AKI-to-CKD progression is shaped by sustained tubular stress, ferroptosis-related iron imbalance, and oxidative injury. To target this process, we developed an MHY1485-loaded molybdenum oxide (MoOx) nanozyme coated with a pH-responsive phenylboronic acid-polyethylene glycol-phenylboronic acid (PBA-PEG-PBA) polymer (MHY@MO@PPP). We tested whether this platform could weaken the ferroptosis-associated injury loop and delay AKI-to-CKD transition through regulation of the Fe2+-mechanistic target of rapamycin complex 1 (mTORC1)-glutathione peroxidase 4 (GPX4) axis. Material properties were examined by dynamic light scattering (DLS), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Biological activity was assessed in erastin-induced ferroptotic human renal proximal tubular epithelial (HK-2) cells and in a C57BL/6 mouse unilateral ischemia-reperfusion injury (UIRI) model. MHY@MO@PPP showed stimulus-responsive MHY1485 release under simulated lesion-like conditions, lowered reactive oxygen species (ROS), lipid peroxidation, and free Fe2+, restored mitochondrial function, and improved cell survival. Mechanistic assays showed increased p-mTOR and GPX4 expression with reduced autophagy-related stress, supporting attenuation of the ferroptosis-related feedback state. Proteomic analysis and functional intervention experiments further implicated the Fe2+-mTORC1-GPX4 axis in the protective response. In vivo, MHY@MO@PPP improved renal function and reduced renal tissue injury and fibrosis. These findings support a nanozyme-based strategy that combines catalytic redox regulation with pathway modulation to mitigate AKI-to-CKD progression.

Autophagy is a conserved, lysosome-dependent degradation system that is used by a wide variety of eukaryotes; during autophagy, intracellular substances are transported to lysosomes for degradation, and thus, autophagy plays a crucial role in cell survival under stress conditions such as starvation and hypoxia. Additionally, cells can eliminate foreign pathogens, such as parasites, bacteria, and viruses, via autophagic clearance. Protozoa are categorized as either intracellular parasitic protozoa or extracellular parasites, which are mostly zoonotic pathogens that pose significant threats to public health. In recent years, research on the mutual influences of autophagy and protozoa has focused mainly on Toxoplasma and Plasmodium, with less focus on extracellular parasitic protozoa. In this review, we discuss the crucial role of autophagy in maintaining the dynamic equilibrium between host elimination of extracellular and intracellular parasites and parasitic exploitation of the host.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, which has the potential to advance to fibrosis. CAV1 has the effects of improving liver lipid deposition in MASLD, however, the potential mechanism is largely unknown. Here, we establish a MASLD mouse model in CAV1 knockout (KO) mice and perform transcriptome analysis on livers from mice to investigate the effects of CAV1 in MASLD progression. In addition, we evaluated the expression of CAV1 in human liver samples, and also conducted assays in vitro to investigate the molecular role of CAV1 in MASLD progression. The results illustrate that the expression of liver CAV1 in the decreases during MASLD progression, which aggravates the accumulation of cholesterol in the liver, leading to more severe endoplasmic reticulum (ER) stress and pyroptosis. Mechanistically, CAV1 regulates the expression of FXR/NR1H4 and its downstream cholesterol transporter, ABCG5/ABCG8, suppressing ER stress and alleviating pyroptosis. Our study confirms CAV1 is a crucial regulator of cholesterol homeostasis in MASLD and plays an important role in disease progression.

