Biology subjects

Arimbasseri, G. A.

Publications and source records attributed to Arimbasseri, G. A..

5 recordsLinked to original sources

bioRxiv2026

γLinolenic Acid Induces a Vitamin D Receptor-Independent Mineralization Program by Activating CaMKII--SMAD2/3 Pathway in Calvarial Osteoblasts

Vitamin D receptor (VDR) signaling is essential for osteoblast maturation and skeletal mineralization, yet the intracellular mechanisms linking VDR activity to matrix production remain poorly defined. Here, we show that vdr-/- calvarial osteoblasts initiate differentiation but fail to complete the transition to a mature, mineralizing state, exhibiting suppressed late-stage markers such as Dmp1, Phex, and Col1a1 and defective nodule formation both in vivo and in vitro. Transcriptomic profiling revealed a SMAD network imbalance, with elevated inhibitory SMADs and attenuated phosphorylation of both SMAD1/5/9 and SMAD2/3. Whereas SMAD1/5/9 activation was preserved in vivo and restored by exogenous BMP2 in vitro, consistent with in vivo paracrine BMP availability, reduced SMAD2/3 phosphorylation persisted in both contexts, indicating a cell-autonomous defect. Mechanistically, vdr-/- osteoblasts displayed impaired intracellular Ca2+ dynamics and diminished CaMKII activation, with VDR/RXR occupancy detected near the Camk2g locus. Pharmacological CaMKII inhibition (KN-93) recapitulated the phenotype, reducing SMAD2/3 phosphorylation and mineralization and establishing CaMKII as an upstream regulator of SMAD2/3. A milk-based diet rescued skeletal defects in vdr-/- mice in a calcium-independent manner and selectively restored CaMKII-SMAD2/3 signaling. Metabolomic profiling identified the omega-6 fatty acid y-linolenic acid (GLA) as an elevated circulating mediator; exogenous GLA restored Ca2+ flux, CaMKII activation, SMAD2/3 phosphorylation, matrix production, and mineralization, without reactivating Runx2, Sp7, or BMP-SMAD1/5/9 signaling, and dependent on CaMKII activity. These findings reveal a VDR-independent, GLA-inducible CaMKII-SMAD2/3 mineralization program, positioning metabolic modulation of calcium signaling as a strategy to restore osteoblast function under impaired vitamin D signaling.

physiology↗

bioRxiv2025

JNK2 pathway in colonocytes enhances gut barrier integrity in response to microbial acetate.

Weaning involves a nutritional shift from fat-rich milk to carbohydrate-based solid food, reshaping metabolism, microbiota, and gut immune tolerance. While dairy remains a component of the human diet beyond weaning, the impact of continued milk supplementation on gut epithelial homeostasis remains poorly understood. Here, using a mouse model, we show that continued milk-based feeding post-weaning promotes intestinal barrier function by enriching the commensal bacterium Dubosiella newyorkensis, which produces acetate to activate epithelial JNK2 signaling. This pathway enhances barrier integrity and suppresses inflammation induced by mild Dextran Sodium Sulphate (DSS) treatment. In contrast, feeding a lard-based high-fat diet or transient pharmacologic inhibition of JNK2 induces epithelial P38 activation, resulting in barrier disruption and inflammation. Importantly, the beneficial effects of milk were observed only if initiated during the weaning period, when the microbiome is in a metastable transitional state. Initiation of the same intervention two weeks after weaning led to P38 activation and inflammatory responses. These findings highlight the microbiome-dependent, stage-specific effects of diet and underscore the importance of early-life nutritional interventions for long-term gut health.

