Self-Assembly of Heterogeneous Ferritin Nanocages for Tumor Uptake and Penetration.

Well-defined nanostructures are crucial for precisely understanding nano-bio interactions. However, nanoparticles (NPs) fabricated through conventional synthesis approaches often lack poor controllability and reproducibility. Herein, a synthetic biology-based strategy is introduced to fabricate uniformly reproducible protein-based NPs, achieving precise control over heterogeneous components of the NPs. Specifically, a ferritin assembly toolbox system is developed that enables intracellular assembly of ferritin subunits/variants in Escherichia coli. Using this strategy, a proof-of-concept study is provided to explore the interplay between ligand density of NPs and their tumor targets/penetration. Various ferritin hybrid nanocages (FHn) containing human ferritin heavy chains (FH) and light chains are accurately assembled, leveraging their intrinsic binding with tumor cells and prolonged circulation time in blood, respectively. Further studies reveal that tumor cell uptake is FH density-dependent through active binding with transferrin receptor 1, whereas in vivo tumor accumulation and tissue penetration are found to be correlated to heterogeneous assembly of FHn and vascular permeability of tumors. Densities of 3.7 FH/100 nm2 on the nanoparticle surface exhibit the highest degree of tumor accumulation and penetration, particularly in tumors with high permeability compared to those with low permeability. This study underscores the significance of nanoparticle heterogeneity in determining particle fate in biological systems.

Perforating cutaneous vessels: A key feature of acupoints - Anatomical evidence from five-Shu acupoints in the upper limbs.

Acupuncture has been proven an effective clinical treatment for numerous pathological conditions and malfunctions. However, substantial anatomical evidence for acupuncture points (APs) and meridians is still lacking, so the location of APs is relatively subjective and understanding of the biological mechanisms of acupuncture is limited. All these problems hinder the clinical applications and worldwide acceptance of acupuncture. Our long-term microsurgery experience has indicated that Perforating Cutaneous Vessels (PCVs) are highly relevant to APs but the anatomical evidence is insufficient. To address this lack, two specimens of fresh adult human upper limbs were dissected using an advanced vascular perfusion-fixation method and then examined. The results show that all 30 five-Shu APs in the upper limbs have corresponding PCVs. Both specimens showed a 100% coincidence rate between APs and PCVs, indicating that PCVs could be critical anatomical features of APs. This study also provides an anatomical basis for locating APs objectively via preliminary detection of PCVs. The findings could lead to a better theoretical understanding of mechanisms of acupuncture and the essence of meridians.

Characteristics of fish community structure and environmental driving factors in Taihu Lake during the first year of fishing ban.

Taihu Lake has officially implemented the full fishing ban policy since October 1, 2020. We investigated fish community of Taihu Lake in the four seasons of 2020. A total of 42 fish species were collected, belonging to 6 orders, 7 families, and 33 genera. The first five dominant species ranked by the index of relative importance were Coilia nasus, Toxabramis swinhonis, Hypophthalmichthys molitrix, Hypophthalmichthys nobilis, and Salangichthys tangkahkeii. The number of C. nasus accounted for 85.1% of the total number of catches. According to the distributional characteristics of cyanobacterial blooms and aquatic plants, Taihu Lake could be divided into the northern, central, and eastern regions. There was no significant difference in catch per unit effort (CPUE) among different lake regions, but Shannon diversity index and Pielou evenness index in the eastern region was greater than in the other two regions. The CPUE, Shannon diversity index, and Pielou evenness index were significantly different among the four seasons, with the lowest CPUE in autumn and higher diversity in autumn and winter than in spring and summer. Electrical conductivity, water depth, chloride, and transparency were the main environmental factors driving the seasonal variations of fish community in Taihu Lake, while electrical conductivity, dissolved oxygen, total alkalinity, and transparency were key variables driving the spatial patterns. The results could be used as the baseline data for fish community studies in Taihu Lake after the fishing ban.

Machine-learning-assisted single-vessel analysis of nanoparticle permeability in tumour vasculatures.