For a long time, the decline in lung function has been regarded as a potential factor associated with the risk of osteoporosis (OP). Although several observational studies have investigated the relationship between lung function and OP, their conclusions have been inconsistent. Given that Mendelian randomization (MR) studies can help reduce the interference of confounding factors on outcomes, we adopted this approach to explore the causal relationship between lung function and OP at the genetic level. To investigate the potential causality between lung function (FVC, FEV1, FEV1/FVC, PEF) and OP, we conducted a MR analysis employing three approaches: inverse variance weighted (IVW), MR-Egger, and weighted median. We used Cochran’s Q test to detect potential heterogeneity, MR-Egger regression to evaluate directional pleiotropy, and the MR-PRESSO method to evaluate horizontal pleiotropy. In addition, we used MR-PRESSO and MR radial methods to exclude SNPs exhibiting pleiotropic outliers. Upon identification of potential outliers, we removed them and subsequently ran MR analysis again to assess the reliability of our findings. The MR analysis suggested that there was no causal effect of lung function (FVC, PEF, FEV1/FVC, FEV1) on OP, which is consistent with the. results after excluding potential outliers using MR-PRESSO and MR radial. methods. Sensitivity analysis confirmed the reliability and consistency of these. results. The study concluded that there is no causal link between lung function and OP. The association found in observational studies might be attributable to shared risk factors.

Advances in stem cell technology offer new possibilities for patients with untreated diseases and disorders. Stem cell-based therapy, which includes multipotent mesenchymal stem cells (MSCs), has recently become important in regenerative therapies. MSCs are multipotent progenitor cells that possess the ability to undergo in vitro self-renewal and differentiate into various mesenchymal lineages. MSCs have demonstrated promise in several areas, such as tissue regeneration, immunological modulation, anti-inflammatory qualities, and wound healing. Additionally, the development of specific guidelines and quality control methods that ultimately result in the therapeutic application of MSCs has been made easier by recent advancements in the study of MSC biology. This review discusses the latest clinical uses of MSCs obtained from the umbilical cord (UC), bone marrow (BM), or adipose tissue (AT) in treating various human diseases such as pulmonary dysfunctions, neurological disorders, endocrine/metabolic diseases, skin burns, cardiovascular conditions, and reproductive disorders. Additionally, this review offers comprehensive information regarding the clinical application of targeted therapies utilizing MSCs. It also presents and examines the concept of MSC tissue origin and its potential impact on the function of MSCs in downstream applications. The ultimate aim of this research is to facilitate translational research into clinical applications in regenerative therapies.

BACKGROUND:Tumor immune microenvironment regulates the growth and metastasis of uveal melanoma (UM). This study aims to reveal the possible molecular mechanism of BRCA1-associated protein 1 (BAP1) mutations in affecting the tumor immune microenvironment in UM through mediating the nuclear factor-κB (NF-κB) signaling pathway.METHODS:TCGA and cBioPortal databases jointly analyzed the genes with high mutation frequency in UM samples. Following survival analysis of UM patients, UM samples with BAP1 mutations were subjected to immune cell infiltration analysis. The signaling pathways associated with the mutated genes were screened by GSEA. Subsequently, the differential BAP1 expression was analyzed in the selected UM cell lines with wild type (WT) or mutant type (MUT) BAP1.RESULTS:Bioinformatics analysis identified 12 genes mutated in the UM samples, while only BAP1 mutations were related to the prognosis of UM patients. UM patients with BAP1 mutations had higher immune cell infiltration. BAP1 mutations inhibited the NF-κB signaling pathway, suppressing the cytokine secretion and antigen presentation by macrophages. Rescue experiments confirmed that overexpressed NF-κB could reverse the effect of BAP1 mutations on the immunosuppressive microenvironment, thus suppressing the malignant phenotypes of UM cells.CONCLUSION:BAP1 mutations may inhibit the NF-κB signaling pathway, repressing the cytokine secretion and antigen presentation by macrophages, which induces the immunosuppressive microenvironment, enhances the malignant phenotypes of UM cells and ultimately promotes the growth and metastasis of UM.

