300/CBP expression, and histone acetylation.

A porcine model of relief of unilateral ureteral obstruction: study on self-repairing capability over multiple time points.

It is still controversial whether renal tubular interstitial fibrosis (TIF) is a reversible process. Although previous studies examining TIF have been carried out in rodents, their kidney size and physiological character differ with humans, and the difference among diverse individuals before and after damage was obvious. Thus an experimental animal model to simulate human kidney disease was urged to be established. In order to clarify whether TIF is reversible, and the exact time points that the kidney has the capacity to be repaired, a porcine relief of unilateral ureteral obstruction (R-UUO) model was developed. Kidney damage and reparation were observed dynamically in vivo over various time points. Pigs were randomized divided into three groups (n = 6): UUO 5 days group, UUO 7 days, and UUO 10 days group. Each porcine in that groups underwent UUO and subsequent R-UUO for three time points. Renal function, histological structure, and protein expressions of α-smooth muscle actin (α-SMA), vimentin and E-cadherin were evaluated at different time points. Following R-UUO after 5 and 7 days of UUO, compared to UUO, serum creatinine levels were significantly decreased. Renal pathological tissue damage was repaired. The expressions of α-SMA and vimentin were decreased and E-cadherin expression was increased (P < 0.05). However, during R-UUO 14, 28, and 56 days after 10 days of UUO, serum creatinine was not decreased significantly. The expressions of α-SMA and vimentin consistently remained at high levels. Renal damage was unable to be restored and resulted in chronic lesions. Kidney damage induced by UUO can be reversed in early stages. However, longer time of UUO with significant levels of TIF showed limited reversibility. The porcine R-UUO model provides an ideal animal model for the investigation of kidney injury and repair as well as for the evaluation of the effect of drug treatment.

Induction of ROS Overload by Alantolactone Prompts Oxidative DNA Damage and Apoptosis in Colorectal Cancer Cells.

Cancer cells typically display higher than normal levels of reactive oxygen species (ROS), which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells via induction of oxidative stress, though they target both cancer and normal cells. Recently, alantolactone (ATL), a natural sesquiterpene lactone, has been shown to induce apoptosis by increasing ROS levels specifically in cancer cells; however, the molecular mechanisms linking ROS overproduction to apoptosis remain unclear. Here we show that the ATL-induced ROS overload in human SW480 and SW1116 colorectal cancer cells was followed by a prominent accumulation of cellular oxidized guanine (8-oxoG) and immediate increase in the number of DNA strand breaks, indicating that increased ROS resulted in extensive oxidative DNA damage. Consequently, the G1/S-CDK suppresser CDKN1B (p21) and pro-apoptotic proteins Bax and activated caspase-3 were upregulated, while anti-apoptotic Bcl-2 was downregulated, which were followed by cell cycle arrest at G1 and marked apoptosis in ATL-treated cancer but not non-cancer cells. These results suggest that the ATL-induced ROS overload triggers cell death through induction of massive oxidative DNA damage and subsequent activation of the intrinsic apoptosis pathway.

Sirtuin 1: A Target for Kidney Diseases.

Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD(+)-dependent histone deacetylase that is necessary for caloric restriction-related lifespan extension. SIRT1, as an intracellular energy sensor, detects the concentration of intracellular NAD(+) and uses this information to adapt cellular energy output to cellular energy requirements. Previous studies on SIRT1 have confirmed its beneficial effects on cellular immunity to oxidative stress, reduction of fibrosis, suppression of inflammation, inhibition of apoptosis, regulation of metabolism, induction of autophagy and regulation of blood pressure. All of the above biological processes are involved in the pathogenesis of kidney diseases. Therefore, the activation of SIRT1 may become a therapeutic target to improve the clinical outcome of kidney diseases. In this review, we give an overview of SIRT1 and its molecular targets as well as SIRT1-modulated biological processes, with a particular focus on the role of SIRT1 in kidney diseases.

Association of serum Nrf2 protein levels with disease activity and renal impairment in lupus nephritis.

