Identifying novel chemical-related susceptibility genes for five psychiatric disorders through integrating genome-wide association study and tissue-specific 3'aQTL annotation datasets.

The establishment of 3'aQTLs comprehensive database provides an opportunity to help explore the functional interpretation from the genome-wide association study (GWAS) data of psychiatric disorders. In this study, we aim to search novel susceptibility genes, pathways, and related chemicals of five psychiatric disorders via GWAS and 3'aQTLs datasets. The GWAS datasets of five psychiatric disorders were collected from the open platform of Psychiatric Genomics Consortium (PGC, https://www.med.unc.edu/pgc/ ) and iPSYCH ( https://ipsych.dk/ ) (Demontis et al. in Nat Genet 51(1):63-75, 2019; Grove et al. in Nat Genet 51:431-444, 2019; Genomic Dissection of Bipolar Disorder and Schizophrenia in Cell 173: 1705-1715.e1716, 2018; Mullins et al. in Nat Genet 53: 817-829; Howard et al. in Nat Neurosci 22: 343-352, 2019). The 3'untranslated region (3'UTR) alternative polyadenylation (APA) quantitative trait loci (3'aQTLs) summary datasets of 12 brain regions were obtained from another public platform ( https://wlcb.oit.uci.edu/3aQTLatlas/ ) (Cui et al. in Nucleic Acids Res 50: D39-D45, 2022). First, we aligned the GWAS-associated SNPs of psychiatric disorders and datasets of 3'aQTLs, and then, the GWAS-associated 3'aQTLs were identified from the overlap. Second, gene ontology (GO) and pathway analysis was applied to investigate the potential biological functions of matching genes based on the methods provided by MAGMA. Finally, chemical-related gene-set analysis (GSA) was also conducted by MAGMA to explore the potential interaction of GWAS-associated 3'aQTLs and multiple chemicals in the mechanism of psychiatric disorders. A number of susceptibility genes with 3'aQTLs were found to be associated with psychiatric disorders and some of them had brain-region specificity. For schizophrenia (SCZ), HLA-A showed associated with psychiatric disorders in all 12 brain regions, such as cerebellar hemisphere (P = 1.58 × 10-36) and cortex (P = 1.58 × 10-36). GO and pathway analysis identified several associated pathways, such as Phenylpropanoid Metabolic Process (GO:0009698, P = 6.24 × 10-7 for SCZ). Chemical-related GSA detected several chemical-related gene sets associated with psychiatric disorders. For example, gene sets of Ferulic Acid (P = 6.24 × 10-7), Morin (P = 4.47 × 10-2) and Vanillic Acid (P = 6.24 × 10-7) were found to be associated with SCZ. By integrating the functional information from 3'aQTLs, we identified several susceptibility genes and associated pathways especially chemical-related gene sets for five psychiatric disorders. Our results provided new insights to understand the etiology and mechanism of psychiatric disorders.

Assessing the joint effects of mitochondrial genes and physical activity on the psychiatric phenotype of subjective well-being based on the UK Biobank data.

Subjective well-being (SWB) is an important measure for mental health status. Previous research has shown that physical activity can affect an individual's well-being, yet the underlying molecular mechanism remains to be clarified. In this study, we aim to evaluate the potential interactions between mitochondrial genes and physical activity (PA) as well as their combined effects on individual well-being. SWB phenotype data in UK Biobank were enrolled for this study including nine aspects such as work/job satisfaction, health satisfaction, family relationship satisfaction, friendships satisfaction, financial situation satisfaction, ever depressed for a whole week, general happiness, general happiness with own health and belief that own life is meaningful. We made analysis for each aspects separately. Firstly, mitochondria-wide association studies (MiWAS) was conducted to assess the association of mitochondrial Single Nucleotide Polymorphisms SNP with each aspect of SWB. Then an interaction analysis of mitochondrial DNA (mtDNA) mutation and PA was performed to evaluate their joint effect on SWB status. Meanwhile, these two analysis were made for female and male group separately as well as the total samples, all under the control of possible confounding factors including gender, age, Townsend Deprivation Index (TDI), education, alcohol consumption, smoking habits, and 10 principal components. MiWAS analysis identified 45 mtSNPs associated with 9 phenotypes of SWB. For example, m.15218A > G on MT-CYB in the health satisfaction phenotype of the total subjects. Gender-specific analyses found 30 mtSNPs in females and 58 in males, involving 13 mtGenes. In mtDNA-PA interaction analysis, we also identified 10 significant mtDNA-PA interaction sets for SWB. For instance, m.13020 T > C (MT-ND5) was associated with the SWB financial situation satisfaction phenotype in all subjects (P = 0.00577). In addition, MiWAS analysis identified 12 mtGene variants associated with SWB, as MT-ND1 and MT-ND2. However, in mtDNA-PA interactions we detected 7 mtDNA affecting psychiatric disorders occurring, as in the friendships satisfaction phenotype (m.3394 T > C on MT-ND1). Our study results suggest an implication of the interaction between mitochondrial function and physical activity in the risk of psychiatric disorder development.