physiology↗

bioRxiv2025

VDR-calcium axis regulates the diet-driven metabolic shift during weaning

Weaning in mammals is associated with a shift in the metabolism, driven by the differences in the macronutrient composition of milk and post-weaning diet. Milk has a higher fat content compared with the carbohydrate-enriched solid food. Malnutrition during this stage could affect this transition with long-term adverse effects. The role of micronutrients during this transition is not well understood. Mice lacking a functional vitamin D receptor (VDR) progressively develop severe skeletal muscle and adipose atrophy after weaning, suggesting a role for vitamin D signaling in the metabolic transition during weaning. Here, we demonstrate that after weaning, VDR knock-out mice exhibit systemic energy deprivation and higher lipolysis in inguinal white adipose tissue, probably due to increased norepinephrine signaling via protein kinase A (PKA) and extracellular signalling-regulated kinase (ERK) pathways. Energy deprivation in vdr-/- mice is associated with defective liver glycogenolysis, characterized by increased expression of protein phosphatase-1 and decreased phosphorylation of glycogen phosphorylase. However, restoration of serum calcium levels by a rescue diet is sufficient to restore energy metabolism in vdr-/- mice. Interestingly, maintaining a high-fat-containing milk-based diet post-weaning could prevent the onset of energy deprivation, liver glycogen storage defect, and adipose atrophy in these mice without restoring serum calcium levels. Our data show that the vitamin D-calcium axis is essential for the adaptation of mice to the dietary shift from high-fat-containing milk to post-weaning carbohydrate-enriched diets. It also reveals a novel macronutrient-micronutrient interaction that shapes the metabolic flexibility of the individual based on the dietary composition of nutrients.

physiology↗

bioRxiv2023

Vitamin D signaling orchestrates skeletal muscle metabolic flexibility by regulating its fuel choice.

Vitamin D deficiency is associated with skeletal muscle pathologies. However, the role of vitamin D signaling in maintenance of muscle function is not well understood. Mice lacking vitamin D receptor (VDR) exhibit severe muscle wasting after weaning and this is associated with accumulation of muscle glycogen and energy deprivation. Here we show that the skeletal muscles of vdr-/- mice exhibit upregulation of fatty acid oxidation pathway and PPAR pathway and are predisposed to utilize fatty acids as the energy source even in a carbohydrate-enriched diet. As a result, fat-enriched diets could alleviate energy deprivation and atrophy of vdr-/- skeletal muscles. However, the complete restoration of muscle mass and systemic metabolism of vdr-/- mice depended on the quality of diets. Despite increasing muscle energy levels, a lard-based high-fat diet (HFD) disrupted glucose homeostasis by specifically inhibiting the insulin synthesis in pancreatic islets. Surprisingly, milk-based high-fat diets (MBD) could restore both muscle mass and pancreatic insulin response. This study reveals a micronutrient-macronutrient interaction network that connects vitamin D signaling with muscle fuel selection and pancreatic insulin response to enable energy homeostasis under different metabolic landscapes.

physiology↗

bioRxiv2021

A vitamin D-RelB/NF-κB pathway limits Chandipura virus multiplication by rewiring the homeostatic state of autoregulatory type 1 interferon-IRF7 signaling

Besides its functions in the skeletomuscular system, vitamin D also promotes protective immunity against viral pathogens. Viral sensing by mammalian cells triggers nuclear activation of RelA/NF-{kappa}B and IRF3 factors, which collaborate in mediating the early induction of antiviral type 1 interferons (T1-IFNs). Autocrine T1-IFN signaling further accumulates otherwise negligibly expressed IRF7 in virus-infected cells that then sustains T1-IFN production in a positive feedback. Surprisingly, prior cell-culture studies revealed that vitamin D actually suppresses signal-induced RelA activation. Indeed, it remains unclear how vitamin D limits viral multiplication in a cell-autonomous manner. Here, we examined the role of vitamin D in controlling cellular infections by the Chandipura virus (CHPV), a cytoplasmic RNA virus implicated in human epidemics. We found that vitamin D conditioning produced an altered cell state less permissive for CHPV multiplication because of the heightened expression of T1-IFNs. It is thought that viruses also induce a distinct RelB/NF-{kappa}B activity, which counteracts RelA-driven T1-IFN expressions in infected cells. Our analyses instead characterized a basal nuclear RelB activity, which was downregulated upon vitamin D-mediated suppression of RelB synthesis. Interestingly, this vitamin D-RelB pathway provoked IRF7-mediated positive autoregulation augmenting constitutive T1-IFN expressions even in the absence of viral infections. Accordingly, RelB deficiency rendered redundant, while IRF7 depletion abrogated antiviral vitamin D actions. In sum, our study suggests that the homeostatic state of the signaling circuitry comprising of the NF-{kappa}B and T1-IFN pathways connects micronutrients to antiviral immunity at the cellular level. Significance statementVitamin D limits viral infections, but the underlying mechanism remains unclear. Linking micronutrients to antiviral immunity, Ratra et al. characterize an immune signaling circuitry engaged by vitamin D that generates a cellular state less permissive to infections by Chandipura virus, a pathogen of public health importance.

immunology↗