Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic–pituitary–adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenerative diseases, like Alzheimer’s and Parkinson’s, driven by excessive cortisol production and HPA axis dysregulation, along with neuroinflammation in the central nervous system. The relationship between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mechanisms and their effects is essential, as they offer insights into potential interventions to mitigate the detrimental consequences of chronic stress and cortisol dysregulation in these conditions.

Lung vascular endothelial barrier disruption and the accompanying inflammation are primary pathogenic features of acute lung injury (ALI); however, the basis for the development of both remains unclear. Studies have shown that activation of transient receptor potential canonical (TRPC) channels induces Ca²⁺ entry, which is essential for increased endothelial permeability. Here, we addressed the role of Toll-like receptor 4 (TLR4) intersection with TRPC6-dependent Ca²⁺ signaling in endothelial cells (ECs) in mediating lung vascular leakage and inflammation. We find that the endotoxin (lipopolysaccharide; LPS) induces Ca²⁺ entry in ECs in a TLR4-dependent manner. Moreover, deletion of TRPC6 renders mice resistant to endotoxin-induced barrier dysfunction and inflammation, and protects against sepsis-induced lethality. TRPC6 induces Ca²⁺ entry in ECs, which is secondary to the generation of diacylglycerol (DAG) induced by LPS. Ca²⁺ entry mediated by TRPC6, in turn, activates the nonmuscle myosin light chain kinase (MYLK), which not only increases lung vascular permeability but also serves as a scaffold to promote the interaction of myeloid differentiation factor 88 and IL-1R–associated kinase 4, which are required for NF-κB activation and lung inflammation. Our findings suggest that TRPC6-dependent Ca²⁺ entry into ECs, secondary to TLR4-induced DAG generation, participates in mediating both lung vascular barrier disruption and inflammation induced by endotoxin.

RhoA activation and increased intracellular Ca²⁺ concentration mediated by the activation of transient receptor potential channels (TRPC) both contribute to the thrombin-induced increase in endothelial cell contraction, cell shape change, and consequently to the mechanism of increased endothelial permeability. Herein, we addressed the possibility that TRPC signals RhoA activation and thereby contributes in actinomyosin-mediated endothelial cell contraction and increased endothelial permeability. Transduction of a constitutively active Gα_q mutant in human pulmonary arterial endothelial cells induced RhoA activity. Preventing the increase in intracellular Ca²⁺ concentration by the inhibitor of Gα_q or phospholipase C and the Ca²⁺ chelator, BAPTA-AM, abrogated thrombin-induced RhoA activation. Depletion of extracellular Ca²⁺ also inhibited RhoA activation, indicating the requirement of Ca²⁺ entry in the response. RhoA activation could not be ascribed to storeoperated Ca²⁺ (SOC) entry because SOC entry induced with thapsigargin or small interfering RNA-mediated inhibition of TRPC1 expression, the predominant SOC channel in these endothelial cells, failed to alter RhoA activity. However, activation of receptor-operated Ca²⁺ entry by oleoyl-2-acetyl-sn-glycerol, the membrane permeable analogue of the Gα_q-phospholipase C product diacylglycerol, induced RhoA activity. Receptor-operated Ca²⁺ activation was mediated by TRPC6 because small interfering RNA-induced TRPC6 knockdown significantly reduced Ca²⁺ entry. TRPC6 knockdown also prevented RhoA activation, myosin light chain phosphorylation, and actin stress fiber formation as well as inter-endothelial junctional gap formation in response to either oleoyl-2-acetyl-sn-glycerol or thrombin. TRPC6-mediated RhoA activity was shown to be dependent on PKCα activation. Our results demonstrate that Gα_q activation of TRPC6 signals the activation of PKCα, and thereby induces RhoA activity and endothelial cell contraction.

Millions of people are affected by pain-related conditions worldwide. Literature has consistently shown that each individual experiences and perceives pain in a unique manner due to biological, environmental, and cultural factors in which they have been raised. It has been established that biological males and females perceive pain differently and that it may be partially explained by their distinct hormonal profiles since birth, which are only further magnified during puberty. For biological males, high levels of testosterone have shown to increase their pain threshold; and for biological females, estrogen fluctuations have shown to increase pain intensity and perception. However, sex hormones have not been studied in the context of pain treatment or their impact on biochemical pathways involved in pain perception. For this purpose, the transgender community serves as a unique population to investigate the impact of hormone replacement therapy on molecular pathways involved in the perception of pain. The purpose of this review is to explore the biochemistry of hormone replacement in transgender patients who also have other pain-related conditions such as headaches, fibromyalgia, temporomandibular myalgia, and visceral pain.

The lipid mediator sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SPHK)-induced phosphorylation of sphingosine, is known to stabilize interendothelial junctions and prevent microvessel leakiness. Here, we investigated the role of SPHK1 activation in regulating the increase in pulmonary microvessel permeability induced by challenge of mice with lipopolysaccharide or thrombin ligation of protease-activating receptor (PAR)-1. Both lipopolysaccharide and thrombin increased mouse lung microvascular permeability and resulted in a delayed activation of SPHK1 that was coupled to the onset of restoration of permeability. In contrast to wild-type mice, Sphk1 ^−/− mice showed markedly enhanced pulmonary edema formation in response to lipopolysaccharide and PAR-1 activation. Using endothelial cells challenged with thrombin concentration (50 nmol/L) that elicited a transient but reversible increase in endothelial permeability, we observed that increased SPHK1 activity and decreased intracellular S1P concentration preceded the onset of barrier recovery. Thus, we tested the hypothesis that released S1P in a paracrine manner activates its receptor S1P1 to restore the endothelial barrier. Knockdown of SPHK1 decreased basal S1P production and Rac1 activity but increased basal endothelial permeability. In SPHK1-depleted cells, PAR-1 activation failed to induce Rac1 activation but augmented RhoA activation and endothelial hyperpermeability response. Knockdown of S1P1 receptor in endothelial cells also enhanced the increase in endothelial permeability following PAR-1 activation. S1P treatment of Sphk1 ^−/− lungs or SPHK1-deficient endothelial cells restored endothelial barrier function. Our results suggest the crucial role of activation of the SPHK1→S1P→S1P1 signaling pathway in response to inflammatory mediators in endothelial cells in regulating endothelial barrier homeostasis.