Assessing the effect of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes.

Longitudinal changes in brain structure and lifestyle can affect sleep phenotypes. However, the influence of the interaction between longitudinal changes in brain structure and lifestyle on sleep phenotypes remains unclear. Genome-wide association study dataset of longitudinal changes in brain structure was obtained from published study. Phenotypic data of lifestyles and sleep phenotypes were obtained from UK Biobank cohort. Using genotype data from UK Biobank, we calculated polygenetic risk scores of longitudinal changes in brain structure phenotypes. Linear/logistic regression analysis was conducted to evaluate interactions between longitudinal changes in brain structure and lifestyles on sleep duration, chronotype, insomnia, snoring and daytime dozing. Multiple lifestyle × longitudinal changes in brain structure interactions were detected for 5 sleep phenotypes, such as physical activity×caudate_age2 for daytime dozing (OR = 1.0389, P = 8.84 × 10-3) in total samples, coffee intake×cerebellar white matter volume_age2 for daytime dozing (OR = 0.9652, P = 1.13 × 10-4) in females. Besides, we found 4 overlapping interactions in different sleep phenotypes. We conducted sex stratification analysis and identified one overlapping interaction between female and male. Our results support the moderate effects of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes, and deepen our understanding of the pathogenesis of sleep disorders.

Assessing the association of coffee consumption on the relationship of chronic pain with depression and anxiety.

BACKGROUND: A bidirectional relationship between chronic pain (CP) and mental disorders has been reported, and coffee was believed to be associated with both. However, the association of coffee in this bidirectional relationship remains unclear. We aim to analyze the association of coffee consumption on the relationship of CP with depression and anxiety. METHODS: A total of 376,813 participants from UK Biobank were included. We collected data on anxiety, depression and CP from objects of our study population. The association of coffee consumption on the relationship of CP with depression and anxiety was assessed through logistic/linear regression models. Moreover, seemingly unrelated estimation test (SUEST) was used to compare whether the coefficients differed in two different groups. RESULTS: We observed significant associations of coffee consumption in the interaction of CP with depression and anxiety, such as the association of multisite chronic pain (MCP) on self-reported depression (ßcoffee = 0.421, ßnon-coffee = 0.488, PSUEST = 0.001), and the association of MCP on generalized anxiety disorder-7 (GAD-7) scores (ßcoffee = 0.561, ßnon-coffee = 0.678, PSUEST = 0.004) were significantly different between coffee drinking and non-coffee drinking groups. Furthermore, in analysis stratified by gender, we found headache (ßmale = 0.392, ßfemale = 0.214, PSUEST = 0.022) and hip pain (ßmale = 0.480, ßfemale = 0.191, PSUEST = 0.021) had significant associations with self-reported depression between males and females groups in coffee drinkers. CONCLUSIONS: Our results suggested that coffee consumption has a significant association on the relationship of CP with depression and anxiety.

Combined effects of inflammation and coronavirus disease 2019 (COVID-19) on the risks of anxiety and depression: A cross-sectional study based on UK Biobank.