The central dogma that nanoparticle delivery to tumours requires enhanced leakiness of vasculatures is a topic of debate. To address this, we propose a single-vessel quantitative analysis method by taking advantage of protein-based nanoprobes and image-segmentation-based machine learning (nano-ISML). Using nano-ISML, >67,000 individual blood vessels from 32 tumour models were quantified, revealing highly heterogenous vascular permeability of protein-based nanoparticles. There was a >13-fold difference in the percentage of high-permeability vessels in different tumours and >100-fold penetration ability in vessels with the highest permeability compared with vessels with the lowest permeability. Our data suggest passive extravasation and transendothelial transport were the dominant mechanisms for high- and low-permeability tumour vessels, respectively. To exemplify the nano-ISML-assisted rational design of nanomedicines, genetically tailored protein nanoparticles with improved transendothelial transport in low-permeability tumours were developed. Our study delineates the heterogeneity of tumour vascular permeability and defines a direction for the rational design of next-generation anticancer nanomedicines.

Tumor Cell Nanovaccines Based on Genetically Engineered Antibody-Anchored Membrane.

Despite the promise in whole-tumor cell vaccines, a key challenge is to overcome the lack of costimulatory signals. Here, agonistic-antibody-boosted tumor cell nanovaccines are reported by genetically engineered antibody-anchored membrane (AAM) technology, capable of effectively activating costimulatory pathways. Specifically, the AAM can be stably constructed following genetic engineering of tumor cell membranes with anti-CD40 single chain variable fragment (scFv), an agonistic antibody to induce costimulatory signals. The nanovaccines are versatilely designed and obtained based on the anti-CD40 scFv-anchored membrane and nanotechnology. Following vaccination, the anti-CD40 scFv-anchored membrane nanovaccine (Nano-AAM/CD40) significantly facilitates dendritic cell maturation in CD40-humanized transgenic mice and subsequent adaptive immune responses. Compared to membrane-based nanovaccines alone, the enhanced antitumor efficacy in both "hot" and "cold" tumor models of the Nano-AAM/CD40 demonstrates the importance of agonistic antibodies in development of tumor-cell-based vaccines. To expand the design of nanovaccines, further incorporation of cell lysates into the Nano-AAM/CD40 to conceptually construct tumor cell-like nanovaccines results in boosted immune responses and improved antitumor efficacy against malignant tumors inoculated into CD40-humanized transgenic mice. Overall, this genetically engineered AAM technology provides a versatile design of nanovaccines by incorporation of tumor-cell-based components and agonistic antibodies of costimulatory immune checkpoints.

KYA1797K, a Novel Small Molecule Destabilizing ß-Catenin, Is Superior to ICG-001 in Protecting against Kidney Aging.

Introduction: Aged kidney is characterized by mitochondrial dysfunction, cellular senescence, and fibrogenesis. The activation of Wnt/ß-catenin signaling plays an important role in the initiation of kidney aging. However, the inhibiting strategies have not been discovered in detail. Here, we compared the therapeutic effects of two ß-catenin inhibitors, KYA1797K and ICG-001, to assess their superiority. Methods: Two-month-old male C57BL/6 mice which had undergone unilateral nephrectomy and received D-galactose (D-gal) injection were co-treated with KYA1797K or ICG-001 at 10 mg/kg/day for 4 weeks. Human proximal renal tubular cells were treated with D-gal and KYA1797K/ICG-001 to compare their effects. Results: Compared with ICG-001, which inhibits ß-catenin pathway through blocking the binding of ß-catenin and cAMP response element-binding protein (CREB)-binding protein (CBP), KYA1797K, a novel small molecule destabilizing ß-catenin through activating Axin-GSK3ß complex, possesses the superior effects on protecting against kidney aging. In D-gal-treated accelerated aging mice, KYA1797K could greatly inhibit ß-catenin pathway, preserve mitochondrial homeostasis, repress cellular senescence, and retard age-related kidney fibrosis. In cultured proximal tubular cells, KYA1797K shows a better effect on inhibiting cellular senescence and could better suppress mitochondrial dysfunction and ameliorate the fibrotic changes, at the same dose as that in ICG-001. Conclusion: These results show that effectively eliminating ß-catenin is a necessity to target against age-related kidney injury, suggesting the multiple transcriptional regulation of ß-catenin in kidney aging besides T-cell factor/lymphoid enhancer-binding factor family of transcription factors (TCF/LEF-1).

