Novel Protein Biomarkers and Therapeutic Targets for Type 1 Diabetes and Its Complications: Insights from Summary-Data-Based Mendelian Randomization and Colocalization Analysis.

Millions of patients suffer from type 1 diabetes (T1D) and its associated complications. Nevertheless, the pursuit of a cure for T1D has encountered significant challenges, with a crucial impediment being the lack of biomarkers that can accurately predict the progression of T1D and reliable therapeutic targets for T1D. Hence, there is an urgent need to discover novel protein biomarkers and therapeutic targets, which holds promise for targeted therapy for T1D. In this study, we extracted summary-level data on 4907 plasma proteins from 35,559 Icelanders and 2923 plasma proteins from 54,219 UK participants as exposures. The genome-wide association study (GWAS) summary statistics on T1D and T1D with complications were obtained from the R9 release results from the FinnGen consortium. Summary-data-based Mendelian randomization (SMR) analysis was employed to evaluate the causal associations between the genetically predicted levels of plasma proteins and T1D-associated outcomes. Colocalization analysis was utilized to investigate the shared genetic variants between the exposure and outcome. Moreover, transcriptome analysis and a protein-protein interaction (PPI) network further illustrated the expression patterns of the identified protein targets and their interactions with the established targets of T1D. Finally, a Mendelian randomization phenome-wide association study evaluated the potential side effects of the identified core protein targets. In the primary SMR analysis, we identified 72 potential protein targets for T1D and its complications, and nine of them were considered crucial protein targets. Within the group were five risk targets and four protective targets. Backed by evidence from the colocalization analysis, the protein targets were classified into four tiers, with MANSC4, CTRB1, SIGLEC5 and MST1 being categorized as tier 1 targets. Delving into the DrugBank database, we retrieved 11 existing medications for T1D along with their therapeutic targets. The PPI network clarified the interactions among the identified potential protein targets and established ones. Finally, the Mendelian randomization phenome-wide association study corroborated MANSC4 as a reliable target capable of mitigating the risk of various forms of diabetes, and it revealed the absence of adverse effects linked to CTRB1, SIGLEC5 and MST1. This study unveiled many protein biomarkers and therapeutic targets for T1D and its complications. Such advancements hold great promise for the progression of drug development and targeted therapy for T1D.

The role of RUNX1/NF-κB in regulating PVAT inflammation in aortic dissection.

The pathogenesis of aortic dissection (AD), an aortic disease associated with high mortality, involves significant vascular inflammatory infiltration. However, the precise relationship between perivascular adipose tissue (PVAT) and aortic dissection remains incompletely understood. The objective of this study is to investigate the role of PVAT inflammation in the pathogenesis of aortic dissection and identify novel therapeutic targets for this disease. The mouse model of aortic dissection was established in this study through intraperitoneal injection of Ang II and administration of BAPN in drinking water. Additionally, control groups were established at different time points including the 2-week group, 3-week group, and 4-week group. qPCR and immunohistochemistry techniques were employed to detect the expression of inflammatory markers and RUNX1 in PVAT surrounding the thoracic aorta in mice. Additionally, an aortic dissection model was established using RUNX1 knockout mice, and the aforementioned indicators were assessed. The 3T3-L1 cells were induced to differentiate into mature adipocytes in vitro, followed by lentivirus transfection for the knockdown or overexpression of RUNX1. The study aimed to investigate the potential cell-to-cell interactions by co-culturing 3T3-L1 cells with A7r5 or RAW264.7 cells. Subsequently, human aortic PVAT samples were obtained through clinical surgery and the aforementioned indicators were detected. In comparison to the control group, the aortic dissection model group exhibited decreased expression of MMP-2 and NF-κB in PVAT, while TNF-α and RUNX1 expression increased. Suppression of RUNX1 expression resulted in increased MMP-2 and NF-κB expression in PVAT, along with decreased TNF-α expression. Overexpression of RUNX1 upregulated the expression levels of NF-Κb, MMP-2, and TNF-α in adipocytes, whereas knockdown of RUNX1 exerted an opposite effect. Macrophages co-cultured with adipocytes overexpressing RUNX1 exhibited enhanced CD86 expression, while vascular smooth muscle cells co-cultured with these adipocytes showed reduced α-SMA expression. In human samples, there was an increase in both RUNX1 and MMP-2 expression levels, accompanied by a decrease in TNF-α and NF-Κb expression. The presence of aortic dissection is accompanied by evident inflammatory alterations in the PVAT, and this phenomenon appears to be associated with the involvement of RUNX1. It is plausible that the regulation of PVAT's inflammatory changes by RUNX1/NF-κB signaling pathway plays a role in the pathogenesis of aortic dissection.

