Extracts from Radix Astragali and Radix Rehmanniae promote keratinocyte proliferation by regulating expression of growth factor receptors.

Chinese herbal medicine has long been used as a treatment for wounds. However, the underlying cellular and molecular mechanisms remain largely unknown. In this study it was shown that the proliferation of keratinocytes, which is known to play an important role in wound healing as the major cell type in the epidermis, was promoted by three herbal extracts/natural compounds: NF3 (an extract from the mixture of Radix Astragali (RA) and Radix Rehmanniae (RR) in the ratio of 2:1), stachyose (an isolated compound from Radix Rehmanniae) and extract P2-2 (a sub-fraction from the extract of Radix Astragali). The effect of the herbal extracts/natural compounds on the growth of keratinocytes was not influenced by a high glucose level, a condition similar to diabetic patients who usually suffer from diabetic foot ulcers. Real time RT-PCR results showed that the expression of epidermal growth factor (EGF) receptor, but not transforming growth factor-ß (TGF-ß) receptor, was up-regulated by NF3. Moreover, treatments with the EGF receptor kinase inhibitor AG1478 and the MEK inhibitor U0126 resulted in the diminishment of the effect of the three herbal extracts/natural compounds on keratinocyte proliferation, indicating that EGF receptor might have a significant role in this action. This study has further elucidated the molecular mechanism under which herbal extracts/natural compounds exert their effects on the wound healing process.

Does Delivery Length Impact Measures of Whole-Body Biomechanical Load During Pace Bowling?

PURPOSE: To investigate whether changes in delivery length (ie, short, good, and full) lead to alterations in whole-body biomechanical loading as determined by ground reaction force during front-foot contact of the delivery stride for pace bowlers. Current load-monitoring practices of pace bowling in cricket assume equivocal biomechanical loading as only the total number of deliveries are monitored irrespective of delivery length. METHODS: A total of 16 male pace bowlers completed a 2-over spell at maximum intensity while targeting different delivery lengths (short, 7-10 m; good, 4-7 m; and full, 0-4 m from the batter's stumps). In-ground force plates were used to determine discrete (vertical and braking force, impulse, and loading rates) and continuous front-foot contact ground reaction force. Repeated-measures analysis of variance (P < .05), effects size, and statistical parametrical mapping were used to determine differences between delivery lengths. RESULTS: There were no significant differences between short, good, and full delivery lengths for the discrete and continuous kinetic variables investigated (P = .19-1.00), with trivial to small effect sizes. CONCLUSION: There were minimal differences in front-foot contact biomechanics for deliveries of different lengths (ie, short, good, and full). These data reinforce current pace bowling load-monitoring practices (ie, counting the number of deliveries), as changes in delivery length do not affect the whole-body biomechanical loading experienced by pace bowlers. This is of practical importance as it retains simplicity in load-monitoring practice that is used widely across different competition levels and ages.

The Effects of an Eight over Cricket Bowling Spell upon Pace Bowling Biomechanics and Performance within Different Delivery Lengths.

Pace bowlers must often perform extended bowling spells with maximal ball release speed (BRS) while targeting different delivery lengths when playing a multi-day match. This study investigated the effect of an eight over spell upon pace bowling biomechanics and performance at different delivery lengths. Nine male bowlers (age = 18.8 ± 1.7 years) completed an eight over spell, while targeting different lengths (short: 7-10 m, good: 4-7 m, full: 0-4 m from the batter's stumps, respectively) in a randomized order. Trunk, knee and shoulder kinematics and ground reaction forces at front foot contact (FFC), as well as run-up velocity and BRS were measured. Paired sample t-tests (p ≤ 0.01), Hedges' g effect sizes, and statistical parametrical mapping were used to assess differences between mean variables from the first and last three overs. No significant differences (p = 0.05-0.98) were found in any discrete or continuous variables, with the magnitude of difference being trivial-to-medium (g = 0.00-0.73) across all variables. Results suggest pace bowlers sustain BRS through a single eight over spell while tolerating the repeatedly high whole-body biomechanical loads as suggested by maintaining the kinematics or technique at the assessed joints during FFC. Practically, the findings are advantageous for bowling performance and support current bowling load monitoring practices.

Design and synthesis of tetracyclic nonpeptidic biaryl nitrile inhibitors of cathepsin K.

The synthesis and biological profile of a novel series of potent and selective inhibitors of cysteine protease cathepsin K (Cat K) are described. Pharmacokinetic evaluation of 12 indicated that some members of this series could be suitable candidates to develop new orally active therapeutic agents for the treatment of osteoporosis.

Identification of metabolites of the tryptase inhibitor CRA-9249: observation of a metabolite derived from an unexpected hydroxylation pathway.

The metabolites of the tryptase inhibitor CRA-9249 were identified after exposure to liver microsomes. CRA-9249 was found to be degraded rapidly in liver microsomes from rabbit, dog, cynomolgus monkey, and human, and less rapidly in microsomes from rat. The key metabolites included cleavage of an aryl ether, in addition to an unexpected hydroxylation of the amide side chain adjacent to the amide nitrogen. The chemical structures of both metabolites were confirmed by synthesis and comparison to material isolated from the liver microsomes. Several suspected hydroxylated metabolites were also synthesized and analyzed as part of the structure identification process.

3,4-disubstituted azetidinones as selective inhibitors of the cysteine protease cathepsin K. Exploring P3 elements for potency and selectivity.

The synthesis of a series of highly potent and selective inhibitors of cathepsin K based on the 3,4-disubstituted azetidin-2-one warhead is reported. A high degree of potency and selectivity was achieved by introducing a basic nitrogen into the distal part of the P3 element of the molecule. Data from kinetic and mass spectrometry experiments are consistent with the interpretation that compounds of this series transiently acylate the sulfhydrile of cathepsin K.