Metabolic Changes Associated With Cardiomyocyte Dedifferentiation Enable Adult Mammalian Cardiac Regeneration.

BACKGROUND: Cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes (CMs). However, certain animals readily regenerate lost myocardium through a process involving dedifferentiation, which unlocks their proliferative capacities. METHODS: We bred mice with inducible, CM-specific expression of the Yamanaka factors, enabling adult CM reprogramming and dedifferentiation in vivo. RESULTS: Two days after induction, adult CMs presented a dedifferentiated phenotype and increased proliferation in vivo. Microarray analysis revealed that upregulation of ketogenesis was central to this process. Adeno-associated virus-driven HMGCS2 overexpression induced ketogenesis in adult CMs and recapitulated CM dedifferentiation and proliferation observed during partial reprogramming. This same phenomenon was found to occur after myocardial infarction, specifically in the border zone tissue, and HMGCS2 knockout mice showed impaired cardiac function and response to injury. Finally, we showed that exogenous HMGCS2 rescues cardiac function after ischemic injury. CONCLUSIONS: Our data demonstrate the importance of HMGCS2-induced ketogenesis as a means to regulate metabolic response to CM injury, thus allowing cell dedifferentiation and proliferation as a regenerative response.

The transdermal performance, pharmacokinetics, and anti-inflammatory pharmacodynamics evaluation of harmine-loaded ethosomes.

Harmine (HAR) is a ß-carboline alkaloid with anti-inflammatory and antipruritic effect. However, the low bioavailability and side effects of HAR severely limited its clinical application. The main objective of this study was to develop harmine-loaded ethosomes (HLE) drug delivery system for topical application to treat inflammation. HLE were obtained by ethanol injection method and characterized. The morphology of HLE was evaluated by transmission electron microscopy (TEM). HLE exhibited a good biocompatibility with human embryonic skin fibroblasts and rat skin. The in vitro skin penetration studies showed that HLE had the greatest skin deposition than harmine-loaded liposomes (HLL) and harmine solution (HS). In vivo pharmacokinetic study demonstrated that AUC(0-∞) and Cmax of HLE in subcutaneous tissues were much higher than that of in blood. Moreover, for convenience of fixing on skin, HLE were mixed with gel. HLE gel significantly inhibited the overexpression of inflammation cytokines prostaglandin E2, interleuking (IL)-1ß, nitric oxide, and tumor necrosis factor-alpha (TNF-α) in the inflammation model of rat paw edema compared with HS gel. In short, HLE was promising formulation for topical delivery in treatment of inflammatory diseases.

Extracts of compound Muniziqi granule suppressed uterus contraction and ameliorated oxytocin-induced primary dysmenorrhea.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Muniziqi granule (CMG) is usually used as a traditional Uighur medicine to treat acne, chloasma, skin inflammation, primary dysmenorrhea (PDM), and menopausal syndrome. However, there are no sufficient data to support the clinic uses of CMG in PDM. AIM OF THE STUDY: This work aims to examine the effect of CMG as a treatment for PDM and reveal its possible therapeutic mechanism. MATERIALS AND METHODS: In vivo and in vitro mouse PDM models were utilized in this study. The mouse uterine contraction was induced by oxytocin after progynova or estradiol benzoate pretreatment. CMG, alkaloid extracts from seeds of Peganum harmala (AEP), and 10% and 95% ethanol extracts from seeds of Nigella glandulifera (EEN10 and EEN95) were given to mice in three doses by gavage. The writhing times within 30 min after oxytocin treatment were recorded to evaluate the analgesic effect, and the glutathione peroxidase (GSH-Px), malondialdehyde (MDA), 6-keto-prostaglandin F1α (6-k-PGF1α), prostaglandin F2α (PGF2α), thromboxane B2 (TXB2), and nitric oxide (NO) levels in uterine tissues and PGF2α and MDA in serum were determined. The effects (contractile curve) of CMG, AEP, EEN10, and EEN95 on uterus contraction induced by oxytocin in isolated mouse uterus were recorded. RESULTS: In contrast to the control group, CMG, AEP, N10, and N95 could display analgesic activities dose dependently by reducing the writhing response of the PDM model mice. CMG, AEP, EEN10, and EEN95 could also remarkably decrease the level of PGF2α, 6-k-PGF1α, TXB2, NO and MDA in uterine tissues and PGF2α and MDA in serum, whereas the activity of GSH-Px in uterine tissues was increased. Furthermore, CMG, AEP, EEN10, and EEN95 could significantly inhibit the frequency and amplitude of isolated uterus induced by oxytocin in a concentration-dependent manner. CONCLUSIONS: CMG exhibited a significant protective effect on experimental PDM. The mechanisms are probably associated with abating lipid peroxidation and over-inflammatory reaction, and alleviating the contraction of isolated mouse uterus. The seeds of P. harmala and N. glandulifera in the CMG may play an important role in exerting protective effects on PDM. This study provides pre-clinic proof to the use of CMG in clinical practice of PDM.