Targeted delivery of nanomedicines for promoting vascular regeneration in ischemic diseases.

Ischemic diseases, the leading cause of disability and death, are caused by the restriction or blockage of blood flow in specific tissues, including ischemic cardiac, ischemic cerebrovascular and ischemic peripheral vascular diseases. The regeneration of functional vasculature network in ischemic tissues is essential for treatment of ischemic diseases. Direct delivery of pro-angiogenesis factors, such as VEGF, has demonstrated the effectiveness in ischemic disease therapy but suffering from several obstacles, such as low delivery efficacy in disease sites and uncontrolled modulation. In this review, we summarize the molecular mechanisms of inducing vascular regeneration, providing the guidance for designing the desired nanomedicines. We also introduce the delivery of various nanomedicines to ischemic tissues by passive or active targeting manner. To achieve the efficient delivery of nanomedicines in various ischemic diseases, we highlight targeted delivery of nanomedicines and controllable modulation of disease microenvironment using nanomedicines.

Role of the long non-coding RNA, SPRR2C, based on an in vitro psoriatic keratinocyte cell model

Background: Psoriasis is a chronic inflammatory disease of the skin with complex pathogenesis. Long non-coding RNAs (lncRNAs) play an important regulatory role in the occurrence and progression of many diseases, as well as psoriasis. Objectives: This study aimed to investigate the role and mechanism of the lncRNA, SPRR2C, in M5-induced psoriatic keratinocytes. Materials & Methods: SPRR2C expression and subcellular localization was detected using FISH and qRT-PCR. Ker-CT and HaCaT cells stimulated by M5 (IL-17A, tumour necrosis factor-α, IL-1α, IL-22, and oncostatin-M) were used to establish a psoriatic cell model. CCK-8 assay, CFSE proliferation assay, flow cytometry, western blotting and ELISA were used to examine the effects of SPRR2C in the keratinocyte model. Results: SPRR2C was highly expressed in psoriatic samples and M5-induced psoriatic keratinocytes, and SPRR2C was mainly localised to the cytoplasm. In keratinocytes, SPRR2C regulated proliferation, cell cycle and apoptosis, and induced the expression of IL-1ß, IL-6, IL-8, CXCL2 and CCL20. Moreover, SPRR2C cellular effects were shown to be mediated by the PI3K/AKT/mTOR signalling pathway, based on experiments with the AKT-specific inhibitor, MK-2206, which was also shown to suppress overexpression of SPRR2C. Conclusion: Our results indicate that SPRR2C plays a regulatory role and is involved in the PI3K/AKT/mTOR signalling pathway in psoriatic keratinocytes, which may provide a potential diagnostic and therapeutic target for psoriasis.

CXC Chemokine Receptor 2 Accelerates Tubular Cell Senescence and Renal Fibrosis via ß-Catenin-Induced Mitochondrial Dysfunction.

Renal fibrosis is a common feature of various chronic kidney diseases (CKD). However, its underlying mechanism has not been totally clarified. C-X-C motif chemokine receptor (CXCR) family plays a role in renal fibrosis, however, detailed mechanisms have not been elucidated. Here, we report that CXCR2 has a potential role in tubular cell senescence and renal fibrosis, and is associated with ß-catenin-activated mitochondrial dysfunction. CXCR2 is one of most increased members among CXCR family in unilateral ureteral obstruction (UUO) mice. CXCR2 was expressed primarily in tubules and co-localized with p16INK4A, a cellular senescence marker, and ß-catenin. Administration of SB225002, a selective CXCR2 antagonist, significantly inhibited the activation of ß-catenin signaling, restored mitochondrial function, protected against tubular cell senescence and renal fibrosis in unilateral ureteral obstruction (UUO) mice. In unilateral ischemia-reperfusion injury (UIRI) mice, treatment with interlukin-8 (IL-8), the ligand of CXCR2, further aggravated ß-catenin activation, mitochondrial dysfunction, tubular cell senescence and renal fibrosis, whereas knockdown of p16INK4A inhibited IL-8-induced these effects. In vitro, SB225002 inhibited mitochondrial dysfunction and tubular cell senescence. Furthermore, ICG-001, a ß-catenin signaling blocker, significantly retarded CXCR2-induced cellular senescence and fibrotic changes. These results suggest that CXCR2 promotes tubular cell senescence and renal fibrosis through inducing ß-catenin-activated mitochondrial dysfunction.

