Publications by authors named "Zheng Ruan"

148 Publications

Probucol improves erectile function by regulating endoplasmic reticulum stress in rats with streptozotocin-induced diabetes.

Andrologia 2021 Feb 10:e13999. Epub 2021 Feb 10.

Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.

This study was to explore the effect and mechanism of Probucol on STZ-induced erectile dysfunction in diabetic rats. Thirty SD male rats aged 12 weeks were given intraperitoneal injection of STZ after fasting for 12 hr. Diabetic rats were haphazardly partitioned under two assemblies and administered 0 or 500 mg/kg probucol by oral gavage to 12 weeks. Control group was intraperitoneally injected with physiological saline, and saline was administered by oral gavage daily. Intracorporeal pressure was used to evaluate erectile function. Levels of proteins were detected using immunohistochemistry and Western blotting. α-SMA and vWF were detected using immunofluorescence staining. After treatment, erectile function in probucol group was significantly improved. Endoplasmic reticulum stress-related proteins were expressed higher in DM group than in sham group, while expression of these proteins decreased significantly in probucol group. However, α-SMA and vWF were expressed at lower levels in DM group than in sham group, and probucol treatment reversed this phenomenon. Finally, Bax and Caspase3 were expressed at higher levels and Bcl-2 was expressed at lower levels in DM group, while the opposite result was obtained in probucol group. In conclusions, probucol improves erectile function by reducing endothelial dysfunction and inhibiting PERK/ATF4/CHOP pathway in STZ-induced diabetic rats.
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http://dx.doi.org/10.1111/and.13999DOI Listing
February 2021

Uridine attenuates obesity, ameliorates hepatic lipid accumulation and modifies the gut microbiota composition in mice fed with a high-fat diet.

Food Funct 2021 Mar;12(4):1829-1840

School of Food Science and Technology, State Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047, China.

Uridine (UR) is a pyrimidine nucleoside that plays an important role in regulating glucose and lipid metabolism. The aim of this study was to investigate the effect of UR on obesity, fat accumulation in liver, and gut microbiota composition in high-fat diet (HFD)-fed mice. ICR mice were, respectively, divided into 3 groups for 8 weeks, that is, control (CON, n = 12), high fat diet (HFD, n = 16), and HFD + UR groups (0.4 mg mL-1 in drinking water, n = 16). UR supplementation significantly reduced the body weight and suppressed the accumulation of subcutaneous, epididymal, and mesenteric WAT in HFD-fed mice (P < 0.05). Meanwhile, UR also decreased the lipid droplet accumulation in the liver and liver organoids (P < 0.05). In addition, UR supplementation increased bacterial diversity and Bacteroidetes abundance, and decreased the Firmicutes-to-Bacteroidetes ratio in HFD-fed mice significantly (P < 0.05). UR promoted the growth of butyrate-producing bacteria of Odoribacter, unidentified-Ruminococcaceae, Intestinimonas, Ruminiclostridium, and unidentified-Lachnospiraceae. A close correlation between several specific bacterial phyla or genera and the levels of WAT weight, hepatic TC, or hepatic TG genera was revealed through Spearman's correlation analysis. These results demonstrated that UR supplementation could be beneficial by attenuating HFD-induced obesity and nonalcoholic fatty liver disease.
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http://dx.doi.org/10.1039/d0fo02533jDOI Listing
March 2021

Proton-activated chloride channel PAC regulates endosomal acidification and transferrin receptor-mediated endocytosis.

