Daisuke Matsumaru

Although vascular development is fundamental during embryogenesis, the developmental basis and tissue interactions underlying anatomical variation in major veins are not fully understood. The renal segment of the inferior vena cava exhibits significant anatomical variations that often affect the safety of retroperitoneal surgery. Using mouse embryos, we show that the renal segment of the inferior vena cava is not primarily dependent on the subcardinal vein as classically proposed, but instead forms from a vascular plexus closely associated with the developing para-aortic ridge. Genetic models further indicate that sympathoadrenal development in the para-aortic ridge contributes to the proper organization and remodeling of this vascular network. This revised developmental framework highlights a sympathoadrenal–vascular coupling as a developmental basis for inferior vena cava formation and thereby challenges classical subcardinal vein-dependent models.

Summary: Vascular development is fundamental during embryogenesis. Although the molecular and cellular mechanisms of vascular formation have been extensively studied, the developmental basis common to anatomical variations in major veins remains poorly understood ^1–4 . In particular, the renal segment of the inferior vena cava (IVC) exhibits marked anatomical variability, and these structural differences often affect the safety of retroperitoneal surgeries ^5,6 . Here we show that the renal segment of the IVC in mouse embryos does not arise from the subcardinal vein (SubCV), as classically proposed ⁷ , but instead forms from a vascular plexus in the para-aortic ridge (PAR) closely associated with developing sympathetic and adrenal tissues. Three-dimensional imaging with molecular markers revealed the vascular plexus in PAR arises independently of the SubCV and develops in Zuckerkandl organ and adrenal gland primordia. Moreover, genetic models demonstrated that the development of the sympathetic and adrenal tissues contributes to the organization and remodeling of this vascular network. This sympathoadrenal contribution contrasts with the classical mesonephros-centric model and explains the consistent IVC structures observed even in the absence of renal development. Our findings suggest a mammal-specific mode of IVC formation driven by the emergence of dominant sympathetic paraganglia and reduced reliance on mesonephric filtration. This revised developmental framework provides insight into the evolutionary divergence of venous anatomy and may help interpret clinically significant vascular variations during abdominal surgery.

Idiopathic inflammatory myopathies (IIMs) are systemic autoimmune diseases characterised by muscle weakness. Although multiple physiological and pathological processes are associated with IIMs, T‐lymphocyte infiltration into muscle plays a key role in the development and exacerbation of IIMs. Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a key transcription factor that regulates inflammatory responses; therefore, muscle Nrf2 may serve an important role in the development of IIMs. In this study, we demonstrated that experimental autoimmune myositis (EAM) causes loss of muscle mass and function in oxidative and glycolytic muscles in C57BL/6 mice. EAM increased CD4⁺ and CD8⁺ T‐lymphocyte infiltration, as well as interferon‐gamma (IFN‐γ) and tumour necrosis factor‐alpha (TNF‐α) mRNA expression in oxidative soleus and glycolytic extensor digitorum longus muscles, along with elevated chemokine mRNA levels (i.e. CCL3, CCL5, CXCL9, CXCL10 and CXCL16). IFN‐γ and TNF‐α treatments increased the mRNA expression levels of these chemokines in C2C12 myotubes. EAM also increased phosphorylated Nrf2 at Ser40 in soleus and glycolytic white vastus lateralis muscle. Although the expression of several chemokines was affected by Nrf2 activation following tert‐butylhydroquinone treatment or Keap1 knockdown, CCL5 mRNA expression significantly increased in C2C12 myotubes and mouse skeletal muscle. Moreover, muscle‐specific Nrf2 knockout in mice attenuates EAM‐induced loss of muscle mass and function, which was associated with the inhibition of CCL5 mRNA expression, CD8⁺ T‐lymphocyte infiltration and IFN‐γ mRNA expression. Collectively, these findings reveal that regulating Nrf2 activity is a promising therapeutic approach for treating IIM‐mediated muscle weakness. image Key points: Experimental autoimmune myositis (EAM) causes loss of muscle mass and function. Loss of muscle mass and function in EAM were associated with increased chemokine mRNA expression (i.e. CCL3, CCL5, CXCL9, CXCL10 and CXCL16), T‐lymphocyte infiltration and inflammatory cytokine mRNA expression (i.e. IFN‐γ and TNF‐α) in the skeletal muscle. EAM activated Nrf2 in muscle and increased Nrf2 activity in vivo and in vitro increased CCL5 mRNA expression. Muscle‐specific Nrf2 knockout in mice attenuated EAM‐induced muscle weakness by inhibiting CCL5 mRNA expression, CD8⁺ T‐lymphocyte migration and IFN‐γ mRNA expression in muscles. These results provide further evidence for the potential therapeutic targeting of Nrf2 to mitigate EAM‐induced muscle weakness.

