Long-term Outcomes of Endovascular Repair for Blunt Thoracic Aortic Injury: A 10 Year Multi-center Experience.

OBJECTIVE: This study aimed to assess the long-term outcomes in patients treated by thoracic endovascular aortic repair (TEVAR) for blunt thoracic aortic injuries (BTAI). MATERIALS AND METHODS: From January 2010 to December 2019, this retrospective observational study was conducted at 3 centers, involving 62 consecutive BTAI patients who underwent TEVAR. Computed tomography angiography scans were planned to be conducted at 6 months post-procedure, and annually thereafter. RESULTS: Technical success was achieved in all 62 procedures (100%), which included cases of dissection (n=35, 56.45%), pseudoaneurysm (n=20, 32.26%), and rupture (n=7, 11.29%). Mean injury severity score was 31.66±8.30. A total of 21 supra-arch branches were revascularized by chimney technique, with 12 cases involving the left subclavian artery (LSA) and 9 cases involving the left common carotid artery. In addition, 11 LSAs were covered during the procedure. The in-hospital mortality rate was 1.61% (n=1). The mean follow-up time was 86.82±30.58 months. The all-cause follow-up mortality rate was 3.28% (n=2). Stenosis or occlusion of 3 supra-arch branches (4.92%) was identified at follow-up, with 2 cases (3.28%) requiring re-intervention. No spinal cord ischemia, endoleak, or migration was observed. CONCLUSIONS: Despite only including patients with long-term follow-up, this study confirms the long-term safety and effectiveness of TEVAR for BTAI. For young BTAI patients, as the thoracic aorta increases with age, longer follow-up is needed to observe the potential mismatch between the endograft and the aorta. CLINICAL IMPACT: This study confirms the long-term safety and effectiveness of endovascular treatment for blunt thoracic aortic injury (BTAI). For young BTAI patients, as the thoracic aorta increases with age, longer follow-up is needed to observe the potential mismatch between the endograft and the aorta. Through a remarkably extended follow-up period (86.82±30.58 months) conducted at multiple centers in China, this study confirms the long-term safety and effectiveness of endovascular treatment for BTAI.

Rational Design of CoOOH/α-Fe2O3/SnO2 for Boosted Photoelectrochemical Water Oxidation: The Roles of Underneath SnO2 and Surface CoOOH.

Hematite (α-Fe2O3) photoanode is a promising candidate for efficient PEC solar energy conversion. However, the serious charge recombination together with the sluggish water oxidation kinetics of α-Fe2O3 still restricts its practical application in renewable energy systems. In this work, a CoOOH/α-Fe2O3/SnO2 photoanode was fabricated, in which the ultrathin SnO2 underlayer is deposited on the fluorine-doped tin oxide (FTO) substrate, α-Fe2O3 nanorod array is the absorber layer, and CoOOH nanosheet is the surface modifier, respectively. The resulting CoOOH/α-Fe2O3/SnO2 exhibited excellent PEC water splitting with a high photocurrent density of 2.05 mA cm-2 at 1.23 V vs RHE in the alkaline electrolyte, which is ca. 3.25 times that of bare α-Fe2O3. PEC characterizations demonstrated that SnO2 not only could block hole transport from α-Fe2O3 to FTO substrate but also could efficiently enhance the light-harvesting property and reduce the surface states by controlling the growth process of α-Fe2O3, while the CoOOH overlayer as cocatalysts could rapidly extract the photogenerated holes and provide catalytic active sites for water oxidation. Benefiting from the synergistic effects of SnO2 and CoOOH, the efficiency of the charge recombination and the overpotential for water oxidation of α-Fe2O3 are obviously decreased, resulting in the boosted PEC efficiency for water oxidation. The rational design and simple fabrication strategy display great potentials to be used for other PEC systems with excellent efficiency.

Pristimerin protects against pathological cardiac hypertrophy through improvement of PPARα pathway.