Cell Rep 2021 Jan;34(4):108683

Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

During vesicular acidification, chloride (Cl), as the counterion, provides the electrical shunt for proton pumping by the vacuolar H ATPase. Intracellular CLC transporters mediate Cl influx to the endolysosomes through their 2Cl/H exchange activity. However, whole-endolysosomal patch-clamp recording also revealed a mysterious conductance releasing Cl from the lumen. It remains unknown whether CLCs or other Cl channels are responsible for this activity. Here, we show that the newly identified proton-activated Cl (PAC) channel traffics from the plasma membrane to endosomes via the classical YxxL motif. PAC deletion abolishes the endosomal Cl conductance, raises luminal Cl level, lowers luminal pH, and increases transferrin receptor-mediated endocytosis. PAC overexpression generates a large endosomal Cl current with properties similar to those of endogenous conductance, hypo-acidifies endosomal pH, and reduces transferrin uptake. We propose that the endosomal Cl PAC channel functions as a low pH sensor and prevents hyper-acidification by releasing Cl from the lumen.
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http://dx.doi.org/10.1016/j.celrep.2020.108683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869721PMC
January 2021

Tetraphenylporphine-Modified Polymeric Nanoparticles Containing NIR Photosensitizer for Mitochondria-Targeting and Imaging-Guided Photodynamic Therapy.

ACS Biomater Sci Eng 2020 Feb 23;6(2):1043-1051. Epub 2020 Jan 23.

CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, and Department of Chemical Physics, University of Science and Technology of China, Jinzai Road 96, Hefei 230026, Anhui, P. R. China.

Near-infrared (NIR) photodynamic therapy (PDT) is a promising antitumor strategy under NIR light irradiation to kill cancer cells. Mitochondria has a critical function in sustaining cellular viability and death, which is the ideal organelle for PDT. Here, we reported a tetraphenylporphine (TPP)-conjugated amphiphilic copolymer and an iodinated boron dipyrromethene photosensitizer (BDPI) with high singlet oxygen yield to form nanoparticles (PBDPI-TPP), which could realize mitochondria-targeting and improve the NIR imaging-guided PDT. The as-prepared mitochondria-targeting nanoplatform could show effective subcellular localization and bring about significant irreversible mitochondrial injury for enhanced PDT. Both in vitro and in vivo experiments revealed that the mitochondria-targeting PDT system could achieve a remarkable therapeutic effect, indicating that it is a promising nanoplatform for NIR imaging-guided PDT in cancer therapeutics.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01662DOI Listing
February 2020

Optimal Rex shunt procedures as a treatment for pediatric extrahepatic portal hypertension.

Pediatr Surg Int 2021 Jan 10. Epub 2021 Jan 10.

Center of Evidence-Based Medicine, Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, Shandong, China.

Purpose: To assess the long-term results after Rex bypass (RB) shunt and Rex transposition (RT) shunt and determine the optimal approach.

Methods: Between 2010 and 2019, traditional RB shunt was performed in 24 patients, and modified RT shunt was performed in 23 children with extrahepatic portal hypertension (pHTN). A retrospective study was conducted based on comparative symptoms, platelet counts, color Doppler ultrasonography and computed tomographic portography of the portal system, and gastroscopic gastroesophageal varices postoperatively. The portal venous pressure was evaluated intraoperatively.

Results: The operation in the RB group was notably more time-consuming than that in the RT group (P < 0.05). Compared to RT shunt, the reduction in gastroesophageal varix grading, the increases in platelets, and the caliber of the bypass were greater in the RB group (P < 0.05). Although not statistically significant, higher morbidity of surgical complications was found after RT shunt (17.4%) compared with RB shunt (8.3%) with patency rates of 82.6 and 91.7%, respectively. Additionally, patients exhibited a lower rate of rebleeding under the RB procedure (12.5%) than under the RT procedure (21.7%).

Conclusions: The RT procedure is an alternative option for the treatment of pediatric extrahepatic pHTN, and RB shunt is the preferred procedure in our center.
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http://dx.doi.org/10.1007/s00383-020-04847-1DOI Listing
January 2021

Indole-3-propionic Acid Improved the Intestinal Barrier by Enhancing Epithelial Barrier and Mucus Barrier.

J Agric Food Chem 2021 Feb 23;69(5):1487-1495. Epub 2020 Dec 23.

State Key Laboratory of Food Science and Technology, Institute of Nutrition and School of Food Science, Nanchang University, Nanchang 330047, China.