Propolis is a resinous mixture produced by bees from their secretions and plant material, so its composition varies depending on its botanical origin. Propolis has several beneficial bioactivities, but its skin sensitization properties have long been suspected. Nevertheless, the skin sensitization potency of Brazilian green propolis (BGP) has not been scientifically evaluated. Here, we used scientifically reliable tests to evaluate it. In vitro antigenicity test based on the human cell line activation test (OECD TG 442E) was performed by measuring the expression of CD54 and CD86, which are indicators of the antigenicity of test substances, on THP-1 and DC2.4 cells. BGP did not affect the expression of either marker on THP-1 cells, but upregulated the expression of CD86 on DC2.4 cells, suggesting that BGP may be a skin sensitizer. Then, we performed local lymph node assay (LLNA, OECD TG 429) as a definitive in vivo test. LLNA showed that 1.70% BGP primed skin sensitization and is a “moderate sensitizer”. Our results indicate scientific proof of the validity of arbitrary concentrations (1–2%), which have been used empirically, and provide the first scientific information on the safe use of BGP.

Aging is inevitable, but the inherently and genetically programmed aging process is markedly influenced by environmental factors. All organisms are constantly exposed to various stresses, either exogenous or endogenous, throughout their lives, and the quality and quantity of the stresses generate diverse impacts on the organismal aging process. In the current oxygenic atmosphere on earth, oxidative stress caused by reactive oxygen species is one of the most common and critical environmental factors for life. The Kelch-like ECH-associated protein 1-NFE2-related factor 2 (KEAP1-NRF2) system is a critical defense mechanism of cells and organisms in response to redox perturbations. In the presence of oxidative and electrophilic insults, the thiol moieties of cysteine in KEAP1 are modified, and consequently NRF2 activates its target genes for detoxification and cytoprotection. A number of studies have clarified the contributions of the KEAP1-NRF2 system to the prevention and attenuation of physiological aging and aging-related diseases. Accumulating knowledge to control stress-induced damage may provide a clue for extending healthspan and treating aging-related diseases. In this review, we focus on the relationships between oxidative stress and aging-related alterations in the sensory, glandular, muscular, and central nervous systems and the roles of the KEAP1-NRF2 system in aging processes.

The reproductive tract in mammals emerges from two ductal systems during embryogenesis: Wolffian ducts (WDs) and Mullerian ducts (MDs). Most of the female reproductive tract (FRT) including the oviducts, uterine horn and cervix, originate from MDs. It is widely accepted that the formation of MDs depends on the preformed WDs within the urogenital primordia. Here, we found that the WD mesenchyme under the regulation of Hedgehog (Hh) signaling is closely related to the developmental processes of the FRT during embryonic and postnatal periods. Deficiency of Sonic hedgehog (Shh), the only Hh ligand expressed exclusively in WDs, prevents the MD mesenchyme from affecting uterine growth along the radial axis. The in vivo cell tracking approach revealed that after WD regression, distinct cells responding to WD-derived Hh signal continue to exist in the developing FRT and gradually contribute to the formation of various tissues such as smooth muscle, endometrial stroma and vascular vessel, in the mouse uterus. Our study thus provides a novel developmental mechanism of FRT relying on WD.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-20927-9.

Age-related hearing loss (AHL) is a progressive sensorineural hearing loss in elderly people. Although no prevention or treatments have been established for AHL, recent studies have demonstrated that oxidative stress is closely related to pathogenesis of AHL, suggesting that suppression of oxidative stress leads to inhibition of AHL progression. NRF2 is a master transcription factor that regulates various antioxidant proteins and cytoprotection factors. To examine whether NRF2 pathway activation prevents AHL, we used Keap1-knockdown (Keap1^FA/FA) mice, in which KEAP1, a negative regulator of NRF2, is decreased, resulting in the elevation of NRF2 activity. We compared 12-month-old Keap1^FA/FA mice with age-matched wild-type (WT) mice in the same breeding colony. In the Keap1^FA/FA mice, the expression levels of multiple NRF2 target genes were verified to be significantly higher than the expression levels of these genes in the WT mice. Histological analysis showed that cochlear degeneration at the apical and middle turns was ameliorated in the Keap1^FA/FA mice. Auditory brainstem response (ABR) thresholds in the Keap1^FA/FA mice were significantly lower than those in the WT mice, in particular at low–mid frequencies. Immunohistochemical detection of oxidative stress markers suggested that oxidative stress accumulation was attenuated in the Keap1^FA/FA cochlea. Thus, we concluded that NRF2 pathway activation protects the cochlea from oxidative damage during aging, in particular at the apical and middle turns. KEAP1-inhibiting drugs and phytochemicals are expected to be effective in the prevention of AHL.