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.

Platinum(II) 5-substituted-8-hydroxyquinoline coordination compounds induces mitophagy-mediated apoptosis in A549/DDP cancer cells.

For the first time, two new mononuclear platinum(II) coordination compounds, [Pt(L1)(DMSO)Cl] (PtL1) and [Pt(L2)(DMSO)Cl] (PtL2) with the 5-(ethoxymethyl)-8-hydroxyquinoline hydrochloride (H-L1) and 5-bromo-8-hydroxyquinoline (H-L2) have been synthesized and characterized. The cytotoxic activity of PtL1 and PtL2 were screened in both healthy HL-7702 cell line and cancer cell lines, human lung adenocarcinoma A549 cancer cells and cisplatin-resistant lung adenocarcinoma A549/DDP cancer cells (A549R), and were compared to that of the H-L1, H-L2, H-L3 ligands and 8-hydroxyquinoline (H-L3) platinum(II) complex [Pt(L3)(DMSO)Cl] (PtL3). MTT results showed that PtL1 bearing one deprotonated L1 ligand against A549R was more potent by 8.8-48.6 fold than that of PtL2 and PtL3 complexes but was more selective toward healthy HL-7702 cells. In addition, PtL1 and PtL3 overcomes tumour drug resistance by significantly inducing mitophagy and causing the change of the related proteins expression, which leads to cell apoptosis. Moreover, the inhibitory effect of PtL1 on A549 xenograft tumour was 68.2%, which was much higher than that of cisplatin (cisPt, ca. 50.0%), without significantly changing nude mice weight in comparison with the untreated group. This study helps to explore the potential of the platinum(II) 5-substituted-8-hydroxyquinoline coordination compounds for the new Pt-resistant cancer therapy.

Corrigendum: Efficacy and Safety of Shenqu Xiaoshi Oral Liquid Compared With Domperidone Syrup in Children With Functional Dyspepsia.

[This corrects the article DOI: 10.3389/fphar.2022.831912.].

Efficacy and Safety of Shenqu Xiaoshi Oral Liquid Compared With Domperidone Syrup in Children With Functional Dyspepsia.

Background: Treatment of functional dyspepsia (FD) in children is generally symptomatic and unsatisfactory. Traditional Chinese medicines, such as Shenqu Xiaoshi Oral Liquid (SXOL), have been recommended to alleviate dyspeptic symptoms. However, evidence of their safety and efficacy remains limited to date. AIM: To assess whether 2 weeks of therapy with SXOL was non-inferior to domperidone syrup in children with FD. Methods: In this randomized, double-blind, double-simulated, non-inferiority, multi-center clinical trial, we recruited children (3-14 years) with FD according to the Rome IV criteria from 17 tertiary medical centers across China. Patients were randomly allocated (1:1) to receive SXOL or domperidone syrup for 2 weeks. We compared the participants' clinical scores from both groups based on the severity and frequency of dyspepsia symptoms according to Rome IV criteria (0, 1, 2, and 4 weeks after randomization). The primary endpoint was the total response rate, which was defined as the proportion of patients with a decrease of 30% or more in the FD symptoms clinical score from baseline, at the end of the 2-weeks treatment. A non-inferiority margin of -10% was set. Secondary endpoints and adverse events were assessed. This trial is registered with www.Chictr.org.cn, number ChiCTR1900022654. Results: Between February 2019 and March 2021, a total of 373 patients were assessed for eligibility, and 356 patients were enrolled and randomized. The clinical response rate at week two was similar for SXOL [118 (83.10%) of 142] and domperidone [128 (81.01%) of 158]; difference 2.09; 95% CI -6.74 to 10.71, thereby establishing non-inferiority. The total FD symptom scores were significantly improved in the two groups at 1-, 2-, and 4-weeks follow-up periods (p < 0.005). The decrease in symptom score compared with the baseline were similar between these two groups. Over the total study period, 10 patients experienced at least one treatment-related adverse event [six (3.37%)] in the SXOL group, four [(2.25%) in the domperidone group], although no serious adverse event was noted. Conclusion: Treatment with SXOL effectively improves dyspeptic symptoms and is well tolerated. In addition, it is not inferior to domperidone syrup and leads to sustained improvement in Chinese children with FD.