Recent years have witnessed an increasing research interest in the therapeutic value of aberrant chromatin regulatory processes in carcinogenesis. Our study was performed to explore the possible carcinogenic mechanism of the chromatin regulator RuvB-like protein 1 (RUVBL1) in uveal melanoma (UVM). The expression pattern of RUVBL1 was retrieved in bioinformatics data. The correlation between RUVBL1 expression and the prognosis of patients with UVM was analyzed in publicly available database. The downstream target genes of RUVBL1 were predicted and further verified by co-immunoprecipitation. The bioinformatics analysis results showed that RUVBL1 may be associated with the transcriptional activity of CTNNB1 by regulating chromatin remodeling, and that RUVBL1 functioned as an independent prognostic factor for patients with UVM. The UVM cells manipulated with RUVBL1 knockdown were introduced for in vitro investigation. CCK-8 assay, flow cytometry, scratch assay, Transwell assay and Western blot analysis were used for detection on the resultant UVM cell proliferation, apoptosis, migration, invasion and cell cycle distribution. In vitro cell experimental data showed that RUVBL1 expression was significantly increased in UVM cells and RUVBL1 knockdown inhibited the proliferation, invasion and migration of UVM cells, accompanied by augmented apoptosis rate and blocked cell cycle progression. To sum up, RUVBL1 enhances the malignant biological characteristics of UVM cells by increasing the chromatin remodeling and subsequent transcription activity of CTNNB1.

Background:Observational studies have indicated an association between polyunsaturated fatty acids (PUFAs) and chronic pain, but the potential causal link remains controversial. Here, we aimed to investigate whether a causal relationship exists between the concentration of circulating PUFAs and chronic pain as well as the direction of this association. Methods:We collected statistical data from relevant genome-wide association studies to explore the causal link between four PUFAs, along with the ratio of omega-6 fatty acids (FAs) to omega-3 FAs (omega-6:3 ratio), and chronic pain in eight specific body parts. We used the inverse-variance weighting (IVW) method for two-sample Mendelian randomization (MR) analysis and conducted supplementary analyses using four other methods (MR-Egger, weighted median, weighted mode, and simple mode). To verify the robustness of the MR study, we performed multiple sensitivity analyses. Results:The results revealed a negative correlation between omega-3 FAs [IVW, OR 95% CI: 0.952 (0.914, 0.991), p = 0.017] and docosahexaenoic acid (DHA) [IVW, OR 95% CI: 0.935 (0.893, 0.978), p = 0.003] with abnormal and pelvic pain. Furthermore, a positive correlation was observed between the omega-6:3 ratio [IVW, OR 95% CI: 1.057 (1.014, 1.101), p = 0.009] with abdominal and pelvic pain. Additionally, we found a negative correlation between omega-3 FAs [IVW, OR 95% CI: 0.947 (0.902, 0.994), p = 0.028] and lower back pain or sciatica. However, no causal relationship was found between the concentration of circulating PUFAs and pain in other body parts, including the face, throat and chest, joints, limbs, lower back, and gynecological parts. The robustness of these MR results was verified through multi-validity and retention method analyses. Conclusion:Our analysis suggests that higher circulating concentrations of omega-3 FAs and DHA and a lower omega-6:3 ratio are associated with a reduced risk of abdominal and pelvic pain. Additionally, a higher concentration of circulating omega-3 FAs is linked to a reduced risk of lower back pain and/or sciatica. These findings have major implications for the targeted prevention and treatment of chronic pain using PUFAs.

Alterations in DNA methylation in malignant diseases have been heralded as promising targets for diagnostic, prognostic, and predictive values. This study was based on epigenetic alterations and immune cell infiltration analysis to investigate the mechanism of CD3D methylation in uveal melanoma (UM). Bioinformatics analysis was performed on transcriptome data, 450 K methylation data, and clinical information of UM patients from the TCGA database. Stromal and immune cell infiltration was evaluated by calculating the StromalScore and ImmuneScore of UM samples. UM samples were divided into high and low StromalScore and ImmuneScore groups, followed by differential and enrichment analyses. PPI network construction and correlation analysis was used to identify the core prognosis-related genes. The bioinformatics analysis results were confirmed in UM cell experiments. StromalScore and ImmuneScore were significantly associated with the prognosis of UM patients. CD3D, IRF1, CCL3, and FN1 were identified as core genes driven by methylation that affected the prognosis of UM patients. CD3D expression showed the highest correlation with its methylation and was closely related to the four key immune cells in UM development. CD3D was hypomethylated and abundantly expressed in UM cells, while silencing of CD3D inhibited the proliferation, migration, and invasion of UM cells in vitro. In summary, this study identifies hypomethylation of CD3D promoter in UM, which was associated with immune cell infiltration of UM.