ILF2 Contributes to Hyperproliferation of Keratinocytes and Skin Inflammation in a KLHDC7B-DT-Dependent Manner in Psoriasis.

Background: The extensive involvement of interleukin enhancer binding factor 2 (ILF2) in RNA stability and the inflammatory response is well documented. Aberrant long noncoding RNA (lncRNA) expression contributes to the pathogenesis of psoriasis. However, little is known about the role of ILF2 in psoriasis. Objective: To investigate the role of ILF2 and KLHDC7B-DT in psoriasis. Methods: LncRNA expression in psoriatic tissues was measured by lncRNA microarray and qRT-PCR. Normal human epidermal keratinocytes (NHEKs), HaCaT cells, and Ker-CT cells stimulated with M5 (IL-17A, IL-22, IL-1α, oncostatin M, and TNF-α) were used to establish a psoriasis model in vitro. Fluorescence in situ hybridization was used to detect the distribution of KLHDC7B-DT and ILF2 in keratinocytes. The proliferative effects of KLHDC7B-DT and ILF2 on keratinocytes were demonstrated by EdU assay and flow cytometry. ELISA was used to detect the secretion levels of cytokines. RNA pull-down and RNA immunoprecipitation (RIP) were used to detect the direct binding of KLHDC7B-DT with ILF2. Western blotting was used to detect the proteins related to STAT3/JNK signalling pathways. Results: ILF2 and KLHDC7B-DT were significantly overexpressed in psoriatic tissues and M5-induced keratinocytes. KLHDC7B-DT promoted the proliferation of keratinocytes and induced the secretion of IL-6 and IL-8. KLHDC7B-DT could directly bind to ILF2 and activate the STAT3 and JNK signalling pathways. KLHDC7B-DT expression was regulated by ILF2. M5-induced proliferation and inflammatory cytokine secretion in keratinocytes was inhibited after ILF2 knockdown. Furthermore, we found that ILF2 promoted keratinocyte proliferation and the inflammatory response in a KLHDC7B-DT-dependent manner. Conclusions: ILF2 and KLHDC7B-DT are involved in the hyperproliferation of keratinocytes and skin inflammation in psoriasis. In addition, ILF2 functions in a KLHDC7B-DT-dependent manner.

Mechanistic Insights Into Co-Administration of Allosteric and Orthosteric Drugs to Overcome Drug-Resistance in T315I BCR-ABL1.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, driven by the BCR-ABL1 fusion oncoprotein. The discovery of orthosteric BCR-ABL1 tyrosine kinase inhibitors (TKIs) targeting its active ATP-binding pocket, such as first-generation Imatinib and second-generation Nilotinib (NIL), has profoundly revolutionized the therapeutic landscape of CML. However, currently targeted therapeutics still face considerable challenges with the inevitable emergence of drug-resistant mutations within BCR-ABL1. One of the most common resistant mutations in BCR-ABL1 is the T315I gatekeeper mutation, which confers resistance to most current TKIs in use. To resolve such conundrum, co-administration of orthosteric TKIs and allosteric drugs offers a novel paradigm to tackle drug resistance. Remarkably, previous studies have confirmed that the dual targeting BCR-ABL1 utilizing orthosteric TKI NIL and allosteric inhibitor ABL001 resulted in eradication of the CML xenograft tumors, exhibiting promising therapeutic potential. Previous studies have demonstrated the cooperated mechanism of two drugs. However, the conformational landscapes of synergistic effects remain unclear, hampering future efforts in optimizations and improvements. Hence, extensive large-scale molecular dynamics (MD) simulations of wide type (WT), WT-NIL, T315I, T315I-NIL, T315I-ABL001 and T315I-ABL001-NIL systems were carried out in an attempt to address such question. Simulation data revealed that the dynamic landscape of NIL-bound BCR-ABL1 was significantly reshaped upon ABL001 binding, as it shifted from an active conformation towards an inactive conformation. The community network of allosteric signaling was analyzed to elucidate the atomistic overview of allosteric regulation within BCR-ABL1. Moreover, binding free energy analysis unveiled that the affinity of NIL to BCR-ABL1 increased by the induction of ABL001, which led to its favorable binding and the release of drug resistance. The findings uncovered the in-depth structural mechanisms underpinning dual-targeting towards T315I BCR-ABL1 to overcome its drug resistance and will offer guidance for the rational design of next generations of BCR-ABL1 modulators and future combinatory therapeutic regimens.

