HL156A, an AMP-Activated Protein Kinase Activator, Inhibits Cyst Growth in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disorder. While metformin has demonstrated the ability to inhibit cyst growth in animal models of ADPKD via activation of adenosine monophosphate-activated protein kinase (AMPK), its effectiveness in humans is limited due to its low potency. This study explored the impact of HL156A, a new and more potent AMPK activator, in a mouse model of ADPKD. METHODS: To investigate whether HL156A inhibits the proliferation of renal cyst cells in ADPKD in vitro, exogenous human telomerase reverse transcriptase (hTERT)-immortalized renal cyst cells from ADPKD patients were treated with HL156A, and an MTT (dimethylthiazol-diphenyltetrazolium bromide) assay was performed. To assess the cyst-inhibitory effect of HL156A in vivo, we generated Pkd1 conditional knockout (KO) mice with aquaporin 2 (AQP2)-Cre, which selectively expresses Cre recombinase in the collecting duct. The effectiveness of HL156A in inhibiting cyst growth and improving renal function was confirmed by measuring the number of cysts and blood urea nitrogen (BUN) levels in the collecting duct-specific Pkd1 KO mice. RESULTS: When cyst cells were treated with up to 20 µM of metformin or HL156A, HL156A reduced cell viability by 25% starting at a concentration of 5 µM, whereas metformin showed no effect. When AQP2-Cre male mice were crossed with Pkd1flox/flox female mice, and when AQP2-Cre female mice were crossed with Pkd1flox/flox male mice, the number of litters produced by both groups was comparable. In collecting duct-specific Pkd1 KO mice, HL156A was found to inhibit cyst growth, reducing both the number and size of cysts. Furthermore, it was confirmed that kidney function improved as HL156A treatment led to a reduction in elevated BUN levels. Lastly, it was observed that the increase in AMPK phosphorylation induced by HL156A decreased ERK phosphorylation and α-SMA expression. CONCLUSION: HL156A has potential as a drug that can restore kidney function in ADPKD patients by inhibiting cyst growth.

Combination of Superior and Posterior Capsular Release Versus Superior Capsular Release Alone in Arthroscopic Repair of Large-to-Massive Rotator Cuff Tears.

Background: Superior capsular release has been used to reduce tendon tension, especially in arthroscopic repair of large-to-massive rotator cuff tears. Some clinicians have used a more extensive release of capsules in arthroscopic cuff repair for adequate reduction of torn tendons to footprints. Purpose: To explore the effects of additional posterior capsular release for superior capsular release in arthroscopic repair of large-to-massive rotator cuff tears. Study Design: Cohort study; Level of evidence, 3. Methods: We compared 26 shoulders that underwent superior and posterior capsular release (group S&P) with 26 shoulders that underwent superior capsular release alone (group S) in arthroscopic repair of large-to-massive rotator cuff tears between January 23, 2013 and December 2, 2015. The visual analog scale for pain, American Shoulder and Elbow Surgeons score, Constant score, and range of motion (ROM) and muscle power were checked preoperatively and at 2 years postoperatively. Follow-up ultrasound was checked at 2 years postoperatively. Results: In both groups, the overall mean functional outcomes improved from preoperatively to postoperatively. Patients in group S&P showed more pre- to postoperative improvement than patients in group S with regard to internal rotation ROM (mean difference, 30.0° vs 20.6°; P < .001) and internal rotation power (3.4 vs 1.8 kgf; P = .001). Patients in group S had a higher retear rate on the follow-up ultrasound than patients in group S&P, but this difference did not reach statistical significance (23.1% vs 11.5%, respectively; P = .465). Conclusion: In the current study, patients who underwent superior and posterior capsular release in arthroscopic repair of large-to-massive rotator cuff tears had greater postoperative improvement in internal rotation ROM and power compared with patients who underwent superior capsular release alone.

Protocatechuic acid impacts rotator cuff healing and reduces fatty degeneration in a chronic rotator cuff tear model in rats.

BACKGROUND: The purpose of this study was to verify the effect of protocatechuic acid (PCA) on tendon healing and fatty degeneration in a chronic rotator cuff model. METHODS: Twenty-eight Sprague-Dawley male rats were randomly allocated into two groups: Saline+repair (SR) and PCA+repair (PR). The right shoulder was used for experimental interventions, and the left served as a control. PCA (30 mg/kg/day) was administered intraperitoneally at the site of infraspinatus tendon detachment in rats in the PR group, and the same volume of saline was administered to the same site in the SR group. The torn tendon was repaired 4 weeks after infraspinatus detachment. Four weeks after repair, hematoxylin and eosin (H&E), S100, and CD68 stains were performed to evaluate the degree of fatty degeneration and H&E and Masson trichrome stains were performed to assess tendon healing. Superoxide dismutase (SOD) was measured to test the efficacy of PCA as an antioxidant. RESULTS: Results from histological evaluation indicated that SOD and CD68 levels at the musculotendinous region and collagen fiber parallel to the orientation at the tendon-to-bone junction were not significantly different between the SR and PR groups. The mean load-to-failure of the PR group (20.32±9.37 N) was higher than that of the SR group (16.44±6.90 N), although this difference was not statistically significant (p=0.395). The SOD activity in the operative side infraspinatus muscle of the PR group was higher than that of the SR group, but the difference was not statistically significant (p=0.053). CONCLUSIONS: The use of PCA could improve tendon healing and decrease fatty degeneration after rotator cuff repair.

Comparison of the effectiveness of extensor muscle strengthening exercise by itself, exercise with polydeoxyribonucleotide injection, and exercise with extracorporeal shockwave therapy in lateral epicondylitis: a randomized controlled trial.

BACKGROUND: Extensor muscle strengthening exercises with counterforce braces (EX) is a conventional conservative treatment for lateral epicondylitis (LE) of the elbow. In addition, polydeoxyribonucleotide (PDRN) or extracorporeal shockwave therapy (ESWT) has been recently used for LE. METHODS: Sixty-three patients with chronic LE participated in this study and randomly allocated in three groups (G1: EX, G2: EX+PDRN injection, and G3: EX+ESWT). All of the three groups were taught to perform EX at the first out-patient department (OPD) visit. Group 2 was injected with 3 mL PDRN (5.625 mg/3 mL), while group 3 received ESWT at the first OPD visit. Visual analog scale pain score, Mayo elbow performance score (MEPS), and ultrasonographic examination were checked before, 6 weeks, and 12 weeks after the treatments. RESULTS: Overall functional scores and ultrasonographic findings in all three groups improved after treatment. The mean MEPS in group 2 improved more than groups 1 and 3 at 6 weeks (G1, 56.9>62.4; G2, 54.3>65.0; G3, 55.7>62.6), and more than group 1 at 12 weeks (G1, 56.9>67.9; G2, 54.3>73.6). The mean common extensor tendon depth (CETD) on ultrasonography in group 2 increased more than groups 1 and 3 at 6 and 12 weeks (6 weeks: G1, 0.385>0.386; G2, 0.332>0.392; G3, 0.334>0.357; 12 weeks: G1, 0.385>0.409; G2, 0.332>0.438; G3, 0.334>0.405 [cm]). CONCLUSIONS: PDRN injections combined with EX exhibited a greater improvement in mean MEPS and mean CETD compared to EX only or EX combined with ESWT for LE within the 12 weeks follow-up.