Introduction: We aimed to investigate the relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression levels, lupus nephritis (LN) disease activity, and the degree of renal injury (based on the estimated glomerular filtration rate [eGFR]) in patients with LN. Methods: We selected 40 healthy control participants and 102 patients with LN who were treated in the Second Hospital of Jilin University, China, for inclusion in this study. Patients with LN were classified into LN with high-eGFR and LN with low-eGFR groups. Nrf2 protein levels were measured in the serum and renal tissues of the participants in both groups to assess the correlation between Nrf2 protein levels and different LN disease states. Results: There was a significantly positive correlation between serum Nrf2 protein levels, the degree of renal injury, and systemic lupus erythematosus disease activity index (SLEDAI) scores in patients with LN. Nrf2 protein levels were higher in the LN with high-eGFR group than in the healthy control and LN with low-eGFR groups. In follow-up patients in the LN high eGFR group, Nrf2 protein levels decreased significantly after remission of disease activity. Conclusion: Nrf2 protein expression has a dual role in patients with LN. Nrf2 protein levels not only correlate with disease activity in patients with LN, but also with the degree of kidney injury. Before implementing targeted therapy for Nrf2, evaluating both Nrf2 protein expression and the disease state in patients with LN is necessary to better identify and place each patient in an appropriate patient group.

Obesity-related glomerulopathy: recent advances in inflammatory mechanisms and related treatments.

Obesity-related glomerulopathy, which is an obesity-triggered kidney damage, has become a significant threat to human health. Several studies have recently highlighted the critical role of inflammation in obesity-related glomerulopathy development. Additionally, excess adipose tissue and adipocytes in patients with obesity produce various inflammatory factors that cause systemic low-grade inflammation with consequent damage to vascular endothelial cells, exacerbating glomerular injury. Therefore, we conducted a comprehensive review of obesity-related glomerulopathy and addressed the critical role of obesity-induced chronic inflammation in obesity-related glomerulopathy pathogenesis and progression, which leads to tubular damage and proteinuria, ultimately impairing renal function. The relationship between obesity and obesity-related glomerulopathy is facilitated by a network of various inflammation-associated cells (including macrophages, lymphocytes, and mast cells) and a series of inflammatory mediators (such as tumor necrosis factor α, interleukin 6, leptin, adiponectin, resistin, chemokines, adhesion molecules, and plasminogen activator inhibitor 1) and their inflammatory pathways. Furthermore, we discuss a recently discovered relationship between micronutrients and obesity-related glomerulopathy inflammation and the important role of micronutrients in the body's anti-inflammatory response. Therefore, assessing these inflammatory molecules and pathways will provide a strong theoretical basis for developing therapeutic strategies based on anti-inflammatory effects to prevent or delay the onset of kidney injury.

Application of vacuum-sealing drainage in buttonhole-related arteriovenous fistula infection: A case report.

Few studies have reported the application of vacuum-sealing drainage of infected dialysis vascular access wounds. Herein, we present a case of buttonhole-related arteriovenous fistula infection treated with vacuum-sealing drainage. A 53-year-old female hemodialysis patient was hospitalized with an inflamed arteriovenous fistula. The patient underwent non-tunneled catheterization for dialysis and was treated with moxifloxacin and vancomycin for staphylococcal infection. On Day 3, the skin overlying the inflamed fistula was ulcerated, resulting in severe hemorrhage. Emergency surgery was performed along with vacuum-sealing drainage for fistula reconstruction. Vacuum-sealing drainage accelerated the recovery of the wound without complications. No further access complications occurred during over a 3-year follow-up.

Zinc deficiency increases lung inflammation and fibrosis in obese mice by promoting oxidative stress.

BACKGROUND: Zinc deficiency can lead to multiple organ damage. In this study, we investigated the effects of zinc deficiency on obesity-related lung damage. METHODS: C57BL/6 J mice were fed a diet with differing amounts of zinc and fat over a 6-month period. Palmitic acid was used to stimulate A549 cells to construct a high-fat alveolar epithelial cell model. Western blotting and histopathological staining were performed on animal tissues. Nuclear expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was detected in cultured cells. A reactive oxygen species (ROS) assay kit was used to detect intracellular ROS. Furthermore, Nrf2 siRNA was used to examine zinc deficiency effects on A549 cells. RESULTS: Pathological results showed significant damage to the lung structure of mice in the high-fat and low-zinc diet group, with a significant increase in the expression of inflammatory (IL-6, TNF-α) and fibrosis (TGFß1, PAI-1) factors, combined with a decrease in the expression of Nrf2, HO-1 and NQO1 in the antioxidant pathway. In A549 cells, high fat and low zinc levels aggravated ROS production. Western blot and immunofluorescence results showed that high fat and zinc deficiency inhibited Nrf2 expression. After Nrf2-specific knockout in A549 cells, the protective effect of zinc on oxidant conditions induced by high fat was reduced. Phosphorylated Akt and PI3K levels were downregulated on the high-fat and low-zinc group compared with the high-fat group. CONCLUSIONS: Zinc attenuated lung oxidative damage in obesity-related lung injury and Nrf2 activation is one of the important mechanisms of this effect. GENERAL SIGNIFICANCE: Regulating zinc homeostasis through dietary modifications or supplemental nutritional therapy can contribute to the prevention and treatment of obesity-related lung injury.