Mitochondria-localizing curcumin-cryptolepine Zn(II) complexes and their antitumor activity.

Many metal complexes are potent candidates as mitochondrial-targeting agents. In this study, four novel Zn(II) complexes, [Zn(BPQA)Cl2] (Zn1), [Zn(BPQA)(Curc)]Cl (Zn2), [Zn(PQA)Cl2] (Zn3), and [Zn(PQA)(Curc)]Cl (Zn4), containing N,N-bis(pyridin-2-ylmethyl)benzofuro[3,2-b]quinolin-11-amine (BPQA), N-(pyridin-2-ylmethyl)benzofuro[3,2-b]quinolin-11-amine (PQA), and curcumin (H-Curc) were synthesized. An MTT assay showed that Zn1-Zn4 had strong anticancer activities against SK-OV-3/DDP and T-24 tumor cells with IC50 values of 0.03-6.19 µM. Importantly, Zn1 and Zn2 displayed low toxicities against normal HL-7702 cells. Mechanism experiments demonstrated that probe Zn2 showed appreciable fluorescence in the red region of the spectrum, and substantial accumulation of Zn2 occurred in the mitochondria after treatment, indicating increases in Ca2+ and reactive oxygen species levels, loss of the mitochondrial membrane potential, and consequent induction of mitochondrial dysfunction at low concentrations. In addition, the probe Zn2 effectively (50.7%) inhibited the growth of T-24 bladder tumor cells in vivo. The probe Zn2 shows potential for use in cancer therapy while retaining the H-Curc as an imaging probe.

Solution NMR structure of CHU_1110 from Cytophaga hutchinsonii, an AHSA1 protein potentially involved in metal ion stress response.

We report the solution nuclear magnetic resonance (NMR) structure of CHU_1110 from Cytophaga hutchinsonii. CHU_1110 contains three α-helices and one antiparallel ß-sheet, forming a large cavity in the center of the protein, which are consistent with the structural characteristics of AHSA1 protein family. This protein shows high structural similarities to the prokaryotic proteins RHE_CH02687 from Rhizobium etli and YndB from Bacillus subtilis, which can bind with flavinoids. Unlike these two homologs, CHU_1110 shows no obvious interaction with flavonoids in NMR titration experiments. In addition, no direct interaction has been observed between CHU_1110 and ATP, although many homologous sequences of CHU_1110 have been annotated as ATPase. Combining the analysis of structural similarity of CHU_1110 and genomic context of its encoding gene, we speculate that CHU_1110 may be involved in the stress response of bacteria to heavy metal ions, even though its specific biological functions that need to be further investigated.

Linear shadows that connect oblique fissures and costal pleurae on the superior segments of lower lobes: evaluating the imaging findings on thin-slice lung CT.

OBJECTIVE: To retrospectively analyse the imaging findings of the linear shadows that connect the oblique fissures and the costal pleurae on the superior segments of the lower lobes on thin-slice lung CT. MATERIALS AND METHODS: Thin-slice CT scans of 221 cases of normal lungs and 86 abnormal lungs were collected. The parameters of the imaging observations included the existence of the superior segmental linear shadow, its morphology, length, and starting position, bird-beak sign, and adjacent structures on the pleural end. RESULTS: The linear shadows were more common on the left lower lobe (43.44%) than on the right side (19.46%). The pleural origins of the linear shadows were mainly located above the carina (69.78%); the adjacent structure on the left lung was the descending aorta (70.83%), and for the right lung, it was next to the thoracic vertebrae (60.47%). In the presence of pulmonary lobectomy or atelectasis, the linear shadows could be extended, which could pull the oblique fissures and costal pleurae to form the bird-beak sign. CONCLUSION: The linear shadows on the superior segments of the lower lobes are common structures fixing the oblique fissures. Recognition of the linear shadows can help radiologists distinguish normal structures from abnormal ones.