Pristimerin (PM), serving as a biological component mainly obtained from Celastraceae and Hippocrateaceae families, has been extensively explored for its numerous pharmacological activities, especially anti-cancer activity. However, the function of PM on pathological cardiac hypertrophy is poorly understood. This work was intended to investigate the effects of PM on pressure-overload induced myocardial hypertrophy and its potential pathways. Mouse model of pathological cardiac hypertrophy was generated by transverse aortic constriction (TAC) or minipump administration of the ß-adrenergic agonist ISO for 4 weeks, and PM (0.5 mg/Kg/d, i.p.) was treated for 2 weeks. PPARα-/- mice received TAC surgery were used for mechanism exploration. Moreover, neonatal rat cardiomyocytes (NRCMs) were utilized to explore the effect of PM following Angiotensin II (Ang II, 1.0 µM) administration. We found that PM attenuated pressure-overload induced cardiac dysfunction, myocardial hypertrophy and fibrosis in mice. Likewise, PM incubation dramatically reversed Ang II-mediated cardiomyocytes hypertrophy in NRCMs. RNA-Sequence showed that PM selectively contributed to improvement of PPARα/PGC1 signaling, while silencing PPARα abrogated the beneficial effects of PM on Ang II-treated NRCMs. Importantly, PM ameliorated Ang II-induced mitochondrial dysfunction and decrease in metabolic genes, whereas knockdown of PPARα eliminated these alterations in NRCMs. Similarly, PM presented limited protective effects on pressure-overload induced systolic dysfunction and myocardial hypertrophy in PPARα deficient mice. Overall, this study revealed that PM exerted protective activity against pathological cardiac hypertrophy through improvement of PPARα/PGC1 pathway.

In Vitro Studies on Hemodynamics of Type B Aortic Dissection: Accuracy and Reliability.

CLINICAL IMPACT: 1. Hemodynamic of TBAD is important to improve the long-term outcome of TEVAR.2. This review provides an overview of the in-vitro for the hemodynamic study of TBAD.3. The accuracy and validity of in-vitro TBAD experiments should be further studied.

The Role of Location, Length, and Thickness of the Intimal Flap in the Propagation of Stanford Type B Aortic Dissection Based on Ex Vivo Porcine Aorta Models.

PURPOSE: To explore the role of location, length, and thickness of the intimal flap in the propagation of Stanford type B aortic dissection (TBAD) based on ex vivo porcine aorta models based on ex vivo porcine aorta models. MATERIALS AND METHODS: The porcine aortas were harvested and randomly divided into 6 groups to create various TBAD aortic models. We constructed intimal flaps for different locations (group A [entry tear on outer curvature] and group B [entry tear on inner curvature]), lengths (group C [long] and group D [short]), and thicknesses (group E [thick] and group F [thin]). For the ex vivo perfusion experiments conducted on model aortas, an experimental circulation loop (ECL) was employed. The pressure in false lumen (FL) was constantly monitored. A comparison was made between the morphological data collected before and after the experiment to quantify the changes in the FL after the experiment. RESULTS: Compared the results with group B, the mean peak pressures of the FL in group A were lower (106.87±15.55 vs. 124.01±22.75 mm Hg, p=0.028). The mean axial propagation length in group A was shown to be shorter than that of group B (88.14±33.38 vs. 197.43±41.65 mm, p<0.001). The mean peak pressure was higher in group C than in group D (144.04±19.37 vs. 92.51±26.70 mm Hg, p<0.001). The mean peak pressure of group E was higher than that of group F (160.83±32.83 vs. 109.33±15.62 mm Hg, p<0.001), as was the mean axial propagation length of group E (143.11±39.73 vs. 100.45±35.44 mm, p=0.021). According to the results of multivariable linear regression, axial propagation length=45.873-0.703×length of initial FL+0.863× peak pressure (p<0.001). CONCLUSION: There was a relationship between FL propagation and the location, length, and thickness of the intimal flap. The axial propagation length was related to the length of the intimal flap and the peak pressure of propagation. It may be helpful to evaluate the risk of propagation in patients with TBAD. CLINICAL IMPACT: This study found that the locations, lengths, and thickness of the intimal flap significantly contributed to propagation pressure of FL. Using dissection flap characteristics, a physician can predict FL development in a patient and formulate a treatment plan.The purpose was to investigate the relationship between the dissection flap characteristics (location, length, and thickness) and the propagation of the FL, which is not clear at present. This study employed porcine models to create an experimental circulation loop. The perfusion experiment was conducted using a FL without distal re-entry and a non-pulsating flow.

Risk Factors Associated with Poor Prognosis in Patients with Stanford Type B Aortic Dissection after Thoracic Endovascular Aortic Repair.