Research Progress on Podocyte Pyroptosis in Diabetic Nephropathy.

Pyroptosis is a recently discovered type of lytic-programmed cell necrosis. The process involves cells assembling an inflammasome and cleaving gasdermin (GSDM) to trigger the release of pro-inflammatory cytokines that eventually induce inflammatory cell death. Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus, which leads to end-stage renal disease. Podocyte damage or loss is an important feature of diabetic kidney injury. Pyroptosis involvement in podocyte injury is closely associated with DN progression, manifesting as increased renal fibrosis, glomerulosclerosis, and tubular injury. The study aims to elucidate the mechanism of pyroptosis and summarize the pathways and potential inhibitors related to pyroptosis activation in DN podocytes. We undertook a search of bibliographic databases for peer-reviewed research literature on various aspects of pyroptosis. Multiple different pathways mediate podocyte pyroptosis to promote DN progression. Inhibition of pyroptosis can reduce podocyte damage and improve renal function in DN, suggesting that pyroptosis may help identify potential new therapeutic targets for DN treatment.

[Retracted] MicroRNA­320a suppresses tumour cell proliferation and invasion of renal cancer cells by targeting FoxM1.

Subsequently to the publication of the above paper, the authors drew to the attention of the Editorial Office that they made a couple of errors in terms of the data assembly in Figs. 2 and 4 in their paper; specifically, the Transwell assay data shown for the 'miR-320a+/FoxM1+' panel in Fig. 5D on p. 1923 also appeared as the 'ACTN/NC' data panel in Fig. 4E on the same page (Fig. 4E contained the erroneously duplicated panel). In addition, data featured in Fig. 2D of the above paper were strikingly similar to data that appeared in Fig. 6e of the following paper, published subsequently to this article, written by different authors (although a Dr Shiyue Zhao worked in the molecular biology laboratory of Harbin Medical University from 2017 to 2018, and the research collaboration was conducted with Dr Chenlong Li's research group): Li C, Zheng H, Hou W, Bao H, Xiong J, Che W, Gu Y, Sun H and Liang P: Long non-coding RNA linc00645 promotes. TGF-ß-induced epithelial-mesenchymal transition by regulating miR-205-3p-ZEB1 axis in glioma. Cell Death Dis 10: 17, 2019. Finally, after having conducted an independent investigation of the data in this paper, the Editorial Office noted that one of the Petri dish images in Fig. 2C was also strikingly similar to data that appeared in Fig. 2H of the abovementioned article in the journal Cell Death & Disease. After having considered the authors' request for corrigendum, in view of the problems that were identified with the data, the Editor of Oncology Reports has decided that, owing to a lack of confidence in the presented data, the paper should instead be retracted from the journal. After having informed the authors of this decision, they accepted the decision to retract this paper. The Editor apologizes to the readership for any inconvenience caused.  [Oncology Reports 40: 1917­1926, 2018; DOI: 10.3892/or.2018.6597].

Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study.