Many studies have shown that patients with Coronavirus disease 2019 (COVID-19) have different degrees of liver injury. However, the mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion into the liver are still not fully understood. This review mainly summarizes the recently published works on the abnormal liver biochemical indicators and the mechanism of viral invasion with liver injury in COVID-19 patients. Generally, SARS-CoV-2 infection of the liver was caused by blood circulation or retrograde infection of the digestive tract, which led to the liver injury through direct cytopathic effect induced by virus or immunopathological effect caused by excessive inflammation. Besides these, hypoxia, endothelial injury and drug-induced jury were also the main reasons of liver injury in COVID-19 patients. In the liver function indicators, elevated alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, and lactate dehydrogenase levels with reduced albumin levels were observed in COVID-19 patients.

Retraction: 'Phosphorylation of histone H4 at serine 1 is associated with GCN5 and mediates autophagy in osteosarcoma bone cell lines', by Rui Jiang, Ziyan Zhang, Zhiwei Zhong, Yuxuan Dai, Guangyao Liu, Chao Zhang, J Cell Physiol. The above article, published online on 05 January 2020 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/full/10.1002/jcp.29434), has been retracted by agreement between the journal's Editor in Chief, Prof. Dr. Gregg Fields, and Wiley Periodicals LLC. The retraction has been agreed following an investigation based on allegations raised by a third party. Several flaws and inconsistencies between results presented and experimental methods described were found, the editors consider the conclusions of this article to be invalid. The authors collaborated in the investigation initially, but were not available for a final confirmation of the retraction.

目的:探讨血栓形成易感基因芯片的研制方法及初步临床验证,建立一种快速且高通量检测血栓形成易感基因突变的方法.方法:根据GenBank上已发表的血栓形成易感基因序列,将设计好的参照探针和特异性探针点置于醛基化处理的玻片上,经紫外交联后固定,制成血栓形成易感基因芯片.以阳性参考品(各检测位点突变型和正常型基因)和阴性参考品(双蒸水)为模板,经PCR反应后与芯片进行杂交,对基因芯片的有效性进行检测.以靶序列经过测序验证的人类基因组DNA为模板,经PCR反应后芯片进行杂交,检测基因芯片的特异度和灵敏度,并对来自吉林、河南和云南3个地区的健康受试者150人和有不明原因血栓性疾病家族史的血栓患者24例进行临床验证.分析指标为检测相应位点的杂交信号强度.结果:以阳性参考品和阴性参考品为模板进行杂交,相应位点出现特异性的杂交信号,说明基因芯片检测位点有效.用于检测选定突变位点的基因芯片均有特异性的杂交信号,说明基因芯片的特异性良好.标准基因组DNA逐级稀释后检测基因芯片的灵敏度为50～100 mg·L-1.临床验证结果,在健康受试者150人中8人检出血栓形成易感基因突变,在有不明原因血栓性疾病家族史的血栓患者24例中20例检出血栓形成易感基因突变,该芯片对不明原因血栓性疾病家族史的血栓患者血栓形成易感基因突变检出率明显高于健康受试者(P<0.05).结论:研制的血栓形成易感基因芯片具有良好的特异度和灵敏度,对血栓形成易感基因有较高的检出率,在血栓性疾病的早期诊断和易感风险评估中具有潜在价值.

