Neurobiological effects of a probiotic-supplemented diet in chronically stressed male Long-Evans rats: Evidence of enhanced resilience

AUTHORS

Nick R. Natale, Molly Kent, Nathan Fox, Dylan Vavra, Kelly Lambert

ABSTRACT

Probiotics that regulate the microbiome-gut-brain axis and provide mental health benefits to the host are referred to as psychobiotics. Preclinical studies have demonstrated psychobiotic effects on early life stress-induced anxiety- and depression-related behavior in rodents; however, the specific mechanisms remain ill-defined. In the current study, we investigated the effects of probiotic supplementation on neurobiological responses to chronic stress in adult male Long-Evans rats. Twenty-four rats were randomly assigned to probiotic (PB) or vehicle control (VEH) groups, then to either chronic unpredictable stress (CUS) or no-stress control (CON) conditions within each group (n = 6/subgroup). We hypothesized that PB supplementation would reduce markers of anxiety and enhance emotional resilience, especially in the CUS animals. In the cognitive uncertainty task, a nonsignificant trend was observed indicating that the PB-supplemented animals spent more time oriented toward the food reward than VEH animals. In the open-field task, CUS-PB animals spent more time in the center of the arena than CUS-VEH animals, an effect not observed between the two CON groups. In the swim task, the PB animals, regardless of stress assignment, exhibited increased floating, suggesting a conserved response in a challenging context. Focusing on the endocrine measures, higher dehydroepiandrosterone (DHEA)-to-corticosterone fecal metabolite ratios, a correlate of emotional resilience, were observed in PB animals. Further, PB animals exhibited reduced microglia immunoreactivity in the basolateral amygdala, possibly indicating a neuroprotective effect of PB supplements in this rodent model. These results provide evidence that PB supplementation interacts with stress exposure to influence adaptive responses associated with endocrine, neural, and behavioral indices of anxiety.

Preliminary study on the osseointegration effects of contactless automated implant cavity preparation via femtosecond laser ablation

AUTHORS

Shanshan Liang, Jianqiao Zheng, and Fusong Yuan

ABSTRACT

Microrobots were used to control the femtosecond laser ablation of bone tissues to prepare implant cavities for dental implant surgery. The method was optimized through depth-of-cut experiments of ex vivo rabbit femurs, and the optimized method was used to prepare implant cavities on the left femurs of eight live rabbits. A power of 10 W and a scanning rate of 4000 mm/s were found to be optimal. After seven days of osteoinduction, the expression of collagen type I was significantly higher in the experimental group than in the control group (manually drilled implant cavities). The bone–implant contacts of the experimental group at 4 and 8 weeks were 9.65% and 23.08%, respectively.

Fibroblast Growth Factor Receptor 1 Drives the Metastatic Progression of Prostate Cancer

AUTHORS

Estefania Labanca, Jun Yang, Peter D.A. Shepherd, Xinhai Wan, Michael W. Starbuck, Leah D. Guerra, Nicolas Anselmino, Juan A. Bizzotto, Jiabin Dong, Arul M. Chinnaiyan, Murali K. Ravoori, Vikas Kundra, Bradley M. Broom, Paul G. Corn, Patricia Troncoso, Geraldine Gueron, Christopher J. Logothethis, Nora M. Navone

ABSTRACT

Background

No curative therapy is currently available for metastatic prostate cancer (PCa). The diverse mechanisms of progression include fibroblast growth factor (FGF) axis activation.

Objective

To investigate the molecular and clinical implications of fibroblast growth factor receptor 1 (FGFR1) and its isoforms (α/β) in the pathogenesis of PCa bone metastases.

Design, setting, and participants

In silico, in vitro, and in vivo preclinical approaches were used. RNA-sequencing and immunohistochemical (IHC) studies in human samples were conducted.

Outcome measurements and statistical analysis

In mice, bone metastases (chi-square/Fisher’s test) and survival (Mantel-Cox) were assessed. In human samples, FGFR1 and ladinin 1 (LAD1) analysis associated with PCa progression were evaluated (IHC studies, Fisher’s test).

Results and limitations

FGFR1 isoform expression varied among PCa subtypes. Intracardiac injection of mice with FGFR1-expressing PC3 cells reduced mouse survival (α, p < 0.0001; β, p = 0.032) and increased the incidence of bone metastases (α, p < 0.0001; β, p = 0.02). Accordingly, IHC studies of human castration-resistant PCa (CRPC) bone metastases revealed significant enrichment of FGFR1 expression compared with treatment-naïve, nonmetastatic primary tumors (p = 0.0007). Expression of anchoring filament protein LAD1 increased in FGFR1-expressing PC3 cells and was enriched in human CRPC bone metastases (p = 0.005).

Conclusions

FGFR1 expression induces bone metastases experimentally and is significantly enriched in human CRPC bone metastases, supporting its prometastatic effect in PCa. LAD1 expression, found in the prometastatic PCa cells expressing FGFR1, was also enriched in CRPC bone metastases. Our studies support and provide a roadmap for the development of FGFR blockade for advanced PCa.