AMPK Activator O304 Protects Against Kidney Aging Through Promoting Energy Metabolism and Autophagy.

Aging is an important risk factor for kidney injury. Energy homeostasis plays a key role in retarding aging, and mitochondria are responsible for energy production. In the kidney, renal tubular cells possess high abundance of mitochondria to meet the high energy consumption. AMPK is an evolutionarily conserved serine/threonine kinase which plays a central role in maintaining energy homeostasis and mitochondrial homeostasis. Besides that, AMPK also commands autophagy, a clearing and recycling process to maintain cellular homeostasis. However, the effect of AMPK activators on kidney aging has not been fully elucidated. To this end, we testified the effects of O304, a novel direct AMPK activator, in naturally aging mice model and D-Galactose (D-Gal)-treated renal tubular cell culture. We identified that O304 beneficially protects against cellular senescence and aged-related fibrosis in kidneys. Also, O304 restored energy metabolism, promoted autophagy and preserved mitochondrial homeostasis. Transcriptomic sequencing also proved that O304 induced fatty acid metabolism, mitochondrial biogenesis and ATP process, and downregulated cell aging, DNA damage response and collagen organization. All these results suggest that O304 has a strong potential to retard aged kidney injury through regulating AMPK-induced multiple pathways. Our results provide an important therapeutic approach to delay kidney aging.

In2S3 nanoparticles coupled to In-MOF nanorods: The structural and electronic modulation for synergetic photocatalytic degradation of Rhodamine B.

Enhancing photocatalytic performance via electronic modulation have attracted much attention for synergetic photocatalytic degradation of antibiotic pollutant. In this study, a new hetero-structured system is raised, which comprises In2S3 coupled to In-MOF and operates as an efficient photocatalyst for RhB degradation. The formation of hetero-structure and occurred electron modulation of In2S3/In-MOF hybrid was confirmed by relevant characterizations. Surprisingly, the In2S3/In-MOF hybrid represented enhanced photocatalytic ability over In-MOF. The photocatalysis of Rhodamine B in presence of In2S3/In-MOF hybrid has achieved 92.2 % degradation.

Application of ß-Cyclodextrin metal-organic framework/titanium dioxide hybrid nanocomposite as dispersive solid-phase extraction adsorbent to organochlorine pesticide residues in honey samples.