BACKGROUND: The aim of the study was to analyze the clinical characteristics of patients with Stanford type B aortic dissection (TBAD) and risk factors for poor prognosis after thoracic endovascular aortic repair (TEVAR). METHODS: Clinical records for patients with TBAD presenting to a medical center between March 1, 2012 and July 31, 2020 were reviewed. Clinical data including demographics, comorbidities, and postoperative complications were obtained from electronic medical records. Comparative analysis and subgroup analysis were performed. A logistic regression model was used to analyze prognostic factors in patients with TBAD after TEVAR. RESULTS: TEVAR was performed on all 170 patients with TBAD, and poor prognosis was identified in 28.2% (48/170) of cases. Patients with a poor prognosis were younger (38.5 [32.0, 53.8] years vs. 55.0 [48.0, 62.0] years, P < 0.001), had higher systolic blood pressure (SBP) (138.5 [127.8, 152.8] mm Hg vs. 132.0 [120.8, 145.3] mm Hg, P = 0.013) and more complicated aortic dissection patients (19 [60.4] vs. 71 [41.8], P = 0.029) than those without a poor prognosis. According to the results of binary logic regression analysis, the possibility of a poor prognosis after TEVAR decreased with each 10 years increase in age (odds ratio: 0.464, 95% confidence interval: 0.327-0.658, P < 0.001). CONCLUSIONS: There is an association between younger age and a poor prognosis after TEVAR in patients with TBAD, with the condition that those with poor prognoses have higher SBP and more complicated cases. In younger patients, postoperative follow-up should be more frequent, and complications should be managed in time.

Angioplasty for Supra-Aortic Arterial Lesions from Takayasu Arteritis: Efficacy of Cutting Balloon Angioplasty Versus Conventional Balloon Angioplasty.

BACKGROUND: This retrospective study aimed to evaluate the safety and efficacy of cutting balloon angioplasty and conventional balloon angioplasty in supra-aortic arterial lesions caused by Takayasu arteritis. METHODS: A total of 46 patients with supra-aortic arterial lesions between January 2011 and December 2018 were included. Cutting balloon angioplasty was applied for 17 patients with 24 supra-aortic arterial lesions (group A), while 29 patients with 36 supra-aortic arterial lesions received conventional balloon angioplasty (group B). The preoperative clinical manifestation, operation result, and postoperative outcomes were recorded and compared in the 2 groups. RESULTS: Dizziness, visual disturbance, and unequal/absent pulses were the most common manifestations. The technical success of revascularization was 93.5% (43/46) in patients and 93.3% (56/60) in lesions. The stent implantation rate in group A was significantly lower than that in group B (4.2% vs. 50% in lesions, P < 0.05). Restenosis was the most common complication in both groups. Although the early (≤30 days) and late (>30 days) complications in group A were less than those in group B, there was no significant difference between the 2 groups (P > 0.05). Moreover, the primary-assisted patency of cutting balloon angioplasty and conventional balloon angioplasty at 1, 2, and 5 years were 66.7%, 62.5%, and 62.5% and 61.1%, 58.2%, and 49.8%, there was no significant difference between the 2 groups (P > 0.05), respectively. CONCLUSIONS: Compared with conventional balloon angioplasty, cutting balloon angioplasty could be considered a safe and effective alternative for supra-aortic arterial lesions caused by Takayasu arteritis, demonstrating better patency and clinical benefit.

False Lumen Stent-Grafts for Repair of Postdissection Aortic Aneurysms.

PURPOSE: To evaluate the safety and efficacy of false lumen (FL) stent-grafts in the treatment of postdissection aortic aneurysms. MATERIALS AND METHODS: Eleven patients who underwent endovascular repair using FL stent-grafts from January 2016 to June 2019 were included. Among them, 2 patients had a prior history of type A aortic dissection, whereas 9 had undergone a prior endovascular repair for type B aortic dissection. Computed tomography angiography was performed to evaluate the reintervention and technical success rate, aortic remodeling, and other related aortic complications. RESULTS: The mean age of patients was 55.6 ± 10.4 years. Technical success was achieved in all patients, and neither early mortality nor paralysis occurred. In total, 8 visceral branch arteries originating from the FL were reconstructed. The true lumen areas at the celiac axis, superior mesenteric artery, renal artery, and abdominal aortic bifurcation were significantly increased from 230.1 mm2 to 312.3 mm2, 212.1 mm2 to 277.5 mm2, 209.1 mm2 to 291.6 mm2, and 214.4 mm2 to 300.6 mm2, respectively (P < .05). The total diameter of the aorta at the 4 designated levels was stable or had shrunk in all patients. At a mean follow-up of 18.9 ± 7.6 months, 1 patient received re-intervention owing to iliac stent-graft occlusion. No aortic-related mortality occurred. CONCLUSIONS: FL stent-grafts can safely and effectively treat patients with postdissection aortic aneurysms. This strategy can be used to promote thrombosis of the FL and aortic remodeling. A larger sample and an extended follow-up period are needed to produce more conclusive results.