Proteome-Wide Mendelian Randomization and Colocalization Analysis Identify Therapeutic Targets for Knee and Hip Osteoarthritis.

Osteoarthritis (OA) is a common degenerative disease. Although some biomarkers and drug targets of OA have been discovered and employed, limitations and challenges still exist in the targeted therapy of OA. Mendelian randomization (MR) analysis has been regarded as a reliable analytic method to identify effective therapeutic targets. Thus, we aimed to identify novel therapeutic targets for OA and investigate their potential side effects based on MR analysis. In this study, two-sample MR, colocalization analysis, summary-data-based Mendelian randomization (SMR) and Mendelian randomization phenome-wide association study (MR-PheWAS) were conducted. We firstly analyzed data from 4907 plasma proteins to identify potential therapeutic targets associated with OA. In addition, blood expression quantitative trait loci (eQTLs) data sources were used to perform additional validation. A protein-protein interaction (PPI) network was also constructed to delve into the interactions among identified proteins. Then, MR-PheWASs were utilized to assess the potential side effects of core therapeutic targets. After MR analysis and FDR correction, we identified twelve proteins as potential therapeutic targets for knee OA or hip OA. Colocalization analysis and additional validation supported our findings, and PPI networks revealed the interactions among identified proteins. Finally, we identified MAPK3 (OR = 0.855, 95% CI: 0.791-0.923, p = 6.88 × 10-5) and GZMK (OR = 1.278, 95% CI: 1.131-1.444, p = 8.58 × 10-5) as the core therapeutic targets for knee OA, and ITIH1 (OR = 0.847, 95% CI: 0.784-0.915, p = 2.44 × 10-5) for hip OA. A further MR phenome-wide association study revealed the potential side effects of treatments targeting MAPK3, GZMK, and ITIH1. This comprehensive study indicates twelve plasma proteins with potential roles in knee and hip OA as therapeutic targets. This advancement holds promise for the progression of OA drug development, and paves the way for more efficacious treatments of OA.

Therapeutic Potential of Exosomes in Tendon and Tendon-Bone Healing: A Systematic Review of Preclinical Studies.

Exosomes have been proven to play a positive role in tendon and tendon-bone healing. Here, we systematically review the literature to evaluate the efficacy of exosomes in tendon and tendon-bone healing. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic and comprehensive review of the literature was performed on 21 January 2023. The electronic databases searched included Medline (through PubMed), Web of Science, Embase, Scopus, Cochrane Library and Ovid. In the end, a total of 1794 articles were systematically reviewed. Furthermore, a "snowball" search was also carried out. Finally, forty-six studies were included for analysis, with the total sample size being 1481 rats, 416 mice, 330 rabbits, 48 dogs, and 12 sheep. In these studies, exosomes promoted tendon and tendon-bone healing and displayed improved histological, biomechanical and morphological outcomes. Some studies also suggested the mechanism of exosomes in promoting tendon and tendon-bone healing, mainly through the following aspects: (1) suppressing inflammatory response and regulating macrophage polarization; (2) regulating gene expression, reshaping cell microenvironment and reconstructing extracellular matrix; (3) promoting angiogenesis. The risk of bias in the included studies was low on the whole. This systematic review provides evidence of the positive effect of exosomes on tendon and tendon-bone healing in preclinical studies. The unclear-to-low risk of bias highlights the significance of standardization of outcome reporting. It should be noted that the most suitable source, isolation methods, concentration and administration frequency of exosomes are still unknown. Additionally, few studies have used large animals as subjects. Further studies may be required on comparing the safety and efficacy of different treatment parameters in large animal models, which would be conducive to the design of clinical trials.

Sparsity-based continuous wave terahertz lens-free on-chip holography with sub-wavelength resolution.

We demonstrate terahertz (THz) lens-free in-line holography on a chip in order to achieve 40 µm spatial resolution corresponding to ~0.7λ with a numerical aperture of ~0.87. We believe that this is the first time that sub-wavelength resolution in THz holography and the 40 µm resolution were both far better than what was already reported. The setup is based on a self-developed high-power continuous wave THz laser at 5.24 THz (λ = 57.25 µm) and a high-resolution microbolometer detector array (640 × 512 pixels) with a pitch of 17 µm. This on-chip in-line holography, however, suffers from the twin-image artifacts which obfuscate the reconstruction. To address this problem, we propose an iterative optimization framework, where the conventional object constraint and the L1 sparsity constraint can be combined to efficiently reconstruct the complex amplitude distribution of the sample. Note that the proposed framework and the sparsity-based algorithm can be applied to holography in other wavebands without limitation of wavelength. We demonstrate the success of this sparsity-based on-chip holography by imaging biological samples (i.e., a dragonfly wing and a bauhinia leaf).