Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Bartter′s syndrome(BS) is a rare renal tubular diseases and an autosomal recessive hereditary disease. The characteristic findings are hypokalemia, metabolic alkalosis, and raised serum renin and aldosterone levels. Combination of metabolic syndrome with Bartter′s syndrome has not been reported so far. Here in, we report a case in order to call attention to the diagnosis and treatment of typical Bartter′s syndrome combined with metabolic syndrome.

Nuclear envelope voltages of T cells were analyzed with a lumped circuitry for cells in combination with frequency domain power density of Gaussian pulses and monocycle pulses. According to the differences in geometric and electric parameters between normal and malignant T cells, circuitry analysis was performed. Theoretical evaluations indicated that apoptosis of malignant T cells was of feasibility, which could be applied in cancer therapy. The evaluations were in accord with the published experimental findings.
Animals ; Apoptosis ; radiation effects ; Electric Stimulation ; Electromagnetic Fields ; Electrophysiology ; Fourier Analysis ; Humans ; Jurkat Cells ; Nuclear Envelope ; pathology ; radiation effects ; T-Lymphocytes ; cytology ; radiation effects

Objective To establish the chronic low flow myocardial hibernation animal model in pigs, and to assess the diagnostic value for myocardial hibernation by using various imaging methods. Methods A total of 13 miniswine (30-40 kg) were used. All animals underwent general anesthesia and orotracheal intubation while the animals were mechanically ventilated. Under sterile conditions, left ventriculography and coronary angiography were performed by introduction of catheter into the right femoral artery. Further, a left anterolateral thoracotomy was performed in the third intercostal space. The proximal LCX was dissected free to allow placement of an ameroid constrictor. More than 1 month later, left ventriculography and coronary angiography were performed again, followed by cine MRI at rest and during stress with low dose of dobutamine (5 ?g?kg -1 ?min -1 ), respectively. Traditional and/or breath hold cine MRI were used to evaluate regional left ventricular wall motion, corresponding to basal, midventricular and apical short axis tomograms. Regional wall motion score index (WMSI) was calculated. At the same time 99m Tc MIBI myocardial SPECT was performed at rest and during nitroglycerin administration, respectively. All animals were finally sacrificed for pathological examination. Triphenyl tetrazolium chloride (TTC) staining was used to assess the myocardial infarction. Electron microscopy was used to identify myocardial cellular changes characteristic of hibernating myocardium. Results Three pigs died during surgery or within two weeks after surgery. One pig died of anesthesia during SPECT examination, 1 pig suffered from aneurysm, and another one pig showed negative findings. The other 7 pigs were found with hypokinetic ( n =4) or akinetic ( n =3) myocardial regions related to stenosed LCX (70%-99%). Resting cine MRI demonstrated decreased regional motion of the lateral and posteroinferior walls (ischemic regions) of the left ventricle ( n =7), compared with the nonischemic anteroseptal regions; but the low dose dobutamine (5 ?g?kg -1 ?min -1 ) could recover those hypokinetic or akinetic myocardial regions, characteristic of hibernating myocardium. Resting 99m Tc MIBI myocardial SPECT ( n =6) showed a fixed perfusion defect on the corresponding ischemic areas, which became reversible on the nitrate augmented myocardial perfusion imaging. It also indicated myocardial viability presented at the ischemic areas. TTC staining revealed patchy infarction of the area at risk localized to the endocardial surface ( n =3), and no myocardial infarction ( n =4). Electron microscopy of sections from the hibernating regions revealed loss of contractile materials, increased numbers of small mitochondria, and glycogen accumulation within viable cardiomyocytes, which had been described as hallmarks of hibernating myocardium. Conclusion Chronic low flow myocardial hibernation can be reproduced in an animal model during progressive coronary stenosis caused by ameroid constrictor.