Destruction in intestinal barrier is concomitant with the intestinal diseases. There is growing evidence that tryptophan-derived intestinal bacterial metabolites play a critical role in maintaining the balance of intestinal mucosa. In this study, the Caco-2/HT29 coculture model was used to evaluate the effect of indole-3-propionic acid (IPA) on the intestinal barrier and explore its underlying mechanism. We found that IPA increased transepithelial electrical resistance and decreased paracellular permeability which was consistent with the increase in tight junction proteins (claudin-1, occludin, and ZO-1). Furthermore, IPA strengthened the mucus barrier by increasing mucins (MUC2 and MUC4) and goblet cell secretion products (TFF3 and RELMβ). Additionally, IPA weakened the expression of LPS-induced inflammatory factors. These discoveries provide new views for understanding the improvement of intestinal barrier by gut microbial metabolites of aromatic amino acids.
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http://dx.doi.org/10.1021/acs.jafc.0c05205DOI Listing
February 2021

Effects of high hydrostatic pressure on color, texture, microstructure, and proteins of the tilapia (Orechromis niloticus) surimi gels.

J Texture Stud 2020 Nov 15. Epub 2020 Nov 15.

School of Food Science and Engineering, South China University of Technology, Guangzhou, China.

The tilapia (Orechromis niloticus) surimi gels were prepared with high hydrostatic pressure (0, 100, 200, 300, and 400 MPa for 15 min) treatments to investigate the changes in water-holding capacity, color, gel strength, microstructure, texture, and proteins of the gels. Compared it with cooked gel (40°C/30 min + 90°C/30 min). The whiteness of heat-induced and HHP-induced gels were significant (p < .05) higher than that of untreated samples. The gels formed by pressurization were dense and flexible, and formed by cross-linking based on hydrogen bonding. SDS-PAGE patterns showed no major change in the actin and tropomyosin protein profiles of gels induced by HHP-300. Raman spectroscopy confirmed disulfide bonds played an important role in gel formation. A lower intensity ratio observed in HHP-induced protein supported the tyrosine residues involved in hydrogen bond formation. The changes of secondary structure suggested decreased α-helix content and increased β-sheet.
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http://dx.doi.org/10.1111/jtxs.12572DOI Listing
November 2020

Structures and pH-sensing mechanism of the proton-activated chloride channel.

Nature 2020 12 4;588(7837):350-354. Epub 2020 Nov 4.

Department of Structural Biology, Van Andel Institute, Grand Rapids, MI, USA.

The proton-activated chloride channel (PAC) is active across a wide range of mammalian cells and is involved in acid-induced cell death and tissue injury. PAC has recently been shown to represent a novel and evolutionarily conserved protein family. Here we present two cryo-electron microscopy structures of human PAC in a high-pH resting closed state and a low-pH proton-bound non-conducting state. PAC is a trimer in which each subunit consists of a transmembrane domain (TMD), which is formed of two helices (TM1 and TM2), and an extracellular domain (ECD). Upon a decrease of pH from 8 to 4, we observed marked conformational changes in the ECD-TMD interface and the TMD. The rearrangement of the ECD-TMD interface is characterized by the movement of the histidine 98 residue, which is, after acidification, decoupled from the resting position and inserted into an acidic pocket that is about 5 Å away. Within the TMD, TM1 undergoes a rotational movement, switching its interaction partner from its cognate TM2 to the adjacent TM2. The anion selectivity of PAC is determined by the positively charged lysine 319 residue on TM2, and replacing lysine 319 with a glutamate residue converts PAC to a cation-selective channel. Our data provide a glimpse of the molecular assembly of PAC, and a basis for understanding the mechanism of proton-dependent activation.
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http://dx.doi.org/10.1038/s41586-020-2875-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773282PMC
December 2020

Porcine circovirus type 2 (PCV2) and infection induce diarrhea in piglets: Microbial dysbiosis and intestinal disorder.

