Anticancer activity of 8-hydroxyquinoline-triphenylphosphine rhodium(III) complexes targeting mitophagy pathways.

Metallodrugs exhibiting distinct mechanisms of action compared with cisplatin hold promise for overcoming cisplatin resistance and improving the efficacy of anticancer drugs. In this study, a new series of rhodium (Rh)(III) complexes containing tris(triphenylphosphine)rhodium(I) chloride [(TPP)3RhCl] (TPP = triphenylphosphine, TPP=O = triphenylphosphine oxide) and 8-hydroxyquinoline derivatives (H-XR1-H-XR4), namely [Rh(XR1)2(TPP)Cl]·(TPP=O) (Yulin Normal University-1a [YNU-1a]), [Rh(XR2)2(TPP)Cl] (YNU-1b), [Rh(XR3)2(TPP)Cl] (YNU-1c), and [Rh(XR4)2(TPP)Cl] (YNU-1d), was synthesized and characterized via X-ray diffraction, mass spectrometry and IR. The cytotoxicity of the compounds YNU-1a-YNU-1d in Hep-G2 and HCC1806 human cancer cell lines and normal HL-7702 cell line was evaluated. YNU-1c exhibited cytotoxicity and selectivity in HCC1806 cells (IC50 = 0.13 ± 0.06 µM, selectivity factor (SF) = 384.6). The compounds YNU-1b and YNU-1c, which were selected for mechanistic studies, induced the activation of apoptotic pathways and mitophagy. In addition, these compounds released cytochrome c, cleaved caspase-3/pro-caspase-3 and downregulated the levels of mitochondrial respiratory chain complexes I/IV (M1 and M4) and ATP. The compound YNU-1c, which was selected for in vivo experiments, exhibited tumor growth inhibition (58.9 %). Importantly, hematoxylin and eosin staining and TUNEL revealed that HCC1806 tumor tissues exhibited significant apoptotic characteristics. YNU-1a-YNU-1d compounds are promising drug candidates that can be used to overcome cisplatin resistance.

Synthesis and anticancer mechanisms of four novel platinum(II) 4'-substituted-2,2':6',2''-terpyridine complexes.

Mitophagy, a selective autophagic process, has emerged as a pathway involved in degrading dysfunctional mitochondria. Herein, new platinum(II)-based chemotherapeutics with mitophagy-targeting properties are proposed. Four novel binuclear anticancer Pt(II) complexes with 4'-substituted-2,2':6',2''-terpyridine derivatives (tpy1-tpy4), i.e., [Pt2(tpy1)(DMSO)2Cl4]·CH3OH (tpy1Pt), [Pt(tpy2)Cl][Pt(DMSO)Cl3]·CH3COCH3 (tpy2Pt), [Pt(tpy3)Cl][Pt(DMSO)Cl3] (tpy3Pt), and [Pt(tpy4)Cl]Cl·CH3OH (tpy4Pt), were designed and prepared. Moreover, their potential antitumor mechanism was studied. Tpy1Pt-tpy4Pt exhibited more selective cytotoxicity against cisplatin-resistant SK-OV-3/DDP (SKO3cisR) cancer cells compared with those against ovarian SK-OV-3 (SKO3) cancer cells and normal HL-7702 liver (H702) cells. This selective cytotoxicity of Tpy1Pt-tpy4Pt was better than that of its ligands (i.e., tpy1-tpy4), the clinical drug cisplatin, and cis-Pt(DMSO)2Cl2. The results of various experiments indicated that tpy1Pt and tpy2Pt kill SKO3cisR cancer cells via a mitophagy pathway, which involves the disruption of the mitophagy-related protein expression, dissipation of the mitochondrial membrane potential, elevation of the [Ca2+] and reactive oxygen species levels, promotion of mitochondrial DNA damage, and reduction in the adenosine triphosphate and mitochondrial respiratory chain levels. Furthermore, in vivo experiments indicated that the dinuclear anticancer Pt(II) coordination compound (tpy1Pt) has remarkable therapeutic efficiency (ca. 52.4%) and almost no toxicity. Therefore, the new 4'-substituted-2,2':6',2''-terpyridine Pt(II) coordination compound (tpy1Pt) is a potential candidate for next-generation mitophagy-targeting dinuclear Pt(II)-based anticancer drugs.