Chemical shift assignments of RHE_RS02845, a NTF2-like domain-containing protein from Rhizobium etli.

The nuclear transport factor 2 (NTF2) like superfamily includes members of the NTF2 family, delta-5-3-ketosteroid isomerases, and the beta subunit of ring hydroxygenases. This family plays important roles in both eukaryotic and prokaryotic cells, and is taken as a classic example of divergent evolution because proteins in this family exhibit diverse biological functions, although share common structural features. We cloned the gene RHE_RS02845 encoding a predicted NTF2-like domain-containing protein in Rhizobium etli, and prepared U-13C/15N-labeled protein samples for its three-dimensional NMR structural determination. Here, chemical shift assignments for both backbone and side-chain atoms are reported, which is prerequisite for further structural calculation and functional research using NMR spectroscopy.

Chemical shift assignments of CHU_1110: an AHSA1-like protein from Cytophaga hutchinsonii.

AHSA1 protein family is one of the four largest families in the Bet v1-like protein superfamily. The functions and structures of proteins in AHSA1 family are still largely unknown. CHU_1110 with 167 amino acids and a molecular weight of 19.2 kDa is a member of the AHSA1 family from Cytophaga hutchinsonii, a soil bacterium known for its ability to digest crystalline cellulose. Here we report the complete 1H, 13C and 15N chemical shift assignments of CHU_1110. The secondary structural elements of CGL2373 are consistent with the canonical AHSA1 structure. However the sequence identity of CHU_1110 with other members of AHSA1 family with functional and structural reports, such as RHE_CH02687 from Rhizobium etli, Aha1 from Homo sapiens and Yndb from Bacillus subtilis, are very low, which may suggest a different function of CHU_1110. Our chemical shift assignments of CHU_1110 are essential for the following structural and functional research of CHU_1110.

Chemical shift assignments of polyketide cyclase_like protein CGL2373 from Corynebacterium glutamicum.

Protein CGL2373 from Corynebacterium glutamicum, which is 155 amino acids long and 17.7 kDa, is a member of the polyketide_cyc2 family. As a potential polyketide cyclase, it may play an important role in the biosynthesis of aromatic polyketides that are the source of many bioactive molecules. Here we report the complete 1H, 13C and 15N chemical shift assignments of CGL2373, which lays a foundation for further structural and functional research.

Red Light-Emitting Diode Based on Blue InGaN Chip with CdTe x S(1 - x) Quantum Dots.

Thioglycolic acid-capped CdTe x S(1 - x) quantum dots (QDs) were synthesized through a one-step approach in an aqueous medium. The CdTe x S(1 - x) QDs played the role of a color conversion center. The structural and luminescent properties of the obtained CdTe x S(1 - x) QDs were investigated. The fabricated red light-emitting hybrid device with the CdTe x S(1 - x) QDs as the phosphor and a blue InGaN chip as the excitation source showed a good luminance. The Commission Internationale de L'Eclairage coordinates of the light-emitting diode (LED) at (0.66, 0.29) demonstrated a red LED. Results showed that CdTe x S(1 - x) QDs can be excited by blue or near-UV regions. This feature presents CdTe x S(1 - x) QDs with an advantage over wavelength converters for LEDs.

Solution NMR structure of RHE_CH02687 from Rhizobium etli: A novel flavonoid-binding protein.

We report the solution NMR structure of RHE_CH02687 from Rhizobium etli. Its structure consists of two ß-sheets that together with two short and one long α-helix form a hydrophobic cavity. This protein shows a high structural similarity to the prokaryotic protein YndB from Bacillus subtilis, and the eukaryotic protein Aha1. NMR titration experiments confirmed that RHE_CH02687, like its homolog YndB, interacted with flavonoids, giving support for a biological function as a flavonoid sensor in the symbiotic interaction between R. etli and plants. In addition, our study showed no evidence for a direct interaction between RHE_CH02687 and HtpG, the R. etli homolog of Hsp90. Proteins 2017; 85:951-956. © 2016 Wiley Periodicals, Inc.