Anim Nutr 2020 Sep 18;6(3):362-371. Epub 2020 Jul 18.

Yunnan Xinan Tianyou Animal Husbandry Technology Co., Ltd., Kunming, 650032, China.

Diarrhea is considered to be associated with microbial dysbiosis caused by infection of pathogens but poorly understood. We herein characterized the colonic microbiota of diarrheal early-weaning piglets infected with porcine circovirus type 2 (PCV2) and . infection significantly decreased species richness and Shannon diversity index of colonic microbiota together with a significant increase in the proportion of and Enterobacteriaceae, whereas no significant difference on the above indexes was observed in piglets infected with PCV2 compared with healthy piglets. PCV2 and infection could disturb the homeostasis of colonic microbiota through deterioration of ecological network within microbial community, and specially performed as a module hub in ecological networks. The microbial dysbiosis caused metabolic dysfunction and led to a remarkable reduction in production of short chain fatty acids, following by a higher pH level in colon cavity. infection disturbed the function of colonic tract barrier observed in terms of significant lower relative expression of claudin-1, occluding, and zonula occludens protein-1 genes, and PCV2 infection induced intestinal inflammation together with a higher permeability of colon. Generally, these results suggested that PCV2 and infection could induce microbial dysbiosis and metabolic dysfunction, and cause intestinal disorder, all of which finally were associated to contribute to the diarrhea of early-weaning piglets.
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http://dx.doi.org/10.1016/j.aninu.2020.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503086PMC
September 2020

Puerarin Rebuilding the Mucus Layer and Regulating Mucin-Utilizing Bacteria to Relieve Ulcerative Colitis.

J Agric Food Chem 2020 Oct 14;68(41):11402-11411. Epub 2020 Sep 14.

State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition, Nanchang University, Nanchang 330047, China.

The colonic mucus barrier serves as a primary defense against enteric pathogens; destruction of this mucus layer has been observed in ulcerative colitis patients. This study aims to investigate the possibility of rebuilding the colon mucus layer through puerarin supplementation, which can stimulate mucin secretion and goblet cells differentiation. After puerarin supplementation, the thickness of colon mucus layer was increased and the permeability was reduced. The erosion of intestinal epithelium by bacteria was blocked, and the loss of epithelial integrity was alleviated. Puerarin also altered the composition of mucin-utilizing bacteria, which influenced the mucus permeability. Levels of short-chain fatty acids (SCFAs) were increased after puerarin supplementation, which as a direct source of energy for the proliferation of epithelia and goblet cells. This study demonstrated that enhancement of mucin secretion to relieve ulcerative colitis (UC) by puerarin supplementation is feasible, and the regulation of mucin-utilizing bacteria and the increased levels of SCFAs may be the main reasons.
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http://dx.doi.org/10.1021/acs.jafc.0c04119DOI Listing
October 2020

COVID-19 pandemic: study on simple, easy, and practical relaxation techniques while wearing medical protective equipment.

Psychol Med 2020 Aug 24:1-7. Epub 2020 Aug 24.

Division of Neuropsychiatry and Psychosomatics, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.

Background: No studies have reported on how to relieve distress or relax in medical health workers while wearing medical protective equipment in coronavirus disease 2019 (COVID-19) pandemic. The study aimed to establish which relaxation technique, among six, is the most feasible in first-line medical health workers wearing medical protective equipment.

Methods: This was a two-step study collecting data with online surveys. Step 1: 15 first-line medical health workers were trained to use six different relaxation techniques and reported the two most feasible techniques while wearing medical protective equipment. Step 2: the most two feasible relaxation techniques revealed by step 1 were quantitatively tested in a sample of 65 medical health workers in terms of efficacy, no space limitation, no time limitation, no body position requirement, no environment limitation to be done, easiness to learn, simplicity, convenience, practicality, and acceptance.