Histone modification is critical for the process of autophagy in osteosarcoma. Whether phosphorylated histone H4 (H4) mediates autophagy remains to be seen. Here, we aimed to investigate the effects of general control nonderepressible 5 (GCN5)-evoked phosphorylation of H4 on autophagy. Osteosarcoma bone cell lines Saos-2, MG-63, and HOS cells were applied. Kinase activity was monitored in in vitro kinase assay buffer. Immunoprecipitation and glutathione S-transferase (GST) pull-down assay were exploited to confirm the association of GCN5 to H4. Furthermore, we determined green fluorescent protein (GFP)-tagged light chain 3 (LC3), long-lived protein, gene expression, and transcriptional activity. We found that a direct connection of GCN5 to H4 existed in osteosarcoma bone cells. Results indicated that GCN5 was implicated in the modulation of H4 phosphorylation at serine 1 (Ser1). GCN5-mediated phosphorylation of H4 at Ser1 facilitated the formation of GFP-LC3, conversion of LC3-I into LC3-II and transcriptional activity of autophagy-related genes. We reported that GCN5 was included in the modulation of H4 phosphorylation at Ser1. Fortification of epigenetic phosphorylated marks at Ser1 of H4 by GCN5 sensitized osteosarcoma bone cells to autophagy.

Purpose: More recently, literature has emerged providing findings about the novelty of microRNAs (miR)-targeted therapeutics in the treatment of retinoblastoma (RB). The prime objective of this study was to identify the potential role of miR-378a-3p and its regulation in RB cells via forkhead box G1 (FOXG1). Methods: The expression of miR-378a-3p and FOXG1 in the clinical RB tissues was determined using RNA quantitation and Western blot assays. The interaction between miR-378a-3p and FOXG1 was identified using dual luciferase reporter gene assay. The potential effects of miR-378a-3p on the RB cell biological processes were evaluated by conducting gain- and loss-of-function studies of miR-378a-3p and FOXG1, followed by cell viability, cell cycle progression, and apoptosis measurements. Furthermore, experiments were performed in nude mice to assess its effects on tumor formation. Results: miR-378a-3p was poorly expressed, whereas FOXG1 was highly expressed in RB tissues and cells. miR-378a-3p bound to the FOXG1 3′ untranslated region and negatively modulated its expression. The overexpression of miR-378a-3p was found to decrease RB cell viability and to promote cell apoptosis in vitro, whereas overexpressed FOXG1 reversed the regulatory effects of miR-378a-3p on RB cellular behaviors. In nude mice, the restoration of miR-378a-3p by miR-378a-3p agomir was shown to play a role in the reduction of tumor volume and size relative to nude mice injected with negative control-agomir. Conclusions: Our findings identified that increased miR-378a-3p exerted an inhibitory effect on RB cell proliferation by targeting FOXG1, suggesting the role of miR-378a-3p as a novel therapeutic target for RB.

Malaria is a disease of public health importance in many parts of the world. Currently, there is no effective way to eradicate malaria, so developing safe, efficient, and cost-effective vaccines against this disease remains an important goal. Current research on malaria vaccines is focused on developing vaccines against pre-erythrocytic stage parasites and blood-stage parasites or on developing a transmission-blocking vaccine. Here, we briefly describe the progress made towards a vaccine against Plasmodium falciparum, the most pathogenic of the malaria parasite species to infect humans.

患者男,48岁,因触及左侧颈部肿物3个月就诊.1年前于左侧颈中部触及约4 cm×2 cm质韧肿物,彩色多普勒超声示左颈中部约3.8 cm× 1.8 cm椭圆形囊实混合性包块,边界清,形态不规整,实质部分见血流信号(图1A),提示左侧颈部包块(性质待定);颈部CT不除外左侧颈部淋巴结炎性病变;电子鼻咽镜、肺部CT、腹部超声均未见明显异常;行左侧颈部肿物切除术,术中见囊实性肿物与周围组织无粘连,光镜下见囊壁鳞状上皮呈浸润性生长,细胞排列失去极性,可见大量角化珠及核分裂象,提示左侧颈部淋巴结转移癌,免疫组织化学:CK5/6(+),P40(+),CKpan(+),CD56(NK-1)(-),CK14(-),LCA(-),提示低分化鳞状细胞癌转移.本次入院后CDFI示左侧颈中部2.5 cm×1.0 cm包块,与初诊时性质相同,考虑淋巴结转移癌;PET/CT示左侧口咽壁增厚伴代谢较对侧增高,延迟显像代谢进一步增高(图1B),提示恶性肿瘤.电子喉镜:左侧扁桃体表面欠光滑.行双侧扁桃体切除术+颈部淋巴结清扫术,术中见双侧扁桃体呈Ⅱ度肥大,左侧扁桃体表面粗糙.病理诊断:左侧扁桃体中-低分化鳞状细胞癌(图1C),未见明确侵及脉管及神经,右侧慢性肥大性扁桃体炎,左侧颈部淋巴结见癌转移(2/9).