Objective: To elucidate the potential causality of leukocyte telomere length (LTL) with immune-mediated inflammatory diseases (IMIDs), we conducted a Mendelian randomization (MR) study. Methods: The genetically predicted causation between LTL and IMIDs was evaluated using a two-sample MR method. We analyzed 16 major IMIDs, which included systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), ankylosing spondylitis (AS), sicca syndrome (SS), rheumatoid arthritis (RA), type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), atopic dermatitis (AD), sarcoidosis, hypothyroidism, hyperthyroidism, psoriasis, and childhood asthma. The random-effects inverse-variance weighted (IVW) method was performed as the main analytical approach in MR. Various sensitivity analyses, including MR-Egger, MR robust adjusted profile score (MR-RAPS), weighted median, MR pleiotropy residual sum and outlier (MR-PRESSO) methods, weighted mode, radial plot, and radial regression, were used to guarantee the robustness of the results and detect horizontal pleiotropy. Cochran's Q value was calculated to check for heterogeneity, and the MR Steiger approach was used to test the causal direction. Results: The MR results indicated significant inverse associations of LTL with risks of psoriasis (OR: 0.77, 95% CI: 0.66-0.89, and p = 3.66 × 10-4), SS (OR: 0.75, CI: 0.58-0.98, and p = 0.03), RA (OR: 0.77, 95% CI: 0.68-0.88, and p = 9.85 × 10-5), hypothyroidism (OR: 0.84, 95% CI: 0.78-0.91, and p = 7,08 × 10-6), hyperthyroidism (OR: 0.60, 95% CI: 0.44-0.83, and p = 1.90 × 10-3), sarcoidosis (OR: 0.67, 95% CI: 0.54-0.83, and p = 2.60 × 10-4), and IPF (OR: 0.41, 95% CI: 0.29-0.58, and p = 4.11 × 10-7) in the FinnGen study. We observed that longer LTL was associated with an increased risk of AS susceptibility (OR: 1.51, 95% CI: 1.18-1.94, and p = 9.66 × 10-4). The results of the IVW method showed no causal relationship between TL and SLE (OR: 0.92, 95% CI: 0.62-1.38, and p = 0.69) in the FinnGen study; however, a significantly positive correlation was shown between LTL and SLE in another larger GWAS (OR: 1.87, 95% CI: 1.37-2.54, and p = 8.01 × 10-5). Conclusion: Our findings reveal that abnormal LTL has the potential to increase the risk of IMIDs. Therefore, it could be treated as a predictor and may provide new potential treatment targets for IMIDs. However, the change of LTL may not be the direct cause of IMIDs. Further studies should aim at the pathogenic mechanism or potential protective effects of LTL in IMIDs.

SS-31, a Mitochondria-Targeting Peptide, Ameliorates Kidney Disease.

Mitochondria are essential for eukaryotic cell activity and function, and their dysfunction is associated with the development and progression of renal diseases. In recent years, there has been a rapid development in mitochondria-targeting pharmacological strategies as mitochondrial biogenesis, morphology, and function, as well as dynamic changes in mitochondria, have been studied in disease states. Mitochondria-targeting drugs include nicotinamide mononucleotide, which supplements the NAD+ pool; mitochondria-targeted protective compounds, such as MitoQ; the antioxidant coenzyme, Q10; and cyclosporin A, an inhibitor of the mitochondrial permeability transition pore. However, traditional drugs targeting mitochondria have limited clinical applications due to their inability to be effectively absorbed by mitochondria in vivo and their high toxicity. Recently, SS-31, a mitochondria-targeting antioxidant, has received significant research attention as it decreases mitochondrial reactive oxygen species production and prevents mitochondrial depolarization, mitochondrial permeability transition pore formation, and Ca2+-induced mitochondrial swelling, and has no effects on normal mitochondria. At present, few studies have evaluated the effects of SS-31 against renal diseases, and the mechanism underlying its action is unclear. In this review, we first discuss the pharmacokinetics of SS-31 and the possible mechanisms underlying its protective effects against renal diseases. Then, we analyze its renal disease-improving effects in various experimental models, including animal and cell models, and summarize the clinical evidence of its benefits in renal disease treatment. Finally, the potential mechanism underlying the action of SS-31 against renal diseases is explored to lay a foundation for future preclinical studies and for the evaluation of its clinical applications.

Tofacitinib combined with leflunomide for treatment of psoriatic arthritis with IgA nephropathy: a case report with literature review.

Psoriasis is a systemic inflammatory disease that is associated with increased risk of several diseases, such as psoriatic arthritis (PsA), inflammatory bowel disease, and cardiovascular diseases. About 20 to 30% patients with psoriasis subsequently develop PsA. IgA nephropathy is the most common primary glomerular disease world-wide. Psoriasis and IgA nephropathy appear to be associated, but the mechanism underlying this connection is unclear. Tofacitinib and leflunomide are common treatments for psoriatic arthritis. We administered tofacitinib combined with leflunomide to a 38-year-old female patient who presented with PsA and IgA nephropathy. After treatment, she experienced significant reductions in the psoriatic lesions, pain in the right knee joint, and proteinuria. Administration of tofacitinib combined with leflunomide for treatment of a patient who had PsA complicated with IgA nephropathy led to significant resolution of the symptoms of both conditions. These results suggest similarities in the pathogenesis of PsA and IgA nephropathy and a possible new treatment for IgA nephropathy.