Results: Kegel exercise and autogenic relaxation were the most feasible techniques according to step 1. In step 2, Kegel exercise outperformed autogenic relaxation on all the 10 dimensions among the 65 participants while wearing medical protective equipment (efficacy: 24 v. 15, no space limitation: 30 v. 4, no time limitation: 31 v. 4, no body position requirement: 26 v. 4, no environment limitation: 30 v. 11, easiness to learn: 28 v. 5, simplicity: 29 v. 7, convenience: 29 v. 4, practicality: 30 v. 14, acceptance: 32 v. 6).

Conclusion: Kegel exercise seems a promising self-relaxation technique for first-line medical health workers while wearing medical protective equipment among COVID-19 pandemic.
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http://dx.doi.org/10.1017/S0033291720003220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484302PMC
August 2020

A Comparison of Three-Dimensional Speckle Tracking Echocardiography Parameters in Predicting Left Ventricular Remodeling.

J Healthc Eng 2020 30;2020:8847144. Epub 2020 Jul 30.

Department of Geriatric Cardiology, General Hospital of the Southern Theatre Command, PLA, Guangzhou 510016, China.

Three-dimensional speckle tracking echocardiography (3D STE) is an emerging noninvasive method for predicting left ventricular remodeling (LVR) after acute myocardial infarction (AMI). Previous studies analyzed the predictive value of 3D STE with traditional models. However, no models that contain comprehensive risk factors were assessed, and there are limited data on the comparison of different 3D STE parameters. In this study, we sought to build a machine learning model for predicting LVR in AMI patients after effective percutaneous coronary intervention (PCI) that contains the majority of the clinical risk factors and compare 3D STE parameters values for LVR prediction. We enrolled 135 first-onset AMI patients (120 males, mean age 54 ± 9 years). All patients went through a 3D STE and a traditional transthoracic echocardiography 24 hours after reperfusion. A second echocardiography was repeated at the three-month follow-up to detect LVR (defined as a 20 percent increase in left ventricular end-diastolic volume). Six models were constructed using 15 risk factors. A receiver operator characteristic curve and four performance measurements were used as evaluation methods. Feature importance was used to compare 3D STE parameters. 26 patients (19.3%) had LVR. Our evaluation showed that RF can best predict LVR with the best AUC of 0.96. 3D GLS was the most valuable 3D STE parameters, followed by GCS, global area strain, and global radial strain (feature importance 0.146, 0.089, 0.087, and 0.069, respectively). To sum up, RF models can accurately predict the LVR after AMI, and 3D GLS was the best 3D STE parameters in predicting the LVR.
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http://dx.doi.org/10.1155/2020/8847144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416266PMC
July 2020

Probucol enhances the therapeutic efficiency of mesenchymal stem cells in the treatment of erectile dysfunction in diabetic rats by prolonging their survival time via Nrf2 pathway.

Stem Cell Res Ther 2020 07 21;11(1):302. Epub 2020 Jul 21.

Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jingwuweiqi Road 324#, Jinan, 250021, Shandong, People's Republic of China.

Background: Intracavernous injection of mesenchymal stem cells (MSCs) is a promising method for diabetic mellitus-induced erectile dysfunction (DMED), but short survival time of MSCs in cavernous is a fatal defect for therapy. This study investigated therapeutic efficiency and potential mechanism of probucol combined with MSCs.

Methods: In vivo study, a total of forty-eight 10-week-old male Sprague-Dawley (SD) rats were used. Twelve rats received intraperitoneal injection of PBS as the sham group; the rest received intraperitoneal injection of 60 mg/kg streptozotocin to establish DM models. DM rats were randomly divided into three groups: received intracavernosal (IC) injection of either PBS (DM group), MSCs (M group), or administrated probucol after intracavernosal injection of MSCs (P + M group). Erectile function was assessed by electrical stimulation of the cavernous nerves with real-time intracavernous pressure measurement. After euthanasia, penile tissue was investigated for histologic examination and Western blotting. In in vitro experiment, HO was used to create oxidative stress environment to detect changes in cell viability. CCK8 was used to measure cell viability of MSCs treated with or without probucol. Intracellular ROS changes were detected by flow cytometry. Autophagy and apoptosis were detected by Western blotting and confocal microscopy.