Antitumor studies evaluation of triphenylphosphine ruthenium complexes with 5,7-dihalo-substituted-8-quinolinoline targeting mitophagy pathways.

Both ruthenium-containing complexes and 8-quinolinoline compounds have emerged as a potential novel agent for malignant tumor therapy. Here, three triphenylphosphine ruthenium complexes, [Ru(ZW1)(PPh3)2Cl2] (PPh3 = triphenylphosphine) (RuZ1), [Ru(ZW2)(PPh3)2Cl2] (RuZ2) and [Ru(ZW2)2(PPh3)Cl2]·CH2Cl2 (RuZ3) bearing 5,7-dichloro-8-quinolinol (H-ZW1) and 5,7-dichloro-8-hydroxyquinaldine (H-ZW2), have been synthesized, characterized and tested for their anticancer potential. We showed that triphenylphosphine ruthenium complexes RuZ1-RuZ3 impaired the cell viability of ovarian adenocarcinoma cisplatin-resistant SK-OV-3/DDP (SKO3CR) and SK-OV-3 (SKO3) cancer cells with greater selectivity and specificity than cisplatin. In addition, RuZ1-RuZ3 show higher excellent cytotoxicity than cisplatin towards SKO3CR cells, with IC50 values of 9.66 ± 1.08, 4.05 ± 0.67 and 7.18 ± 0.40 µM, respectively, in which the SKO3CR cells was the most sensitive to RuZ1-RuZ3. Depending on the substituent type, the antiproliferative ability of RuZ1-RuZ3 followed the trend: -CH3 > -H. However, RuZ1-RuZ3 have no obvious toxicity to normal cell HL-7702. Besides, RuZ1 and RuZ2 could induce mitophagy related-apoptosis pathways through suppression of mitochondrial membrane potential (ΔΨm), accumulation of [Ca2+] and reactive oxygen species (ROS), and regulation of LC3 II/LC3 I, Beclin-1, P62, FUNDC1, PINK1, Parkin, cleaved-caspase-3, caspase-9 and cytochrome c signaling pathway, and hindering the preparation of mitochondrial respiration complexes I and IV and ATP levels. Mechanistic study revealed that RuZ1 and RuZ2 induce apoptosis in SKO3CR cells via mitophagy related-apoptosis pathways induction and energy (ATP) generation disturbance. Taken together, the studied triphenylphosphine ruthenium complexes RuZ1-RuZ3 are promising chemotherapeutic agents with high effectiveness and low toxicity.

Elementary school comprehensive intervention and myopia development: the Wenzhou Epidemiology of Refraction Error Study.

AIM: To investigate the effects of school-based comprehensive intervention on myopia development in elementary school children. METHODS: As a part of the Wenzhou Epidemiology of Refraction Error Study, there were 1524 participating elementary students (730 girls, 47.9%) in grades 1 to 3 from three campuses of one school, aged 7.3±0.9y, who were examined twice every year for a 2.5y follow up period. Comprehensive intervention and other reminders were given at school every semester for the intervention group. The control group did not receive comprehensive intervention and did not have reminders of it. RESULTS: There were 651 students in the intervention group [mean age 7.3±0.9y; 294 (45.2%) girls] and 737 students in the control group [mean age 7.2±0.9y; 346 (46.9%) girls]. Overall mean myopia progression during the 2.5y follow-up was -0.49±1.04 diopters (D) in the intervention group and -0.65±1.08 D in the control group (P=0.004). The majority that not get myopia at baseline spherical equivalent (SE≤-1.0 D). Their mean myopia progression during the 2.5y follow-up was -0.37±0.89 D in the intervention group and -0.51±0.93 D in the control group (27.5% reduction, P=0.009); Overall, mean axial length elongation was less in the intervention group (0.56±0.32 mm) than in the control group (0.61±0.38 mm, 10.5% reduction, P=0.009). The percentage of close reading distance (<30 cm) in the intervention group was less than in the control group (73.4% vs 76.2%, P<0.001), the percentage of everyday perform eye exercises in the intervention group was more than in the control group (27.8% vs 20.7%, P<0.001) 30mo later. CONCLUSION: The comprehensive intervention program at elementary school has a significant alleviating effect on myopia progression for children during the 2.5y follow-up, especially for those non-myopia at baseline.