Physician-Modified Branched Double-Trunk Stent-Graft (PBDS) for Thoracoabdominal Aortic Aneurysm.

PURPOSE: To describe the preliminary experience of using physician-modified, branched, double-trunk stent-grafts (PBDS) for treating thoracoabdominal aortic aneurysms (TAAA). MATERIALS AND METHODS: Ten (10) patients with TAAA were included in the study from June 2017 to March 2020. The technical success, perioperative complications, re-intervention, and patency of branch arteries were assessed. RESULTS: The technical success rate was 100%. There were four type III endoleaks (40%) recorded in the perioperative period. The median follow-up was 13.4 months (range, 3-36 months). During follow-up, two renal stent-graft occlusions (2 of 37 visceral arteries reconstructed, 5.4%), one cerebral infarction (1 of 10, 10%) and one paraplegia (1 of 10, 10%) occurred. No aortic-related death was recorded. CONCLUSION: PBDS is useful in sealing TAAA and preventing visceral branches, providing an option for patients unsuited for open surgical repair. A larger sample size of patients is required to confirm the safety and effectiveness of this technique.

Real-Time Monitoring of 13C- and 18O-Isotopes of Human Breath CO2 Using a Mid-Infrared Hollow Waveguide Gas Sensor.

Real-time measuring of CO2 isotopes (13CO2, 12CO2, and 18OC16O) in exhaled breath using a mid-infrared hollow waveguide gas sensor incorporating a 2.73 µm distributed feedback laser was proposed and demonstrated for the first time based on calibration-free wavelength modulation spectroscopy. The measurement precisions for δ13C and δ18O were, respectively, 0.26 and 0.57‰ for an integration time of 131 s by Allan variance analysis. These measurement precisions achieved in the present work were at least 3.5 times better than those reported using direct absorption spectroscopy and 1.3 times better than those obtained by calibration-needed wavelength modulation absorption spectroscopy. Continuous measurement of three isotopes in the breathing cycle was performed. Alveolar gas from the expirogram was identified, and the 13C/12C and 18O/16O ratios were found to be almost constant during the alveolar plateau, which enables optimization of breath sampling and provides accurate information on metabolic processes. The 13C/12C and 18O/16O isotope ratios at the alveolar plateau of five breath cycles were averaged, yielding δ13C and δ18O values of (-24.3 ± 3.4) and (-30.7 ± 2.6) ‰, respectively. This study demonstrates the feasibility of real-time analysis of 13C- and 18O-isotopes of human breath CO2 in clinical applications and shows its potential for diagnosing respiratory-related diseases with high sensitivity, selectivity, and specificity.

RADICLELESS 1 (RL1)-mediated nad4 intron 1 splicing is crucial for embryo and endosperm development in rice (Oryza sativa L.).

Pentatricopeptide repeat (PPR) proteins are one of the largest protein families in land plants. PPR proteins exhibit sequence-specific RNA-binding activity and are implicated in plant growth and development related processes. In this study, we report that the radicleless 1 (rl1) mutant in rice (Oryza sativa L.) exhibited defective radicle emergence in embryos and compromised grain filling in endosperms. Gene cloning and confirmation via genetic complementation analyses showed that RL1 encodes a P-type PPR protein, which is localized to mitochondria. The RL1 protein was specifically involved in the splicing of intron 1 of the mitochondrial nad4 transcript, which encodes a subunit of the mitochondrial NADH dehydrogenase complex. Consistent with this observation, the rl1 mutant exhibited altered mitochondrial morphology and lower ATP accumulation compared with the wild type. Thus, our findings suggest that RL1-mediated nad4 splicing is crucial for embryo and endosperm development in rice.

Polyphyllin I activates AMPK to suppress the growth of non-small-cell lung cancer via induction of autophagy.