Infection-induced perturbation of immune homeostasis could promote psychopathology. Psychiatric sequelae have been observed after previous coronavirus outbreaks. However, limited studies were conducted to explore the potential interaction effects of inflammation and coronavirus disease 2019 (COVID-19) on the risks of anxiety and depression. In this study, first, polygenic risk scores (PRS) were calculated for eight COVID-19 clinical phenotypes using individual-level genotype data from the UK Biobank. Then, linear regression models were developed to assess the effects of COVID-19 PRS, C-reactive protein (CRP), systemic immune inflammation index (SII), and their interaction effects on the Generalized Anxiety Disorder-7 (GAD-7, 104 783 individuals) score and the Patient Health Questionnaire-9 (PHQ-9, 104 346 individuals) score. Several suggestive interactions between inflammation factors and COVID-19 clinical phenotypes were detected for PHQ-9 score, such as CRP/SII × Hospitalized/Not_Hospitalized in women group and CRP × Hospitalized/Unscreened in age >65 years group. For GAD-7 score, we also found several suggestive interactions, such as CRP × Positive/Unscreened in the age ≤65 years group. Our results suggest that not only COVID-19 and inflammation have important effects on anxiety and depression but also the interactions of COVID-19 and inflammation have serious risks for anxiety and depression.

A longitudinal genome-wide association study of bone mineral density mean and variability in the UK Biobank.

Bone mineral density (BMD) is an essential predictor of osteoporosis and fracture. We conducted a genome-wide trajectory analysis of BMD and analyzed the BMD change. PURPOSE: This study aimed to identify the genetic architecture and potential biomarkers of BMD. METHODS: Our analysis included 141,261 white participants from the UK Biobank with heel BMD phenotype data. We used a genome-wide trajectory analysis tool, TrajGWAS, to conduct a genome-wide association study (GWAS) of BMD. Then, we validated our findings in previously reported BMD genetic associations and performed replication analysis in the Asian participants. Finally, gene-set enrichment analysis (GSEA) of the identified candidate genes was conducted using the FUMA platform. RESULTS: A total of 52 genes associated with BMD trajectory mean were identified, of which the top three significant genes were WNT16 (P = 1.31 × 10-126), FAM3C (P = 4.18 × 10-108), and CPED1 (P = 8.48 × 10-106). In addition, 114 genes associated with BMD within-subject variability were also identified, such as AC092079.1 (P = 2.72 × 10-13) and RGS7 (P = 4.72 × 10-10). The associations for these candidate genes were confirmed in the previous GWASs and replicated successfully in the Asian participants. GSEA results of BMD change identified multiple GO terms related to skeletal development, such as SKELETAL SYSTEM DEVELOPMENT (Padjusted = 2.45 × 10-3) and REGULATION OF OSSIFICATION (Padjusted = 2.45 × 10-3). KEGG enrichment analysis showed that these genes were mainly enriched in WNT SIGNALING PATHWAY. CONCLUSIONS: Our findings indicated that the CPED1-WNT16-FAM3C locus plays a significant role in BMD mean trajectories and identified several novel candidate genes contributing to BMD within-subject variability, facilitating the understanding of the genetic architecture of BMD.

Tetrahedral Framework Nucleic Acids: A Novel Strategy for Antibiotic Treating Drug-Resistant Infections.

Antibiotic multiresistance (AMR) has emerged as a major threat to human health as millions of people die from AMR-related problems every year. As has been witnessed during the global COVID-19 pandemic, the significantly increased demand for antibiotics has aggravated the issue of AMR. Therefore, there is an urgent need to find ways to alleviate it. Tetrahedral framework nucleic acids (tFNAs) are novel nanomaterials that are often used as drug delivery platforms because of their structural diversity. This study formed a tFNAs-antibiotic compound (TAC) which has a strong growth inhibitory effect on Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA) in vitro owing to the increased absorption of antibiotics by bacteria and improved drug movement across cell membranes. We established a mouse model of systemic peritonitis and local wound infections. The TAC exhibited good biosafety and improved the survival rate of severely infected mice, promoting the healing of local infections. In addition to the better transport of antibiotics to the target, the TAC may also enhance immunity by regulating the differentiation of M1 and M2 macrophages, providing a new option for the treatment of infections.

