Vitamin D3 protects against nitrogen mustard-induced apoptosis of the bronchial epithelial cells via activating the VDR/Nrf2/Sirt3 pathway

Yu, Wenpei; Dong, Xunhu; Dan, Guorong; Ye, Feng; Cheng, Jin; Zhao, Yuanpeng; Chen, Mingliang; Sai, Yan; Zou, Zhongmin

doi:10.1016/j.toxlet.2021.10.016

Cited by 13 publications

(6 citation statements)

References 48 publications

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“…In addition to the ability to generate 1,25(OH) 2 D, the presence of a high density of VDRs in epithelial cells allows them to optimize barrier functions and other biological activities. Examples include the lungs [ 60 ], breast [ 61 ], intestine [ 62 ], prostate [ 63 ], osteoblasts, and chondrocytes [ 64 , 65 ]. Unsurprisingly, all these tissues are targets for calcitriol.…”

Section: Introductionmentioning

confidence: 99%

Physiological Basis for Using Vitamin D to Improve Health

Wimalawansa

2023

Biomedicines

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Vitamin D is essential for life—its sufficiency improves metabolism, hormonal release, immune functions, and maintaining health. Vitamin D deficiency increases the vulnerability and severity of type 2 diabetes, metabolic syndrome, cancer, obesity, and infections. The active enzyme that generates vitamin D [calcitriol: 1,25(OH)2D], CYP27B1 (1a-hydoxylase), and its receptors (VDRs) are distributed ubiquitously in cells. Once calcitriol binds with VDRs, the complexes are translocated to the nucleus and interact with responsive elements, up- or down-regulating the expression of over 1200 genes and modulating metabolic and physiological functions. Administration of vitamin D3 or correct metabolites at proper doses and frequency for longer periods would achieve the intended benefits. While various tissues have different thresholds for 25(OH)D concentrations, levels above 50 ng/mL are necessary to mitigate conditions such as infections/sepsis, cancer, and reduce premature deaths. Cholecalciferol (D3) (not its metabolites) should be used to correct vitamin D deficiency and raise serum 25(OH)D to the target concentration. In contrast, calcifediol [25(OH)D] raises serum 25(OH)D concentrations rapidly and is the agent of choice in emergencies such as infections, for those who are in ICUs, and for insufficient hepatic 25-hydroxylase (CYP2R1) activity. In contrast, calcitriol is necessary to maintain serum-ionized calcium concentration in persons with advanced renal failure and hypoparathyroidism. Calcitriol is, however, ineffective in most other conditions, including infections, and as vitamin D replacement therapy. Considering the high costs and higher incidence of adverse effects due to narrow therapeutic margins (ED50), 1α-vitamin D analogs, such as 1α-(OH)D and 1,25(OH)2D, should not be used for other conditions. Calcifediol analogs cost 20 times more than D3—thus, they are not indicated as a routine vitamin D supplement for hypovitaminosis D, osteoporosis, or renal failure. Healthcare workers should resist accepting inappropriate promotions, such as calcifediol for chronic renal failure and calcitriol for osteoporosis or infections—there is no physiological rationale for doing so. Maintaining the population’s vitamin D sufficiency (above 40 ng/mL) with vitamin D3 supplements and/or daily sun exposure is the most cost-effective way to reduce chronic diseases and sepsis, overcome viral epidemics and pandemics, and reduce healthcare costs. Furthermore, vitamin D sufficiency improves overall health (hence reducing absenteeism), reduces the severity of chronic diseases such as metabolic and cardiovascular diseases and cancer, decreases all-cause mortality, and minimizes infection-related complications such as sepsis and COVID-19-related hospitalizations and deaths. Properly using vitamin D is the most cost-effective way to reduce chronic illnesses and healthcare costs: thus, it should be a part of routine clinical care.

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Section: Introductionmentioning

confidence: 99%

Physiological Basis for Using Vitamin D to Improve Health

Wimalawansa

2023

Biomedicines

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“…As shown in Figure 4 C, NM exposure increased ROS accumulation in a dose-dependent manner, while MSC-CM treatment after NM exposure significantly decreased NM-induced cellular ROS and superoxide generation ( Figure 4 C). Therefore, NM exposure damages mitochondria and increases oxidative stress [ 37 , 38 , 39 ], while MSC-CM functions as an antioxidant to combat these deleterious effects.…”