Polyphyllin I (PPI), a bioactive constituent extracted from the rhizomes of Paris polyphylla, is cytotoxic to several cancer types. This study was designed to explore whether PPI prevents non-small-cell lung cancer (NSCLC) growth and to investigate the molecular mechanism. AMP-activated protein kinase (AMPK) has been implicated in the activation of autophagy in distinct tissues. In cultured human NSCLC cell lines, PPI induces autophagy by activating AMPK and then inhibiting mTOR signaling in a concentration-dependent manner. Furthermore, the activation of autophagy induced by PPI was reversed by the AMPK inhibitor compound C. Computational docking showed that PPI directly interacted with the allosteric drug and metabolite site of AMPK to stabilize its activation. Microscale thermophoresis and Drug Affinity Responsive Targeting Stability (DARTS) assay further confirmed the high affinity between PPI and AMPK. In vivo studies indicated that PPI suppressed the growth of NSCLC and increased the levels of LC3-II and phosphorylated AMPK in tumors isolated from a xenograft model of NSCLC in mice. Moreover, PPI exhibited favorable pharmacokinetics in rats. In summary, PPI conclusively acts as a direct AMPK activator to induce cell autophagy which inhibits the growth of NSCLC cells. In the future, PPI therapy should be applied to treat patients with NSCLC.

Endovascular Treatment of Distal False Lumen Aneurysmal Expansion in Chronic Type B Aortic Dissection with True Lumen Occlusion.

Aneurysmal degeneration of distal false lumen after primary endovascular exclusion or open replacement of the proximal entry tear was not rare. Currently, no endovascular reintervention techniques have been established for this condition because of its pathological complexity, especially when the true lumen is severely stenosed or even occluded. In this report, we presented a case of chronic type B aortic dissection, whose false lumen of the abdominal aorta significantly expanded and true lumen occluded after the primary endovascular treatment of the proximal entry tear. Therefore, this-time endovascular treatment reconstructed the renal artery and lower limb artery through the false lumen. The 3-year follow-up computed tomography angiography confirmed that the reconstructed renal artery was patent and no endoleak was detected. Complete thrombosis and shrink of the aneurysmal false lumen were confirmed. Thus, endovascular treatment could be a feasible strategy for this subset of patients.

Endovascular Reconstruction from Aortic Valve to Aortic Arch Using One-Piece Valved-Fenestrated Stent Graft with a Branch: A Proof-of-Concept Study.

OBJECTIVE: To explore the feasibility of endovascular reconstruction of aortic root including aortic valve, sinus of valsalva and ascending aorta by a single stent-graft, a novel valved stent-graft with two fenestrae for preserving the coronary arteries was designed and performed in-vitro on a pig heart based circulation simulating system. METHODS: Pig hearts were harvested from 30 healthy adult female pigs weighing between 60-65 kilograms. Before sacrifice, all the pigs received aortic computed tomography angiography (CTA) examinations and morphologic parameters of aortic root were measured. Then we customized the valved stent-grafts according to the CTA measurements. After the pig heart was fixed on the special platform according to the original orientation and connected to the circulation system, the stent graft was delivered through transapical access and covered the segment from aortic annulus to proximal part of aortic arch under DSA (digital subtraction angiography) guidance. Then changes of coronary flow before and after the procedure and fenestration alignment with coronary ostia were analyzed. RESULTS: The overall technical success rate was 100%. The valve functions tested by ultrasound were in good condition under 120 mmHg circulation pressure. The flow of left coronary artery (LCA) did not decrease, but increased after the stent-graft implantation (340 ± 2.06 mL/min versus 288 ± 5.29 mL/min, P < .05). Similarly, the flow of right coronary artery (RCA) also increased (392 ± 9.17 mL/min versus 348 ± 8.01 mL/min; P < .05). The final angiography confirmed that both coronary arteries were patent. When generally observed from outer wall of valsalva sinus, both RCA and LCA orifices were aligned with the fenestrae. In 4 cases, the autologous valve leaflets blocked nearly 20% of the LCA fenestra's area, but the flow did not significantly decrease in these cases. CONCLUSION: Stimulated on a pig heart-based circulation simulation system, the one-piece valved-fenestrated stent graft with a branch could be delivered via the transapical access and deployed accurately, which achieved endovascular reconstruction of aortic valve, sinus of valsalva and ascending aorta while preserving the coronary artery perfusion by fenestrations. More in-vivo experiments on animal models are mandatory to further verify its efficacy and safety.

Performance of laser inter-satellite links with dynamic beam waist adjustment.

In this paper, we propose the idea of dynamic beam waist adjustment for laser inter-satellite communications, and study the performance of this dynamic-beam scheme. The beam waist adjustment is based on continuous detection of the instantaneous pointing error angle, which is performed at the transmitter side. Using a square to approximate the circular detector region, we obtain a closed-form expression for calculating the proportion of power that can be collected by the receiver aperture, and derive a simple algebraic solution for the optimum dynamic beam waist. Due to its simple form, the dynamic beam waist value can be computed in real time at the transmitter, and therefore, the adjustment is practically implementable. It is shown that the performance of laser inter-satellite links with dynamic beam waist is better than that with fixed beam waist.