Results: Recovery of erectile function was observed in the P + M group. The combination therapy decreased fibrosis and increased endothelial function compared with MSC therapy alone. Western blotting results confirmed the increased expression of Nrf2 and HO-1 in cavernous body. HO induced high oxidative stress and reduced cell viability in vitro, which was gradually reversed with increased concentration of probucol. HO reduced Nrf2 expression, which was reversed by probucol's intervention. Furthermore, the expression of Bax, Caspase3, and Cleaved-Caspase3 decreased, and the expression of Bcl-2 increased in a dose-dependent manner because of probucol's intervention. In addition, Beclin1 and LC3II both increased in a dose-dependent manner. Meanwhile, the expression of P62 decreased. In the study of autophagy flux, we found probucol did not block it.

Conclusion: Probucol enhanced therapeutic efficiency of MSCs in DMED by prolonging their survival time, which mediated through improving the transplanted microenvironment of MSCs, increasing self-antioxidant ability of MSCs, strengthening protective autophagy, and inhibiting apoptosis of MSCs via Nrf2 pathway. Schematic model showing combined probucol and MSCs to improve DMED. Probucol increases self-antioxidant ability of MSCs, strengthening protective autophagy and inhibiting apoptosis via Nrf2/HO-1 and Nrf2/autophagy pathways.
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http://dx.doi.org/10.1186/s13287-020-01788-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374958PMC
July 2020

Structures of human pannexin 1 reveal ion pathways and mechanism of gating.

Nature 2020 08 3;584(7822):646-651. Epub 2020 Jun 3.

Van Andel Institute, Grand Rapids, MI, USA.

Pannexin 1 (PANX1) is an ATP-permeable channel with critical roles in a variety of physiological functions such as blood pressure regulation, apoptotic cell clearance and human oocyte development. Here we present several structures of human PANX1 in a heptameric assembly at resolutions of up to 2.8 angström, including an apo state, a caspase-7-cleaved state and a carbenoxolone-bound state. We reveal a gating mechanism that involves two ion-conducting pathways. Under normal cellular conditions, the intracellular entry of the wide main pore is physically plugged by the C-terminal tail. Small anions are conducted through narrow tunnels in the intracellular domain. These tunnels connect to the main pore and are gated by a long linker between the N-terminal helix and the first transmembrane helix. During apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP through the main pore. We identified a carbenoxolone-binding site embraced by W74 in the extracellular entrance and a role for carbenoxolone as a channel blocker. We identified a gap-junction-like structure using a glycosylation-deficient mutant, N255A. Our studies provide a solid foundation for understanding the molecular mechanisms underlying the channel gating and inhibition of PANX1 and related large-pore channels.
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http://dx.doi.org/10.1038/s41586-020-2357-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814660PMC
August 2020

Clinical Experience with Thymic Cystectomy: A Single-Institution Study of 117 Cases from 2013 to 2019.

Med Sci Monit 2020 May 20;26:e923967. Epub 2020 May 20.

Department of Thoracic Surgery, The Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China (mainland).