Broadening the biocompatibility of gold nanorods from rat to Macaca fascicularis: advancing clinical potential.

BACKGROUND: The biomedical field has used gold nanorods (GNRs) for decades; however, clinical trials and translation is limited except gold nanoshells. The preparation of gold nanoshells is more complex than that of polyethylene glycol-modified GNRs (PEG-GNRs), and it is difficult to ensure uniform thickness. It is important to encourage and broaden the use of the star member (PEG-GNRs) of gold nanoparticles family for clinical translation. Existing studies on PEG-GNRs are limited with no relevant systematic progression in non-human primates. Herein, we assessed the systematic biocompatibility of PEG-GNRs in rats and clinically relevant Macaca fascicularis. RESULTS: In this small animal study, we administrated multiple doses of PEG-GNRs to rats and observed good biocompatibility. In the non-human primate study, PEG-GNRs had a longer blood half-life and produced a negligible immune response. Histological analysis revealed no significant abnormality. CONCLUSIONS: PEG-GNRs were well-tolerated with good biocompatibility in both small animals and large non-human primates. The information gained from the comprehensive systemic toxicity assessment of PEG-GNRs in M. fascicularis will be helpful for translation to clinical trials.

Targeted and effective glioblastoma therapy via aptamer-modified tetrahedral framework nucleic acid-paclitaxel nanoconjugates that can pass the blood brain barrier.

Targeted DNA nanoparticles have been identified as one of the most promising nanocarriers in anti-glioma drug delivery. We established a multifunctional nanosystem for targeted glioma therapy. Tetrahedral framework nucleic acid (tFNA), entering U87MG cells and bEnd.3 cells, was chosen to deliver two aptamers, GMT8 and Gint4.T, and paclitaxel. GMT8 and Gint4.T, which specifically bind with U87MG cells and with PDGFRß, were linked with tFNA, to form Gint4.T-tFNA-GMT8 (GTG). GTG was efficiently internalized by U87MG and bEnd.3 cells and penetrated an in-vitro blood-brain-barrier model. GTG loaded with paclitaxel (GPC) had potentiated anti-glioma efficacy. It inhibited the proliferation, migration, and invasion of U87MG cells, and enhanced apoptosis induction in these cells. The expression of apoptosis-related proteins was significantly changed after treatment with GPC, confirming apoptosis induction. Our study demonstrated that the combination of GTG and paclitaxel has great potential for glioma treatment and tFNA shows great promise for use in drug delivery.

Inhibiting Methicillin-Resistant Staphylococcus aureus by Tetrahedral DNA Nanostructure-Enabled Antisense Peptide Nucleic Acid Delivery.

One of the biggest obstacles for the use of antisense oligonucleotides as antibacterial therapeutics is their limited uptake by bacterial cells without a suitable carrier, especially in multi-drug-resistant bacteria with a drug efflux mechanism. Existing vectors, such as cell-penetrating peptides, are inefficient and nontargeting, and accordingly are not ideal carriers. A noncytotoxic tetrahedral DNA nanostructure (TDN) with a controllable conformation has been developed as a delivery vehicle for antisense oligonucleotides. In this study, antisense peptide nucleic acids (asPNAs) targeting a specific gene ( ftsZ) were efficiently transported into methicillin-resistant Staphylococcus aureus cells by TDNs, and the expression of ftsZ was successfully inhibited in an asPNA-concentration-dependent manner. The delivery system specifically targeted the intended gene. This novel delivery system provides a better platform for future applications of antisense antibacterial therapeutics and provides a basis for the development of a new type of antibacterial drug for multi-drug-resistant bacterial infections.

Regulating osteogenesis and adipogenesis in adipose-derived stem cells by controlling underlying substrate stiffness.