Patient summary

We studied the role of fibroblast growth factor receptor 1 (FGFR1) in prostate cancer (PCa) progression. We found that PCa cells with high FGFR1 expression increase metastases and that FGFR1 expression is increased in human PCa bone metastases, and identified genes that could participate in the metastases induced by FGFR1. These studies will help pinpoint PCa patients who use fibroblast growth factor to progress and will benefit by the inhibition of this pathway.

Decreased Trabecular Bone Mass in Col22a1-Deficient Mice

AUTHORS

Wenbo Zhao, Philip Wiedemann, Eva Maria Wölfel, Mona Neven, Stephanie Peters, Thomas Imhof, Manuel Koch, Björn Busse, Michael Amling, Thorsten Schinke, Timur Alexander Yorgan

ABSTRACT

The bone matrix is constantly remodeled by the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. Whereas type I collagen is the most abundant bone matrix protein, there are several other proteins present, some of them specifically produced by osteoblasts. In a genome-wide expression screening for osteoblast differentiation markers we have previously identified two collagen-encoding genes with unknown function in bone remodeling. Here we show that one of them, Col22a1, is predominantly expressed in bone, cultured osteoblasts, but not in osteoclasts. Based on this specific expression pattern we generated a Col22a1-deficient mouse model, which was analyzed for skeletal defects by µCT, undecalcified histology and bone-specific histomorphometry. We observed that Col22a1-deficient mice display trabecular osteopenia, accompanied by significantly increased osteoclast numbers per bone surface. In contrast, cortical bone parameters, osteoblastogenesis or bone formation were unaffected by the absence of Col22a1. Likewise, primary osteoblasts from Col22a1-deficient mice did not display a cell-autonomous defect, and they did not show altered expression of Rankl or Opg, two key regulators of osteoclastogenesis. Taken together, we provide the first evidence for a physiological function of Col22a1 in bone remodeling, although the molecular mechanisms explaining the indirect influence of Col22a1 deficiency on osteoclasts remain to be identified.

Activation of cannabinoid receptor 2 alleviates glucocorticoid-induced osteonecrosis of femoral head with osteogenesis and maintenance of blood supply

AUTHORS

Houyi Sun, Weicheng Zhang, Ning Yang, Yi Xue, Tianhao Wang, Hongzhi Wang, Kai Zheng, Yijun Wang, Feng Zhu, Huilin Yang, Wei Xu, Yaozeng Xu & Dechun Geng

ABSTRACT

In glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH), downregulated osteogenic ability and damaged blood supply are two key pathogenic mechanisms. Studies suggested that cannabinoid receptor 2 (CB2) is expressed in bone tissue and it plays a positive role in osteogenesis. However, whether CB2 could enhance bone formation and blood supply in GC-induced ONFH remains unknown. In this study, we focused on the effect of CB2 in GC-induced ONFH and possible mechanisms in vitro and in vivo. By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of CB2 in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms. Micro-CT, histological staining, angiography, calcein labeling, Alizarin red staining (ARS), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) staining, TUNEL staining, migration assay, scratch assay, and tube formation were applied in this study. Our results showed that selective activation of CB2 alleviates GC-induced ONFH. The activation of CB2 strengthened the osteogenic activity of BMSCs under the influence of GCs by promotion of GSK-3β/β-catenin signaling pathway. Furthermore, CB2 promoted HUVECs migration and tube-forming capacities. Our findings indicated that CB2 may serve as a rational new treatment strategy against GC-induced ONFH by osteogenesis activation and maintenance of blood supply.

Evaluation of the neuroprotective effects of methylprednisolone and surgical decompression in a rodent model of traumatic optic neuropathy

AUTHORS

Philippe Korn, Nils-Claudius Gellrich, Simon Spalthoff, Philipp Jehn, Ulf T. Eysel & Martin Zerfowski

ABSTRACT

Purpose of the study

Traumatic optic neuropathy (TON) is a rare but serious consequence of head injuries. The optimal therapy for TON remains controversial, and standardized recommendations are lacking. The most common therapies used are steroid administration and surgical decompression procedures. The aim of the present study was to compare two common conservative and surgical therapies in a rodent model with a standardized traumatic optic nerve lesion.

Materials and Methods

This study employed 59 male Wistar rats. After exposing the optic nerve, defined trauma was exerted on the optic nerve using a micromanipulator to trigger TON. Rats received either “megadose” methylprednisolone applied perioperatively or decompression via nerve sheath fenestration. The number of neurons was histologically evaluated in retinae explanted as whole mounts. Neuronal size was determined histomorphometrically.

Results

Neuronal loss was significantly lower following perioperative “megadose” steroid therapy (p = 0.017), especially in the central retinal area (p = 0.025). Compared to the control group without therapy, on average more than 400 neurons/mm2 were saved. In the central retinal area, more than 600 neurons/mm2 were rescued. In contrast, neuronal loss was not significantly affected by surgical decompression; however, this procedure was associated with a reduction in neuron size (p = 0.003).

Conclusions

The present model revealed significant neuroprotective effects following administration of methylprednisolone for TON treatment. Mitigation of neuronal loss may result in functional benefits. Neuroprotective effects were not observed following surgical therapy, suggesting that this approach should be reserved for individual cases such as hematomas in the area of nerve envelopes.