Responses of matrix metalloproteinases to hyperbaric oxygen treatment: changing for good or ill?

Background: Hyperbaric oxygen (HBO2) is currently emerging as a promising therapeutic option for diseases involving impaired tissue repair and remodeling. In this regard, HBO2 has been shown to modulate signaling pathways responsible for matrix metalloproteinases (MMPs) regulation, which makes the MMPs interesting targets for investigation. However, the understanding regarding how HBO2 treatment affects the expression and activity of the MMP family members in different tissues and diseases needs to be clarified. The precise roles of MMPs in the physiopathology of various tissue repair disorders also remain unclear. Because of potential off-target systemic effects of the HBO2 on MMPs, researchers and physicians should carefully consider whether their patients could be affected adversely by HBO2 exposure. Aims: This narrative review provides an overview of MMP biology (structure, function, and regulation) and summarizes available data showing how MMPs respond to HBO2 in different tissues and pathologies, also highlighting possible mechanisms.

Effect of photobiomodulation and exercise on early remodeling of the Achilles tendon in streptozotocin-induced diabetic rats.

The aim of this study was to compare the treatment effects of laser photobiomodulation (LPBM) therapy and aerobic exercise on the biomechanical properties, tissue morphology and the expression of tendon matrix molecules during early remodeling of Achilles tendon (AT) injury in diabetic rats. Animals were randomly assigned to five groups: injured non diabetic (I, n = 15), injured diabetic (ID, n = 15), injured diabetic plus LPBM (IDL, n = 16), injured diabetic plus aerobic exercise (IDE, n = 16) and injured diabetic plus aerobic exercise and LPBM (IDEAL, n = 17). Type 1 diabetes was induced via a single intravenous injection of Streptozotocin at a dose of 40 mg/kg. A partial tenotomy was performed in the right AT. LPBM was performed with an indium-gallium-aluminum-phosphide 660 nm 10 mW laser device (spot size 0.04 cm2, power density 250 mW/cm2, irradiation duration 16 s, energy 0.16 J, energy density 4 J/cm2) on alternate days for a total of 9 sessions over 3 weeks (total energy 1.44 J), using a stationary contact technique to a single point over the dorsal aspect of the AT. Moderate aerobic exercise was performed on a motorized treadmill (velocity 9 m/min for 60 minutes). At 3 weeks post-injury, biomechanical analyzes as well as assessment of fibroblast number and orientation were performed. Collagen 1 (Col1) and 3 (Col3) and matrix metalloproteinases (MMPs) -3 and 13 protein distributions were studied by immunohistochemistry; while Col1 and Col3 and MMP-2 and 9 gene expression were assessed by quantitative RT-PCR (qRT-PCR). IDEAL exhibited significant increases in several biomechanical parameters in comparison to the other groups. Moreover, IDEAL presented stronger Col1 immunoreactivity when compared to ID, and weaker Col3 immunoreactivity than IDE. Both IDL and IDEAL demonstrated weaker expression of MMP-3 in comparison to I, while IDL presented no expression of MMP-13 when compared to ID. ID, IDL and IDE showed an increased number of fibroblasts in comparison to I, while IDEAL decreased the number of these cells in comparison to ID and IDE. IDL and IDEAL groups exhibited decreased angular dispersion among the fibroblasts when compared to I. The gene expression results showed that IDE demonstrated a downregulation in Col1 mRNA expression in comparison to I and ID. IDEAL demonstrated upregulation of Col1 mRNA expression when compared to IDL or IDE alone and increased MMP-2 expression when compared to IDL and IDE. MMP-9 expression was upregulated in IDEAL when compared to I, IDL and IDE. Our results suggest a beneficial interaction of combining both treatment strategies i.e., aerobic exercise and LPBM, on the biomechanical properties, tissue morphology and the expression of matrix molecules in diabetic tendons.