BACKGROUND The aim of this study was to summarize the clinical experience of thymic cysts treatment from a single center. MATERIAL AND METHODS Clinical data, imaging, pathological results, and follow-up results of thymic cyst patients who underwent surgery from January 2013 to September 2019 were retrospectively reviewed. RESULTS A total of 117 patients were enrolled, including 76 asymptomatic patients and 41 symptomatic patients. The average diameter of thymic cysts, the cysts in asymptomatic patients, and those in symptomatic patients were 31.93±19.92 mm, 29.28±17.97 mm, and 36.85±22.50 mm, respectively. The number of cysts ranged from 1 to 3 cm, 3 to 6 cm, and >6 cm in 73 cases (62.4%), 32 cases (27.3%), and 12 cases (10.3%), respectively. There was no correlation between the size of thymic cysts and the presence or absence of symptoms. Only 20 cases (17.1%) were correctly diagnosed as thymic cysts before surgery. There were 67 patients (57.3%) who underwent video-assisted thoracic surgery (VATS) and 50 cases (42.7%) underwent open surgery. Cystectomy was performed in 93 cases (79.5%) and 24 cases (20.5%) underwent simultaneous resection of thymic cysts and other thoracic tumors. Compared with the thoracotomy group, the VATS group had shorter hospital stay and chest tube indwelling time. No serious complications occurred after surgery. The median follow-up time was 45.0 months (range 4.0-84.0 months) and there was no recurrence. CONCLUSIONS Attention should be paid to the accuracy of preoperative diagnosis of thymic cysts and the reduction of asymptomatic thymic cystectomy. For patients who have both thymic cysts and other thoracic tumors, simultaneous surgery is safe and feasible.
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http://dx.doi.org/10.12659/MSM.923967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254937PMC
May 2020

Integrin β3 Deficiency Results in Hypertriglyceridemia via Disrupting LPL (Lipoprotein Lipase) Secretion.

Arterioscler Thromb Vasc Biol 2020 05 2;40(5):1296-1310. Epub 2020 Apr 2.

From the State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, China (B.X., X.X.).

Objective: Integrin β3 is implicated in numerous biological processes such as its relevance to blood triglyceride, yet whether β3 deficiency affects this metabolic process remains unknown. Approach and Results: We showed that the Chinese patients with β3-deficient Glanzmann thrombasthenia had a 2-fold higher serum triglyceride level together with a lower serum LPL (lipoprotein lipase) level than those with an αIIb deficiency or healthy subjects. The β3 knockout mice recapitulated these phenotypic features. The elevated plasma triglyceride level was due to impaired LPL-mediated triglyceride clearance caused by a disrupted LPL secretion. Further analysis revealed that β3 directly bound LPL via a juxtamembrane TIH (threonine isoleucine histidine) motif in its cytoplasmic domain and functioned as an adaptor protein by interacting with LPL and PKD (protein kinase D) to form the PKD/β3/LPL complex that is required for β3-mediated LPL secretion. Furthermore, the impaired triglyceride clearance in β3 knockout mice could be corrected by adeno-associated virus serotype 9 (AAV9)-mediated delivery of wild-type but not TIH-mutated β3 genes.

Conclusions: This study reveals a hypertriglyceridemia in both β3-deficient Chinese patients and mice and provides novel insights into the molecular mechanisms of the significant roles of β3 in LPL secretion and triglyceride metabolism, drawing attention to the metabolic consequences in patients with β3-deficient Glanzmann thrombasthenia.
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http://dx.doi.org/10.1161/ATVBAHA.119.313191DOI Listing
May 2020

Emerging roles of the αC-β4 loop in protein kinase structure, function, evolution, and disease.

IUBMB Life 2020 Jun 26;72(6):1189-1202. Epub 2020 Feb 26.

Institute of Bioinformatics, University of Georgia, Athens, Georgia.

The faithful propagation of cellular signals in most organisms relies on the coordinated functions of a large family of protein kinases that share a conserved catalytic domain. The catalytic domain is a dynamic scaffold that undergoes large conformational changes upon activation. Most of these conformational changes, such as movement of the regulatory αC-helix from an "out" to "in" conformation, hinge on a conserved, but understudied, loop termed the αC-β4 loop, which mediates conserved interactions to tether flexible structural elements to the kinase core. We previously showed that the αC-β4 loop is a unique feature of eukaryotic protein kinases. Here, we review the emerging roles of this loop in kinase structure, function, regulation, and diseases. Through a kinome-wide analysis, we define the boundaries of the loop for the first time and show that sequence and structural variation in the loop correlate with conformational and regulatory variation. Many recurrent disease mutations map to the αC-β4 loop and contribute to drug resistance and abnormal kinase activation by relieving key auto-inhibitory interactions associated with αC-helix and inter-lobe movement. The αC-β4 loop is a hotspot for post-translational modifications, protein-protein interaction, and Hsp90 mediated folding. Our kinome-wide analysis provides insights for hypothesis-driven characterization of understudied kinases and the development of allosteric protein kinase inhibitors.
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http://dx.doi.org/10.1002/iub.2253DOI Listing
June 2020