Cells reside in a complex microenvironment (niche) in which the biochemical and biophysical properties of the extracellular matrix profoundly affect cell behavior. Extracellular stiffness, one important bio-mechanical characteristic of the cell niche, is important in regulating cell proliferation, migration, and lineage specification. However, the mechanism by which mechanical signals guide osteogenic and adipogenic commitment of stem cells remains difficult to dissect. To explore this question, we generated a range of polydimethylsiloxane-based matrices with differing degrees of stiffness that mimicked the stiffness seen in natural tissues and examined adipose stem cell morphology, spreading, vinculin expression, and differentiation along the osteogenic and adipogenic pathways. Rigid matrices allowed broader cell spreading, faster growth rate and stronger expression of vinculin in adipose-derived stem cells. In the presence of inductive culture media, stiffness-dependent osteogenesis and adipogenesis of the adipose stem cells indicated that there was a combinatorial effect of biophysical and biochemical cues; no such lineage specification was observed in normal media. Osteogenic differentiation behavior showed a correlation with matrix rigidity, as well as with elevated expression of RhoA, ROCK-1/-2, and related proteins in the Wnt/ß-catenin pathway. The result provides a comprehensive understanding of how stem cells respond to the surrounding microenvironment and points to the fact that matrix stiffness is a critical element in biomaterial design and this will be an important advance in stem cell-based tissue engineering.

Effect of tetrahedral DNA nanostructures on proliferation and osteo/odontogenic differentiation of dental pulp stem cells via activation of the notch signaling pathway.

Dental pulp stem cells (DPSCs) derived from the human dental pulp tissue have multiple differentiation capabilities, such as osteo/odontogenic differentiation. Therefore, DPSCs are deemed as ideal stem cell sources for tissue regeneration. As new nanomaterials based on DNA, tetrahedral DNA nanostructures (TDNs) have tremendous potential for biomedical applications. Here, the authors aimed to explore the part played by TDNs in proliferation and osteo/odontogenic differentiation of DPSCs, and attempted to investigate if these cellular responses could be driven by activating the canonical Notch signaling pathway. Upon exposure to TDNs, proliferation and osteo/odontogenic differentiation of DPSCs were dramatically enhanced, accompanied by up regulation of Notch signaling. In general, our study suggested that TDNs can significantly promote proliferation and osteo/odontogenic differentiation of DPSCs, and this remarkable discovery can be applied in tissue engineering and regenerative medicine to develop a significant and novel method for bone and dental tissue regeneration.

Notch Signaling Pathway Regulates Angiogenesis via Endothelial Cell in 3D Co-Culture Model.

This study aimed to investigate the role of Notch signaling pathway for angiogenesis in a three-dimensional (3D) collagen gel model with co-culture of adipose-derived stromal cells (ASCs) and endothelial cells (ECs). A 3D collagen gel model was established in vitro by implanting both ASCs from green fluorescent protein-labeled mouse and ECs from red fluorescent protein-labeled mouse, and the phenomena of angiogenesis with Notch signaling inducer Jagged1, inhibitor DAPT and PBS, respectively were observed by confocal laser scanning microscopy. Semi-quantitative PCR and immunofluorescent staining were conducted to detect expressions of angiogenesis-related genes and proteins. Angiogenesis in the co-culture gels was promoted by Jagged1 treatment while attenuated by DAPT treatment, compared to control group. In co-culture system of ASCs and ECs, the gene expressions of VEGFA, VEGFB, Notch1, Notch2, Hes1, Hey1, VEGFR1,and the protein expression of VEGFA, VEGFB, Notch1, Hes1, Hey1 were increased by Jagged1 treatment and decreased by DAPT treatment in ECs. And the result of VEGFR3 was the opposite. However, the same results did not appear completely in ASCs. These results revealed the VEGFA/B-Notch1/2-Hes1/Hey1- VEGFR1/3 signal axis played an important role in angiogenesis when ASCs and ECs were co-cultured in a 3D collagen gel model. J. Cell. Physiol. 232: 1548-1558, 2017. © 2016 Wiley Periodicals, Inc.

Tetrahedral DNA Nanostructure: A Potential Promoter for Cartilage Tissue Regeneration via Regulating Chondrocyte Phenotype and Proliferation.