Zinc supplementation reduces RANKL/OPG ratio and prevents bone architecture alterations in ovariectomized and type 1 diabetic rats.

Type 1 diabetes mellitus (T1DM) and estrogen deficiency are associated with several alterations in bone turnover. Zinc (Zn) is required for growth, development, and overall health. Zinc has been used in complementary therapy against bone loss in several diseases. We hypothesized that Zn supplementation represents a potential therapy against severe bone loss induced by the combined effect of estrogen deficiency and T1DM. We evaluated the protective effect of Zn against bone alterations in a chronic model of these disorders. Female Wistar rats were ramdomized into 3 groups (5 rats each): control, OVX/T1DM (ovariectomized rats with streptozotocin-induced T1DM), and OVX/T1DM+Zn (OVX/T1DM plus daily Zn supplementation). Serum biochemical, bone histomorphometric, and molecular analyses were performed. Histomorphometric parameters were similar between the control and OVX/T1DM+Zn groups, suggesting that Zn prevents bone architecture alterations. In contrast, the OVX/T1DM group showed significantly lower trabecular width and bone area as well as greater trabecular separation than the control. The OVX/T1DM and OVX/T1DM+Zn groups had significantly higher serum alkaline phosphatase activity than the control. The supplemented group had higher levels of serum-ionized calcium and phosphorus than the nonsupplemented group. The RANKL/OPG ratio was similar between the control and OVX/T1DM+Zn groups, whereas it was higher in the OVX/T1DM group. In conclusion, Zn supplementation prevents bone alteration in chronic OVX/T1DM rats, as demonstrated by the reduced RANKL/OPG ratio and preservation of bone architecture. The findings may represent a novel therapeutic approach to preventing OVX/T1DM-induced bone alterations.

Exercise training ameliorates matrix metalloproteinases 2 and 9 messenger RNA expression and mitigates adverse left ventricular remodeling in streptozotocin-induced diabetic rats.

BACKGROUND: The aim was to investigate whether exercise training (ExT) would ameliorate expression of key genes for myocardial morphostructure and mitigate adverse left ventricular (LV) remodeling in experimental type 1 diabetes (T1D). METHODS AND RESULTS: Male Wistar rats were divided into four groups: sedentary control (SC, n=9), trained control (TC, n=13), sedentary diabetic (SD, n=20), and trained diabetic (TD, n=17). T1D was induced by 40 mg/kg streptozotocin (single dose, i.v.). Training program consisted of 4-week treadmill running (60 min/day, 5 days/wk). Structure of the LV was evaluated using histomorphometric techniques. Gene expression changes of LV collagens I and III, metalloproteinases (MMPs) 2 and 9, and transforming growth factor-ß1 were detected by reverse transcriptase quantitative polymerase chain reaction. Compared with SC, SD rats presented LV eccentric remodeling, myocyte hypertrophy, and fibrosis, whereas TD animals showed normal LV geometry and collagen content but thinner myocytes. Expression of collagens and type I/III collagen messenger RNA (mRNA) ratio were diminished in diabetic hearts compared with SC. MMP-2 gene was down-regulated in SD, whereas TD group showed decreased MMP-9 mRNA levels and MMP-2 expression comparable to that of SC rats. CONCLUSIONS: Attenuation of MMP-2 down-regulation and reduction in MMP-9 mRNA expression may constitute an underlying mechanism by which ExT counteracts progression of adverse LV remodeling in T1D.

