Lymphatic vessel: origin, heterogeneity, biological functions, and therapeutic targets.

Lymphatic vessels, comprising the secondary circulatory system in human body, play a multifaceted role in maintaining homeostasis among various tissues and organs. They are tasked with a serious of responsibilities, including the regulation of lymph absorption and transport, the orchestration of immune surveillance and responses. Lymphatic vessel development undergoes a series of sophisticated regulatory signaling pathways governing heterogeneous-origin cell populations stepwise to assemble into the highly specialized lymphatic vessel networks. Lymphangiogenesis, as defined by new lymphatic vessels sprouting from preexisting lymphatic vessels/embryonic veins, is the main developmental mechanism underlying the formation and expansion of lymphatic vessel networks in an embryo. However, abnormal lymphangiogenesis could be observed in many pathological conditions and has a close relationship with the development and progression of various diseases. Mechanistic studies have revealed a set of lymphangiogenic factors and cascades that may serve as the potential targets for regulating abnormal lymphangiogenesis, to further modulate the progression of diseases. Actually, an increasing number of clinical trials have demonstrated the promising interventions and showed the feasibility of currently available treatments for future clinical translation. Targeting lymphangiogenic promoters or inhibitors not only directly regulates abnormal lymphangiogenesis, but improves the efficacy of diverse treatments. In conclusion, we present a comprehensive overview of lymphatic vessel development and physiological functions, and describe the critical involvement of abnormal lymphangiogenesis in multiple diseases. Moreover, we summarize the targeting therapeutic values of abnormal lymphangiogenesis, providing novel perspectives for treatment strategy of multiple human diseases.

Causal relationship between bipolar disorder and inflammatory bowel disease: A bidirectional two-sample mendelian randomization study.

Background: Growing evidence suggests a bidirectional association between bipolar disorder (BD) and inflammatory bowel disease (IBD); however, observational studies are prone to confounding, making causal inference and directional determination of these associations difficult. Methods: We performed bidirectional two-sample Mendelian randomization (MR) and selected single nucleotide polymorphisms (SNPs) associated with BD and IBD as instrumental variables (IV). SNPs and genetic associations with BD and IBD were obtained from the latest genome-wide association studies (GWAS) in Europeans (BD: cases/controls: 20352/31358; IBD: 12882/21770; Crohn's disease (CD): 5,956/14927; ulcerative colitis (UC): 6968/20464). The inverse-variance-weighted method was the major method used in MR analyses. MR-Egger, weight mode, simple mode, and weighted median were used for quality control. Results: Genetically predicted BD (per log-odds ratio increase) was significantly positively associated with risk of IBD (OR: 1.18, 95% CI: 1.04-1.33), and UC (OR = 1.19, 95% CI: 1.05-1.35), but not CD (OR = 1.18, 95% CI: 0.95-1.48). The validation analysis found that combined OR of IBD, CD, and UC increased per log-OR of BD were 1.16(95% CI: 1.02-1.31), 1.20(95% CI: 0.98-1.48) 1.17(95% CI: 1.02-1.35), respectively. In contrast, no causal relationship was identified between genetically influenced IBD and BD. Conclusion: Our results confirm a causal relationship between BD and IBD, which may influence clinical decisions on the management of BD patients with intestinal symptoms. Although the reverse MR results did not support a causal effect of IBD on BD, the effect of the IBD active period on BD remains to be further investigated.