Utilizing biomaterials to regulate the phenotype and proliferation of chondrocytes is a promising approach for effective cartilage tissue regeneration. Recently, a significant amount of effort has been invested into directing chondrocytes toward a desired location and function by utilizing biomaterials to control the dedifferentiation and phenotypic loss of chondrocytes during in vitro monolayer culture. Here, the transmission signals resulting from tetrahedral DNA nanostructures (TDNs) in the regulation of chondrocyte phenotype and proliferation are exploited. TDNs, new DNA nanomaterials, have been considered as promising materials in biomedical fields. Upon exposure to TDNs, chondrocyte phenotype is significantly enhanced, accompanied by lower gene expression related to Notch signaling pathway and higher expression of type II collagen. In addition, the cell proliferation and morphology of chondrocytes are changed after exposure to TDNs. In conclusion, this work demonstrates that TDNs are potentially useful mechanism in cartilage tissue regeneration from chondrocytes, whereby chondrocyte phenotype and proliferation can be retained.

Effect of tetrahedral DNA nanostructures on osteogenic differentiation of mesenchymal stem cells via activation of the Wnt/ß-catenin signaling pathway.

Adipose-derived stem cells (ADSCs) are considered to be ideal stem cell sources for bone regeneration owing to their ability to differentiate into osteo-like cells. Therefore, they have attracted increasing attention in recent years. Tetrahedral DNA nanostructures (TDNs), a new type of DNA-based biomaterials, have shown great potential for biomedical applications. In the present work, we aimed to investigate the role played by TDNs in osteogenic differentiation and proliferation of ADSCs and tried to explore if the canonical Wnt signal pathway could be the vital biological mechanism driving these cellular responses. Upon exposure to TDNs, ADSCs proliferation and osteogenic differentiation were significantly enhanced, accompanied by the up-regulation of genes correlated with the Wnt/ß-catenin pathway. In conclusion, our results indicate that TDNs are crucial regulators of the increase in osteogenic potential and ADSCs proliferation, and this noteworthy discovery could provide a promising novel approach toward ADSCs-based bone defect regeneration.

Smad signal pathway regulates angiogenesis via endothelial cell in an adipose-derived stromal cell/endothelial cell co-culture, 3D gel model.

Co-implantation of adipose-derived stromal cells (ASCs) and endothelial cells (ECs) can markedly expedite the formation of functional microvascular beds and provides possible methods for cell-based revascularization therapies to treat various diseases. Furthermore, we investigated the role of TGFß/Smad signaling pathway for angiogenesis in a three-dimensional (3D) collagen gel model established in vitro with co-culture between ASCs and ECs. We found that angiogenesis was attenuated in the co-culture gels after inhibition of ALK5/Smad2/3 with SB431542. Genes coding for VEGF-A, VEGF-B, VE-ca, FGF-1, PDGF, BMP-4, and BMP-7 were significantly reduced in both mono-cultured and co-cultured ECs. Furthermore, the decrease in co-cultured ECs was prominent relative to mono-cultured ECs. Taken together, these findings suggest that in the co-culture between ASCs and ECs, TGFß/Smad signal pathway regulates angiogenesis via ECs; moreover, the findings that the co-cultured ECs were regulated more significantly than mono-cultured ECs suggest that suppression of Smad signal pathway may regulate the paracrine secretion of ASCs to further modulate angiogenesis of ECs.

Framework nucleic acids as promising reactive oxygen species scavengers for anti-inflammatory therapy.