Zinc supplementation reduces RANKL/OPG ratio and prevents bone architecture alterations in ovariectomized and type 1 diabetic rats

Type 1 diabetes mellitus (T1DM) and estrogen deficiency are associated with several alterations in bone turnover. Zinc (Zn) is required for growth, development, and overall health. Zinc has been used in complementary therapy against bone loss in several diseases. We hypothesized that Zn supplementation represents a potential therapy against severe bone loss induced by the combined effect of estrogen deficiency and T1DM. We evaluated the protective effect of Zn against bone alterations in a chronic model of these disorders. Female Wistar rats were ramdomized into 3 groups (5 rats each): control, OVX/T1DM (ovariectomized rats with streptozotocin-induced T1DM), and OVX/T1DM+Zn (OVX/T1DM plus daily Zn supplementation). Serum biochemical, bone histomorphometric, and molecular analyses were performed. Histomorphometric parameters were similar between the control and OVX/T1DM+Zn groups, suggesting that Zn prevents bone architecture alterations. In contrast, the OVX/T1DM group showed significantly lower trabecular width and bone area as well as greater trabecular separation than the control...

Efficacy of simple integrated group rehabilitation program for patients with knee osteoarthritis: Single-blind randomized controlled trial.

UNLABELLED: We investigated the role of an evidence-based integrated group rehabilitation program on the treatment of patients with knee osteoarthritis (KOA). This was a two-group, randomized controlled, 8 wk trial with 41 patients with moderate to very severe KOA. Patients were assigned to an intervention group (IG) or control group (CG). After both groups had received a self-management education program, IG participants underwent a rehabilitation program, including educational aspects about KOA followed by exercises. CG participants received only general health orientation about KOA during this period. The outcome measures were the Lequesne algofunctional index; 36-Item Short Form Health Survey (SF-36); and chair-stand, sit-and-reach, timed up-and-go, and 6-minute walk tests. Analysis of covariance revealed significant postintervention improvements of IG participants compared with CG participants (p < 0.05) on Lequesne total score and pain and function subdomains; SF-36 physical function, role physical, bodily pain, general health, vitality, and role emotional subdomains; and performance assessed by chair-stand, timed up-and-go, and 6-minute walk tests. Focusing on the primary outcome (Lequesne total score), the mean +/- standard deviation after 8 wk was 5.50 +/- 2.98 for the IG and 7.87 +/- 3.48 for the CG (p = 0.009). The corresponding effect size (partial eta squared with 90% confidence interval) was 0.23 (0.04-0.42), indicating a large effect. The presented rehabilitation program reduced pain and improved quality of life and function in patients with KOA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Progressive Collective-exercise Program on the Knee Osteoarthritis; NCT01850862; https://clinicaltrials.gov/ct2/show/NCT01850862?term=NCT01850862&rank=1.

Protein kinase C modulates synaptic vesicle acidification in a ribbon type nerve terminal in the retina.

The driving force for neurotransmitter accumulation into synaptic vesicles is provided by the generation of a transmembrane electrochemical gradient (DeltamicroH+) that has two components: a chemical gradient (DeltapH, inside acidic) and an electrical potential across the vesicular membrane (DeltaPsi, inside positive). This gradient is generated in situ by the electrogenic vacuolar H(+)-ATPase, which is responsible for the acidification and positive membrane potential of the vesicle lumen. Here, we investigate the modulation of vesicle acidification by using the acidic-organelle probe LysoTracker and the pH-sensitive probe LysoSensor at goldfish Mb-type bipolar cell terminals. Since phosphorylation can modulate secretory granule acidification in neuroendocrine cells, we investigated if drugs that affect protein kinases modulate LysoTracker staining of bipolar cell terminals. We find that protein kinase C (PKC) activation induces an increase in LysoTracker-fluorescence. By contrast, protein kinase A (PKA) or calcium/calmodulin kinase II (CaMKII) activation or inhibition did not change LysoTracker-fluorescence. Using a pH-dependent fluorescent dye (LysoSensor) we show that the PKC activation with PMA induces an increase in LysoSensor-fluorescence, whereas the inactive analog 4alpha-PMA was unable to cause the same effect. This increase induced by PMA was blocked by PKC inhibitors, calphostin C and staurosporine. These results suggest that phosphorylation by PKC may increase synaptic vesicle acidification in retinal bipolar cells and therefore has the potential to modulate glutamate concentrations inside synaptic vesicles.