Simulating binocular vision for no-reference 3D visual quality measurement.

Perceptual quality measurement of three-dimensional (3D) visual signals has become a fundamental challenge in 3D imaging fields. This paper proposes a novel no-reference (NR) 3D visual quality measurement (VQM) metric that uses simulations of the primary visual cortex (V1) of binocular vision. As the major technical contribution of this study, perceptual properties of simple and complex cells are considered for NR 3D-VQM. More specifically, the metric simulates the receptive fields of simple cells (one class of V1 neurons) using Gaussian derivative functions, and the receptive fields of complex cells (the other class of V1 neurons) using disparity energy responses and binocular rivalry responses. Subsequently, various quality-aware features are extracted from the primary visual cortex; these will change in the presence of distortions. Finally, those features are mapped to the subjective quality score of the distorted 3D visual signal by using support vector regression (SVR). Experiments on two publicly available 3D databases confirm the effectiveness of our proposed metric, compared to the relevant full-reference (FR) and NR metrics.

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations.

Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q(2) (cross-validated correlation coefficient) = 0.557, R(2)ncv (non-cross-validated correlation coefficient) = 0.740, R(2)pre (predicted correlation coefficient) = 0.749 and Q(2) = 0.598, R(2)ncv = 0.767, R(2)pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.

Effect of shikonin on multidrug resistance in HepG2: The role of SIRT1.

CONTEXT: Overexpression of SIRT1 is considered to enhance the resistance of HepG2 cells to irradiation. Shikonin, a naturally occurring naphthoquinone compound, displays anticancer effects and circumvents cancer drug resistance. OBJECTIVES: This study investigated the MDR reversal effect of shikonin induced by the overexpression of SIRT1. MATERIALS AND METHODS: The overexpression of SIRT1 in HepG2 cells was established by lentivirus infection. Five days after transduction, real-time quantitative polymerase chain reaction and western blotting were used to detect the expression of SIRT1 and MDR1/P-gp. Drug resistance was also evaluated by flow cytometry after rhodamine-123 staining. On day 5, the multidrug resistance cells were treated by shikonin (10(-7), 10(-6), and 10(-5) µmol/L) one time. The cell viability was detected by the MTT assay, and apoptosis was evaluated by Hoechst 33342 staining and caspase-3 activity 24 h after shikonin treatment. RESULTS: Overexpression of SIRT1 decreased rhodamine-123 staining and successfully produced the R-HepG2 cell line. Compared with HepG2, the expression of MDR1/P-gp mRNA (3.45 ± 0.35) and protein (1.40 ± 0.05) were both upregulated in R-HepG2. Shikonin inhibited cell viability (from 93.9 ± 2.1 to 66.7 ± 1.5%), induced apoptosis of R-HepG2 (apoptotic ratio from 3.5 ± 0.8 to 47.5 ± 2.7%, caspase-3 activity from 103.5 ± 1.9 to 329.2 ± 14.9%, respectively), downregulated the mRNA and protein expression of SIRT1 and MDR1/P-gp, and decreased rhodamin 123 efflux. DISCUSSION AND CONCLUSION: In the present study, we demonstrated that shikonin is able to overcome drug resistance in hepatocellular carcinoma cells, and the mechanism is related to the SIRT1-MDR1/P-gp signaling pathway.

Profiling the interaction mechanism of quinoline/quinazoline derivatives as MCHR1 antagonists: an in silico method.

Melanin concentrating hormone receptor 1 (MCHR1), a crucial regulator of energy homeostasis involved in the control of feeding and energy metabolism, is a promising target for treatment of obesity. In the present work, the up-to-date largest set of 181 quinoline/quinazoline derivatives as MCHR1 antagonists was subjected to both ligand- and receptor-based three-dimensional quantitative structure-activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The optimal predictable CoMSIA model exhibited significant validity with the cross-validated correlation coefficient (Q²) = 0.509, non-cross-validated correlation coefficient (R²(ncv)) = 0.841 and the predicted correlation coefficient (R²(pred)) = 0.745. In addition, docking studies and molecular dynamics (MD) simulations were carried out for further elucidation of the binding modes of MCHR1 antagonists. MD simulations in both water and lipid bilayer systems were performed. We hope that the obtained models and information may help to provide an insight into the interaction mechanism of MCHR1 antagonists and facilitate the design and optimization of novel antagonists as anti-obesity agents.