Reactive oxygen species (ROS) are an array of derivatives of molecular oxygen that participate in multiple physiological processes under the control of redox homeostasis. However, under pathological conditions, the over-production of ROS often leads to oxidative stress and inflammatory reactions, indicating a potential therapeutic target. With the rapid development of nucleic acid nanotechnology, scientists have exploited various DNA nanostructures with remarkable biocompatibility, programmability, and structural stability. Among these novel organic nanomaterials, a group of skeleton-like framework nucleic acid (FNA) nanostructures attracts the most interest due to their outstanding self-assembly, cellular endocytosis, addressability, and functionality. Surprisingly, different FNAs manifest similarly satisfactory antioxidative and anti-inflammatory effects during their biomedical application process. First, they are intrinsically endowed with the ability to neutralize ROS due to their DNA nature. Therefore, they are extensively involved in the complicated inflammatory signaling network. Moreover, the outstanding editability of FNAs also allows for flexible modifications with nucleic acids, aptamers, peptides, antibodies, low-molecular-weight drugs, and so on, thus further strengthening the targeting and therapeutic ability. This review focuses on the ROS-scavenging potential of three representative FNAs, including tetrahedral framework nucleic acids (tFNAs), DNA origami, and DNA hydrogels, to summarize the recent advances in their anti-inflammatory therapy applications. Although FNAs exhibit great potential in treating inflammatory diseases as promising ROS scavengers, massive efforts still need to be made to overcome the emerging challenges in their clinical translation.

A DNA nanostructure-Hif-1α inducer complex as novel nanotherapy against cisplatin-induced acute kidney injury.

Since its discovery in 1978, cisplatin-based chemotherapy regimens have served a pivotal role in human cancer treatment, saving millions of lives. However, its high risk still poses a significant challenge for cisplatin-induced acute kidney injury (AKI), which occurs in 30% of cisplatin-treated patients. Unfortunately, no effective solution for preventing or managing this severe complication, which greatly impacts its clinical administration. Kidney is the main organ injured by cisplatin, and the injury is related to cisplatin-induced cell apoptosis and DNA injury. Therefore, to achieve the safe use of cisplatin in tumour treatment, the key lies in identifying a kidney treatment that can effectively minimize cisplatin nephrotoxicity. Here, we successfully synthesized and applied a DNA-nanostructure complex, named TFG, which contains tetrahedral framework nucleic acids (tFNAs) and FG-4592, a novel Hif-1α inducer. As cargo, TFG is composed entirely of DNA strands. It possesses low nephrotoxicity and renal aggregation properties while FG-4592 is able to relieve renal injury by downregulating the apoptosis signal pathways. And it can relieve cisplatin-induced renal injury when taken cisplatin treatment. This work aims to enhance chemotherapy protection in tumour patients by using TFG, a DNA-based nanomedicines to kidney. This work has the potential to revolutionize the treatment of renal diseases, particularly drug-induced kidney injury, leading to improved clinical outcomes.

Assessing the interaction effects of mitochondrial DNA polymorphisms and lifestyle on heel bone mineral density.

BACKGROUND: Bone mineral density (BMD) is a major predictor of osteoporotic fractures, and previous studies have reported the effects of mitochondrial dysfunction and lifestyle on BMD, respectively. However, their interaction effects on BMD are still unclear. Therefore, we aimed to investigate the possible interaction of mitochondrial DNA (mtDNA) and common lifestyles contributing to osteoporosis. METHODS: Our analysis included 119,120 white participants (Nfemale=65,949 and Nmale=53,171) from the UK Biobank with heel BMD phenotype data. A generalized linear regression model of PLINK was performed to assess the interaction effects of mtDNA and five life environmental factors on heel BMD, including smoking, drinking, physical activity, dietary diversity score, and vitamin D. In addition, we also performed linear regression analysis for total body BMD. Finally, we assessed the potential causal relationships between mtDNA copy number (mtDNA-CN) and life environmental factors using Mendelian randomization (MR) analysis. RESULTS: Our study identified four mtDNA loci showing suggestive evidence of heel BMD, such as m.16356T>C (MT-DLOOP; P =1.50×10-3) in total samples. Multiple candidate mtDNA×lifetsyle interactions were also detected for heel BMD, such as MT-ND2×physical activity (P = 2.88×10-3) in total samples and MT-ND1×smoking (P = 8.54×10-4) in males. Notably, MT-CYB was a common candidate mtDNA loci for heel BMD to interact with five life environmental factors. Multivariable MR analysis indicated a causal effect of physical activity on heel BMD when mtDNA-CN was considered (P =1.13×10-3). CONCLUSIONS: Our study suggests the candidate interaction between mitochondria and lifestyles on heel BMD, providing novel clues for exploring the pathogenesis of osteoporosis.