Phytochemical constituents of Camellia osmantha fruit cores with antithrombotic activity.

Camellia osmantha is a new species of the genus Camellia and is an economically important ornamental plant. Its activity and ingredients are less studied than other Camellia plants. This study investigated the antithrombotic effect and chemical components of C. osmantha fruit cores using platelet aggregation assays and coagulation function tests. The cores of C. osmantha fruits were extracted with ethanol to obtain a crude extract. The extract was dissolved in water and further eluted with different concentrations of methanol on an MCI resin column to obtain three fractions. These samples were used for antithrombotic activity tests and phytochemical analysis. The results showed that the extract and its fractions of C. osmantha have strong antithrombotic activity, significantly reducing the platelet aggregation rate and prolonging the thrombin time (TT). The total saponins, flavonoids, and polyphenols in the active fractions may be responsible for the antithrombotic activity. The chemical constituents were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS). Twenty-three compounds were identified rapidly and accurately. Among them, ellagic acid, naringenin, and quercetin 3-O-glucuronide may be important antithrombotic constituents. Furthermore, interactions between these compounds and the P2Y1 receptor were investigated via molecular modeling, because the P2Y1 receptor is a key drug target of antiplatelet aggregative activity. The molecular docking results suggested that these compounds could combine tightly with the P2Y1R protein. Our results showed that C. osmantha fruit cores are rich in polyphenols, flavonoids, and saponins, which can be developed into a promising antithrombotic functional beverage for the prevention and treatment of cardiovascular and cerebrovascular diseases.

Effects of baffle and intraocular pressure on aerosols generated in the noncontact tonometer measurement during COVID-19.

AIM: To investigate the effects of baffle and intraocular pressure (IOP) on the aerosols generated in the noncontact tonometer (NCT) measurement and provide recommendations for the standardized use of the NCT during coronavirus disease 2019 (COVID-19). METHODS: This clinical trial included 252 subjects (312 eyes) in The Eye Hospital, Wenzhou Medical University from March 7, 2020, to March 28, 2020. Sixty subjects (120 eyes) with normal IOP were divided into two groups. One group used an NCT without a baffle, another group used an NCT with a baffle. Another 192 subjects (192 eyes) were divided into four groups: Group A1 (without a baffle+normal IOP), Group A2 (without a baffle+high IOP), Group B1 (with a baffle+normal IOP) and Group B2 (with a baffle+high IOP). Particulate matter (PM) 2.5 and PM10 generated by all subjects were quantified during the NCT measurement. The IOP values were recorded simultaneously. Effects of baffle and IOP on aerosols generated during the NCT measurement were analyzed. RESULTS: In the normal eye group with a baffle, the aerosol density decreased in a wave-like shape near the NCT with the increase in the number of people measured for IOP, demonstrating no cumulative effect. However, in the normal eye group without a baffle, there was a cumulative effect. PM2.5 and PM10 in Group A2 were higher than Group A1 (both P<0.001). The PM2.5 and PM10 in Group B2 were higher than Group B1 (P<0.01, P<0.001 respectively). The PM10 of Group B1 was lower than Group A1 (P<0.01). PM2.5 in Group B2 were lower than Group A2 (P<0.01). The median of per capita PM2.5 and PM10 in the combined Group A1+A2 were 0.80 and 1.10 µg/m3 respectively, which were higher than 0.20 and 0.60 µg/m3 in the combined Group B1+B2 (both P<0.01). The median of per capita PM2.5 and PM10 in the combined Group A1+B1 were 0.10 and 0.20 µg/m3 respectively, which were lower than 1.30 and 1.70 µg/m3 in the combined Group A2+B2 (both P<0.001). CONCLUSION: More aerosols could be generated in patients with high IOP. After the NCT is equipped with a baffle, per capita aerosol density generated decreased significantly near the NCT; And with the increase in the number of people measured for IOP, the aerosols gradually dissipated near the NCT, demonstrating no cumulative effect. Therefore, it is suggested that the NCT should be equipped with a baffle, especially for patients with high IOP.