Section: Resultsmentioning

confidence: 99%

“…They found that sphingomyelin metabolites were identified in nitrogen mustard-exposed corneal tissue extracts, although it was not clear which specific inhibitors blocked the potential sphingomyelin–ceramide pathway [ 9 ]. Several studies have demonstrated that NM-mediated activating MAPK/AktAP1 pathway led to the induction of inflammatory and proteolytic mediators in murine skin models, and NM-induced apoptosis is protected by vitamin D3 via activating VDR/Nrf2/Sirt3 pathway [ 38 , 39 ]. While we did not investigate the mechanisms underlying the protective effects of MSC-CM in our current study, considering our current focus on the therapeutic potential of mesenchymal stem cell-secreted factors on nitrogen mustard-induced corneal injury model, it will be of great interest to investigate the NM-involved mechanism in the future.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Mesenchymal Stem Cell-Secreted Factors on Delay in Corneal Wound Healing by Nitrogen Mustard

Shen

Anwar

et al. 2022

IJMS

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Ocular surface exposure to nitrogen mustard (NM) leads to severe ocular toxicity which includes the separation of epithelial and stromal layers, loss of endothelial cells, cell death, and severe loss of tissue function. No definitive treatment for mustard gas-induced ocular surface disorders is currently available. The research was conducted to investigate the therapeutic potential of mesenchymal stem cell-conditioned media (MSC-CM) in NM-induced corneal wounds. NM was added to different types of corneal cells, the ocular surface of porcine, and the ocular surface of mice, followed by MSC-CM treatment. NM significantly induced apoptotic cell death, cellular ROS (Reactive oxygen species), and reduced cell viability, metabolic gene expression, and mitochondrial function, and, in turn, delayed wound healing. The application of MSC-CM post NM exposure partially restored mitochondrial function and decreased intracellular ROS generation which promoted cell survival. MSC-CM therapy enhanced wound healing process. MSC-CM inhibited NM-induced apoptotic cell death in murine and porcine corneal tissue. The application of MSC-CM following a chemical insult led to significant improvements in the preservation of corneal structure and wound healing. In vitro, ex vivo, and in vivo results suggest that MSC-CM can potentially provide targeted therapy for the treatment of chemical eye injuries, including mustard gas keratopathy (MGK) which presents with significant loss of vision alongside numerous corneal pathologies.

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“…48 Sirt3 was not only beneficial in preventing HF but also regulated by VD/VDR axis. 25,49 Thus, we predict that the hepatoprotective effect of AD-2 was by upregulating Sirt3 via the VD/VDR axis. Our experimental results showed that AD-2 promoted the expression of both VDR and Sirt3 (p < 0.01) in vitro and in vivo, further confirming that AD-2 ameliorated HF by upregulating VDR, which was consistent with expectations.…”

Section: ■ Discussionmentioning

confidence: 97%

Ginsenoside AD-2 Ameliorating Lipopolysaccharide-Induced Activation in HSC-T6 Cells and Carbon Tetrachloride-Induced Hepatic Fibrosis in Mice via Regulation of VD-VDR Axis

Chen

Lin

Yang

et al. 2023

J. Agric. Food Chem.

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Ginsenoside 25-hydroxy protopanaxadiol (AD-2) isolated from ginseng was proved to have anti-hepatic fibrosis (HF) effect in our previous study. But the mechanism is unknown. The present study investigated the anti-HF effects and mechanisms of AD-2 on the lipopolysaccharide (LPS)-induced activation in HSC-T6 cells and carbon tetrachloride (CCl4)-induced hepatic fibrosis (HF) in mice. Results showed that AD-2 significantly inhibited the LPS-induced activated HSC-T6 cells in vitro and markedly reduced the serum transaminase and hydroxyproline levels, pathological changes, and hepatic body ratio in CCl4-induced HF mice, indicating AD-2 ameliorated liver injury and reversed HF notably. Moreover, AD-2 decreased the expression of TGF-β1, α-SMA, and MMP2, and maintained TIMP1/MMP9 in balance with the level of vitamin D (VD) and the expression of VD nuclear receptor (VDR) and Sirt3 increased. In conclusion, the anti-HF mechanism of AD-2 is related to the inhibition of HSC activation, promotion of collagen degradation, and regulation of the VD/VDR axis.

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Vitamin D3 protects against nitrogen mustard-induced apoptosis of the bronchial epithelial cells via activating the VDR/Nrf2/Sirt3 pathway

Cited by 13 publications

References 48 publications

Physiological Basis for Using Vitamin D to Improve Health

Physiological Basis for Using Vitamin D to Improve Health

Therapeutic Potential of Mesenchymal Stem Cell-Secreted Factors on Delay in Corneal Wound Healing by Nitrogen Mustard

Ginsenoside AD-2 Ameliorating Lipopolysaccharide-Induced Activation in HSC-T6 Cells and Carbon Tetrachloride-Induced Hepatic Fibrosis in Mice via Regulation of VD-VDR Axis

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