A simple and efficient dispersive solid-phase extraction (D-SPE) method combined with gas chromatography tandem mass spectrometry (GC-MS/MS) was developed to determine organochlorine pesticides (OCP) in honey. Firstly, a type of hybrid nanocomposite (CD-MOF/TiO2) was prepared by grafting a metal-organic framework material synthesized with cyclodextrin as an organic ligand onto titanium dioxide. Then, the CD-MOF/TiO2 was used as a D-SPE adsorbent to extract the OCP, and the effects of the amount of adsorbent, ultrasonic time, vortex time, pH, and salinity on the extraction were investigated using Plackett-Burman design and Box-Behnken Design. Under the optimized adsorption and desorption conditions, an analysis method that combined D-SPE with GC-MS/MS was established. The linear ranges of 14 OCP are 1-500 µg kg-1 and the correlation coefficients are between 0.9991 and 1.000. The limits of detection and quantification vary from 0.01 to 0.04 µg kg-1 and 0.04 to 0.12 µg kg-1, respectively. The intra-day and inter-day precision of this method are suitable (RSDs% less than 11.3%). The established CD-MOF/TiO2 / D-SPE method was used for the extraction of OCP in honey samples with recovery in the range of 76.4 to 114.3%. The results demonstrate that the CD-MOF/TiO2 has a good selective enrichment ability for OCP and is suitable for the D-SPE pretreat of honey sample analysis.

Modular Assembly of Tumor-Penetrating and Oligomeric Nanozyme Based on Intrinsically Self-Assembling Protein Nanocages.

Biomimetic design of nanomaterials with enzyme-like characteristics has emerged as a promising method for the generation of novel therapeutics. However, synthesis of nanomaterials while maintaining a high degree of control over both geometry and valency poses a prominent challenge. Herein, the authors introduce a nanomaterial-based synthetic biology strategy for accurate and quantitative tailoring of high-ordered nanostructures that uses a "bottom-up" hierarchical incorporation of protein building blocks. The assembled nano-oligomers possessed tunable protein motifs and multivalent binding domains, which facilitated prolonged blood circulation time, accumulation within tumor cells through direct targeting of cell receptors, and deep tumor tissue penetration via a transcytosis mechanism. Using these protein/protein nano-oligomers as scaffolds, the authors created a new series of artificial nano-scaled metalloenzymes (nanozymes) by the in situ incorporation of metal nanoclusters within the cavity of the protein nanocages. Nanozymes were capable of mimicking peroxidase-like activity and generated cytotoxic free radicals. Compared to nanozyme alone, the systemic delivery of oligomeric nanozymes demonstrated significantly enhanced therapeutic and anti-tumor benefits. This study shows a new insight into nanotechnology by taking advantage of synthetic biotechnology.

Pachypodol protects newborn rats from anaesthesia-induced apoptosis in the developing brain by regulating the JNK/ERK pathway.

Anaesthesia exposure causes changes in the developing brain and affects behaviour and memory. This study examined the beneficial effect of pachypodol against isoflurane (ISF)-induced neuronal injury. Seven-day-old rats were treated with 10 mg/kg and 30 mg/kg intravenous pachypodol 30 min before exposure to ISF (0.75%) for 6 h. Oxidative stress and other biochemical parameters were assessed in the brain tissue and serum using enzyme-linked immunosorbent assay. Additionally, a terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay was performed to assess neuronal cell apoptosis in several regions of the hippocampus. Cognitive function and neurological scores were determined in the pachypodol-treated neuron-injured rats. Cytokine levels and oxidative stress were reduced in the pachypodol-treated group compared with the ISF group. In addition, cognitive deterioration was reversed in pachypodol-treated compared with ISF-treated rats. Thus, treatment with pachypodol reduced neuronal apoptosis in neuron-injured rats. Moreover, pachypodol ameliorated changes to the JNK/ERK/Akt pathway in brain-injured rats. In conclusion, pachypodol treatment prevents neuronal apoptosis in ISF-treated rats by regulating the JNK/ERK pathway.

Fibrillin-1-enriched microenvironment drives endothelial injury and vascular rarefaction in chronic kidney disease.

Endothelial cell injury leading to microvascular rarefaction is a characteristic feature of chronic kidney disease (CKD). However, the mechanism underlying endothelial cell dropout is poorly defined. Here, we show a central role of the extracellular microenvironment in controlling endothelial cell survival and proliferation in CKD. When cultured on a decellularized kidney tissue scaffold (KTS) from fibrotic kidney, endothelial cells increased the expression of proapoptotic proteins. Proteomics profiling identified fibrillin-1 (FBN1) as a key component of the fibrotic KTS, which was up-regulated in animal models and patients with CKD. FBN1 induced apoptosis of endothelial cells and inhibited their proliferation in vitro. RNA sequencing uncovered activated integrin αvß6/transforming growth factor-ß signaling, and blocking this pathway abolished FBN1-triggered endothelial injury. In a mouse model of CKD, depletion of FBN1 ameliorated renal fibrotic lesions and mitigated vascular rarefaction. These studies illustrate that FBN1 plays a role in mediating vascular rarefaction by orchestrating a hostile microenvironment for endothelial cells.