Estimation of stress distribution and risk of failure for maxillary premolar restored by occlusal veneer with different CAD/CAM materials and preparation designs.

OBJECTIVES: To compare stress distribution and failure probability in maxillary premolars restored by simple occlusal veneer (SOV) and buccal-occlusal veneer (BOV) with 3 different CAD/CAM materials. MATERIALS AND METHODS: A maxillary premolar was digitized by a micro-CT scanner. Three-dimensional dynamic scan data were transformed, and finite element models of 2 different models (SOV and BOV restored teeth) were designed. Three different CAD/CAM materials, including lithium disilicate glass ceramic (LD) IPS e.max CAD, polymer-infiltrated ceramic-network (PICN) Vita Enamic, and resin nano-ceramic (RNC) Lava Ultimate, were designated to both veneers. Maximum principle stresses were determined by applying a 300-N axial load to the occlusal surface. Weibull analyses were performed to calculate the failure probability of the models. RESULTS: LD-restored teeth showed the highest stress in the veneer, lowest stress in substrate teeth, and lowest failure probability for the overall system; RNC-restored teeth showed the lowest stress in the veneer, highest stress in substrate teeth, and highest failure probability. No significant differences were found in the cement layer among the different models. No significant differences of stress and failure probability existed between SOV and BOV preparations. CONCLUSIONS: CAD/CAM composite resin occlusal veneers bear lower maximum stress than ceramic veneers. Teeth restored by composite veneers are more prone to failure than those restored by ceramic veneers. Additional reduction of the buccal surface did not increase the stress on the occlusal veneer under axial load. CLINICAL RELEVANCE: Both occlusal veneers could be used under physiological masticatory force. CAD/CAM glass ceramic was safer than composite resins.

Mutational screening of SLC39A5, LEPREL1 and LRPAP1 in a cohort of 187 high myopia patients.

High myopia (HM) is a leading cause of mid-way blindness with a high heritability in East Asia. Although only a few disease genes have been reported, a small proportion of patients could be identified with genetic predispositions. In order to expand the mutation spectrum of the causative genes in Chinese adult population, we investigated three genes, SLC39A5, LEPREL1 and LRPAP1, in a cohort of 187 independent Chinese patients with high myopia. Sanger sequencing was used to find possible pathogenic mutations, which were further screened in normal controls. After a pipeline of database and predictive assessments filtering, we, thereby, identified totally seven heterozygous mutations in the three genes. Among them, three novel missense mutations, c.860C > T, p.Pro287Leu and c.956G > C, p.Arg319Thr in SLC39A5, c.1982A > G, p.Lys661Arg in LEPREL1, were identified as potentially causative mutations. Additionally, the two heterozygous mutations (c.1582G > A, p.Ala528Thr; c.1982A > G, p.Lys661Arg) in one patient in LEPREL1 gene were reported in this study. Our findings will not only augment the mutation spectrum of these three genes, but also provide insights of the contribution of these genes to adult high myopia in Chinese. However, further studies are still needed to address the pathogenicity of each of the mutations reported in this study.