In in vivo evaluation of the anti-inflammatory and analgesic activities of compound Muniziqi granule in experimental animal models.

BACKGROUND: Compound Muniziqi granule (MNZQ), a traditional Uighur medicinal preparation, comprises 13 species of medicinal plants. MNZQ is traditionally used for regulating body immunity, modulating inflammation and pain, detoxification, and inhibiting tumor growth. This study aims to scientifically evaluate the anti-inflammatory and analgesic activities of MNZQ, support its clinical use and further research with scientific evidence. METHODS: The analgesic activity of MNZQ was evaluated using hot plate test and acetic acid-induced abdominal writhing test. Acute inflammation was evaluated using xylene-induced ear edema and carrageenan-induced paw edema models, while chronic inflammation was evaluated using cotton pellet-induced granuloma model. RESULTS: MNZQ exerted analgesic activities with a significant dose-dependent increase in latency in the hot plate test. The percentage inhibition suggested that MNZQ exhibited analgesic activities in the central nervous system. Meanwhile, MNZQ at 0.8, 2.4, and 7.2 g/kg strongly inhibited the acetic acid-induced writhing response by 25.22% (p < 0.01), 44.60% (p < 0.001), and 49.41% (p < 0.001), respectively. MNZQ also exerted analgesic activities in the peripheral nervous system. Moreover, MNZQ was demonstrated a significant anti-inflammatory effect against xylene-induced edema in a dose-dependent manner. The percentage inhibition was 22.24% (p < 0.01) at the highest dosage of 7.2 g/kg. MNZQ at 1.62 and 4.86 g/kg significantly reduced carrageenan-induced rat hind paw edema by 82.43% and 84.32% (p < 0.001), respectively, 1 h after injecting carrageenan, and the inhibitory effect lasted for 5 h. MNZQ also exerted a significant anti-inflammatory effect against cotton pellet-induced granuloma formation. MNZQ at 1.62 and 4.86 g/kg could inhibit granuloma formation by 17.07% and 17.60%, respectively, whereas the percentage inhibition of diclofenac was 33.12%. CONCLUSIONS: The results obtained suggest that MNZQ possesses potential anti-inflammatory and analgesic activities. This study provides a scientific basis for the use of MNZQ in alleviating pain and treating inflammatory disorders.

[Separation and authentication of tilianin and quality standards of semen of Dracocephalum moldavia].

Tilianin was separated and authenticated from the seeds of Dracocephalum moldavia, a Uygur medicine, by chromatographic technique and spectroscopic method. The purity of tilianin is more than 98% determined by HPLC area normalization method. Thin layer chromatography (TLC) method was used to separate tilianin from D. moldavia by mixture of chloroform-methanol (5: 1) as a developing solvent on high performance silicagel precoated plate (SGF254) and using aluminium trichloride as a chromogenic agent for qualitative identification of D. moldavia. To establish a HPLC method for quantitative analysis of D. moldavia, tilianin was used as a Quantitative marker and separated on a C18 (4.6 mm x 250 mm, 5 µm) column with acetonitrile-01% formic acid (25: 75) as the mobile phase and detected at 330 nm. The calibration curve of tilianin displayed ideal linearity over the range of 0.617 2-123.44 µg x mL(-1) with a regression equation of Y = 33.773X - 0.824 8 (r = 1). The average recovery of tilianin was 101.0% with RSD of 3.7%. The RSD values of intra-day and inter-day precision were less than 2%. The content of tilianin in 4 batches of the authenticated semen of D. Moldavia was between 0.016 and 0.187 mg x g(-1). The qualitative and quantitative method established is suitable for the quality evaluation and assessment of semen of D. Moldavia.