报道1例以急性肾损伤伴抗GBM抗体阳性为主要表现的病例,经肾活检示IgA肾病(Lee分级:Ⅰ～Ⅱ级),未使用免疫抑制治疗的情况下,抗GBM抗体自动转阴,且肾功能及尿量恢复正常,分析了相关原因.为提高临床医生对此类疾病诊断思路、相关机制的认识提供参考.

Geniposide is an active ingredient with anti-apoptotic and anti-inflammatory properties. This study was to examine the effects of geniposide on a cell model of spinal cord injury (SCI). PC12 cells were administrated with geniposide before subjected to LPS. The effects of geniposide were analyzed by utilizing CCK-8 assay, apoptosis assay, ELISA, RT-qPCR and Western blot. We found that PC12 cells viability was unchanged by treating with geniposide. However, geniposide with concentrations of 200 or 300 μg/mL significantly mitigated LPS-evoked viability loss. Meanwhile, apoptosis driven by LPS was mitigated by geniposide, which accompanied with p53, Bax and cleaved caspase-3 down-regulation, and Bcl-2 up-regulation. Besides this, the expression and release of IL-1β, IL-6, IL-8 and TNF-α evoked by LPS were mitigated by geniposide. miR-145-5p was a target of geniposide. miR-145-5p expression was up-regulated by geniposide, and geniposide did not protect PC12 cells against LPS injury when miR-145-5p was silenced. Moreover, geniposide inhibited NF-κB and JNK pathways via up-regulating miR-145-5p. In short, the present work described the neuroprotective effects of geniposide by targeting miR-145-5p. Further mechanisms involved in geniposide’s beneficial effects are correlated with the inhibited NF-κB and JNK pathways.HighlightsGeniposide prevents LPS-induced injury in PC12 cells;Geniposide up-regulates miR-145-5p;Geniposide protects PC12 cells via up-regulation of miR-145-5p;Geniposide inhibits NF-κB and JNK pathways via up-regulation of miR-145-5p.

糖尿病肾病(DN)是糖尿病(DM)最常见的并发症,其中,Nephrin蛋白丢失所导致的足细胞功能异常是糖尿病肾病的主要特征.足细胞分子屏障的破环可导致蛋白尿的产生,随着病情的发展,最终进展为肾小球的纤维化.近年来,有研究提示miR-29的表达异常,在糖尿病肾病的纤维化发生及发展中起到重要作用,其可通过促进Nephrin蛋白的乙酰化来减轻高糖诱导的足细胞损伤,从而起到保护肾小球功能的作用.

Columbianadin (CBN) is one of the main bioactive constituents isolated from the root of Angelica pubescens. Although the anti-inflammatory activity of CBN has been reported, the underpinning mechanism of this remains unclear. In this study, we investigated the anti-inflammatory effect of CBN on lipopolysaccharide (LPS)-stimulated THP-1 cells and explored the possible underlying molecular mechanisms. The results showed that CBN suppressed LPS-mediated inflammatory response mainly through the inactivation of the NOD1 and NF- κ B p65 signaling pathways. Knockdown of NOD1 reduced the degree to which inflammatory cytokines decreased following CBN treatment, whereas forced expression of NOD1 and CBN treatment reduced NF- κ B p65 activation and the secretion of inflammatory cytokines. Furthermore, CBN significantly reduced cellular apoptosis by inhibiting the NOD1 pathway. Collectively, our results indicate that CBN suppressed the LPS-mediated inflammatory response by inhibiting NOD1/NF- κ B activation. Further investigations are required to determine the mechanisms of action of CBN in the inhibition of NOD signaling: However, CBN may be employed as a therapeutic agent for multiple inflammatory diseases.