Advancements in therapeutic drugs targeting of senescence.

Aging leads to a high burden on society, both medically and economically. Cellular senescence plays an essential role in the initiation of aging and age-related diseases. Recent studies have highlighted the therapeutic value of senescent cell deletion in natural aging and many age-related disorders. However, the therapeutic strategies for manipulating cellular senescence are still at an early stage of development. Among these strategies, therapeutic drugs that target cellular senescence are arguably the most highly anticipated. Many recent studies have demonstrated that a variety of drugs exhibit healthy aging effects. In this review, we summarize different types of drugs promoting healthy aging - such as senolytics, senescence-associated secretory phenotype (SASP) inhibitors, and nutrient signaling regulators - and provide an update on their potential therapeutic merits. Taken together, our review synthesizes recent advancements in the therapeutic potentialities of drugs promoting healthy aging with regard to their clinical implications.

Wnt signaling in kidney: the initiator or terminator?

The kidney is a key organ in the human body that excretes toxins and sustains the water-electrolyte balance. During embryonic development and disease progression, the kidney undergoes enormous changes in macrostructure, accompanied by a variety of microstructural histological changes, such as glomerular formation and sclerosis, tubule elongation and atrophy, interstitial establishment, and fibrosis progression. All of these rely on the frequent occurrence of cell death and growth. Notably, to overcome disease, some cells regenerate through self-repair or progenitor cell differentiation. However, the signaling mechanisms underlying kidney development and regeneration have not been elucidated. Recently, Wnt signaling has been noted to play an important role. Although it is a well-known developmental signal, the role of Wnt signaling in kidney development and regeneration is not well recognized. In this review, we review the role of Wnt signaling in kidney embryonic development, tissue repair, cell division, and progenitor cell differentiation after injury. Moreover, we briefly highlight advances in our understanding of the pathogenic mechanisms of Wnt signaling in mediating cellular senescence in kidney parenchymal and stem cells, an irreversible arrest of cell proliferation blocking tissue repair and regeneration. We also highlight the therapeutic targets of Wnt signaling in kidney diseases and provide important clues for clinical strategies.

The incidence, risk factors, and long-term outcomes of acute kidney injury in hospitalized diabetic ketoacidosis patients.

BACKGROUND: Emerging evidence has demonstrated that acute kidney injury (AKI) is an important risk factor associated with increased morbidity and mortality in diabetic ketoacidosis (DKA) patients. The current study aimed to investigate the incidence rate, risk factors, long-term renal outcomes, and mortality in DKA patients with AKI. METHODS: A total of 179 patients diagnosed with DKA at Sun Yat-sen Memorial Hospital from January 2012 to January 2018 were included in the analysis. AKI was diagnosed according to the 2012 KDIGO criteria. Risk factors, long-term renal outcomes, and mortality were analyzed by logistic regression and Cox proportional hazards models. RESULTS: Among 179 DKA patients, 98 patients (54.75%) were diagnosed as AKI. Aging; increased blood glucose, serum uric acid and white blood cells; decreased serum pH and albumin; coma; and preexisting chronic kidney disease (CKD) were risk factors of AKI in patients with DKA. During follow-up, DKA patients with AKI showed more than a two-fold decline in eGFR within 1 year after discharge from the hospital when compared with non-AKI DKA patients. Furthermore, AKI was also an independent risk factor for poor long-term renal outcomes and mortality in DKA patients. CONCLUSIONS: Multiple risk factors contribute to the development of AKI in DKA patients. AKI and advanced AKI stage are associated with rapid progressive CKD and long-term mortality in patients with DKA.