Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability

Cancer poses a serious health problem in society and is increasingly surpassing cardiovascular disease as the leading cause of mortality in the United States. Current therapeutic strategies for cancer are extreme and harsh to patients and often have limited success; the danger of cancer is intensified as it metastasizes to secondary locations such as lung, bone, and liver, posing a dire threat to patient treatment and survival. Hedgehog signaling is an important pathway for normal development. Initially identified in Drosophila, the vertebrate and mammalian equivalent of the pathway has been studied extensively for its role in cancer development and progression. As this pathway regulates key target genes involved in development, its action also allows for the modulation of the microenvironment to prepare a tumor-suitable niche by manipulating tumor cell growth, differentiation, and immune regulation, thus creating an enabling environment for progression and metastasis. In this review, we will summarize recent scientific discoveries reporting the impact of the Hedgehog signaling pathway on the tumor initiation process and metastatic cascade, shedding light on the ability of the tumor to take over a mechanism crucially intended for development and normal function.

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Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment.

The exercise-glucocorticoid paradox: How exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels.

Major depressive disorder (MDD) is a global problem for which current pharmacotherapies are not completely effective. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has long been associated with MDD; however, the value of assessing cortisol as a biological benchmark of the pathophysiology or treatment of MDD is still debated. In this review, we critically evaluate the relationship between HPA axis dysfunction and cortisol level in relation to MDD subtype, stress, gender and treatment regime, as well as in rodent models. We find that an elevated cortisol response to stress is associated with acute and severe, but not mild or atypical, forms of MDD. Furthermore, the increased incidence of MDD in females is associated with greater cortisol response variability rather than higher baseline levels of cortisol. Despite almost all current MDD treatments influencing cortisol levels, we could find no convincing relationship between cortisol level and therapeutic response in either a clinical or preclinical setting. Thus, we argue that the absolute level of cortisol is unreliable for predicting the efficacy of antidepressant treatment. We propose that future preclinical models should reliably produce exaggerated HPA axis responses to acute or chronic stress a priori, which may, or may not, alter baseline cortisol levels, while also modelling the core symptoms of MDD that can be targeted for reversal. Combining genetic and environmental risk factors in such a model, together with the interrogation of the resultant molecular, cellular, and behavioral changes, promises a new mechanistic understanding of MDD and focused therapeutic strategies.

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Cortisol and Major Depressive Disorder-Translating Findings From Humans to Animal Models and Back.

Gardenia jasminoides Ellis: Ethnopharmacology, phytochemistry, and pharmacological and industrial applications of an important traditional Chinese medicine.

Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus–pituitary–adrenal axis

Objectives

We investigated whether inhibition of hedgehog (Hh) signal by cyclopamine attenuated inflammation and cartilage damage in adjuvant-induced arthritis (AIA) rats.



Methods

Cyclopamine (2.5, 5, 10 mg/kg) was given by intraperitoneal injection once daily from day 12 to 21 after AIA induction. Paw swelling (volume changes), serum pro-inflammatory cytokines levels (ELISA), histological analysis of joint damage (H&E staining), proteoglycans expression (Alcian blue staining), mRNA levels of sonic Hh (Shh), glioma-associated oncogene homologue 1 (Gli1), type II collagen (COII) and aggrecan in cartilage (real-time PCR) and articular chondrocyte apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) were measured respectively.



Key findings

Cyclopamine effectively attenuated inflammation and cartilage damage of AIA rats, as evidenced by reduced paw swelling, serum levels of tumor necrosis factors (TNF)-α, IL-1β, IL-6 and histological scores of joint damage, increased proteoglycans expression and mRNA levels of COII and aggrecan in articular cartilage. Shh or Gli1 mRNA level was correlated negatively with COII and aggrecan mRNA levels, suggesting Hh signal inhibition was associated with promotion of cartilage extracellular matrix production. Furthermore, cyclopamine decreased the number of apoptotic articular chondrocytes of AIA rats, which might be partly related to its mechanisms on relieving cartilage damage.



Conclusions

Our findings present some experimental evidence that Hh signal inhibition might be of potential clinical interest in rheumatoid arthritis treatment.

Xiang-yang Hu

Papers

Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus–pituitary–adrenal axis

Inhibition of hedgehog signal pathway by cyclopamine attenuates inflammation and articular cartilage damage in rats with adjuvant-induced arthritis.