Application of Maillard reaction product of xylose-pea protein enzymatic hydrolysate in 3D printing.

J Sci Food Agric 2020 May 2;100(7):2982-2990. Epub 2020 Mar 2.

State Key Laboratory of Food Science and Technology, Institute of Nutrition and School of Food Science, Nanchang University, Nanchang, China.

Background: This paper aims to provide a basis for the application of Maillard reaction products and ideas for 3D printing of functional food.

Results: We evaluated the effects of pea protein enzymatic hydrolysate-xylose Maillard reaction products (xMRPs) on the printability of 3D printing materials and the structure using various techniques. It was found that compared with the addition of enzymatic hydrolysate, the materials with xMRPs and 3D printing could significantly improve the structure, physical properties, formability of 3D printing materials and 3D print products, among which the xMRPs with 6 g of xylose had the most significant effect.

Conclusions: This study has important scientific value and practical significance for the high-valued application of Millard reaction products and the promotion of the practical application of 3D printing technology in the food industry. © 2020 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.10327DOI Listing
May 2020

Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells.

Science 2020 02 9;367(6478). Epub 2020 Jan 9.

Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia.

Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2 T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9 TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell-based immunotherapies.
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http://dx.doi.org/10.1126/science.aay5516DOI Listing
February 2020

Endosomes and Microtubles are Required for Productive Infection in Aquareovirus.

Virol Sin 2020 Apr 19;35(2):200-211. Epub 2019 Dec 19.

State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.

Grass carp reovirus (GCRV), the genus Aquareovirus in family Reoviridae, is viewed as the most pathogenic aquareovirus. To understand the molecular mechanism of how aquareovirus initiates productive infection, the roles of endosome and microtubule in cell entry of GCRV are investigated by using quantum dots (QDs)-tracking in combination with biochemical approaches. We found that GCRV infection and viral protein synthesis were significantly inhibited by pretreating host cells with endosome acidification inhibitors NHCl, chloroquine and bafilomycin A1 (Bafi). Confocal images indicated that GCRV particles could colocalize with Rab5, Rab7 and lysosomes in host cells. Further ultrastructural examination validated that viral particle was found in late endosomes. Moreover, disruption of microtubules with nocodazole clearly blocked GCRV entry, while no inhibitory effects were observed with cytochalasin D treated cells in viral infection, hinting that intracellular transportation of endocytic uptake in GCRV infected cells is via microtubules but not actin filament. Notably, viral particles were observed to transport along microtubules by using QD-labeled GCRV. Altogether, our results suggest that GCRV can use endosomes and microtubules to initiate productive infection.
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http://dx.doi.org/10.1007/s12250-019-00178-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198692PMC
April 2020

Sharp pH-responsive mannose prodrug polypeptide nanoparticles encapsulating a photosensitizer for enhanced near infrared imaging-guided photodynamic therapy.

J Mater Chem B 2019 11 9;7(43):6770-6777. Epub 2019 Oct 9.

CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, and Department of Chemical Physics, iCHEM, University of Science and Technology of China, Jinzai road 96, Hefei, 230026, Anhui, China.

Mannose has been reported as a novel drug to kill cancer cells. The prodrug of mannose will promote its targeted delivery and enrichment at the tumor site and cancer cells. Here, a pH-sensitive polypeptide copolymer with a tertiary amine group has been prepared and a mannose molecule was conjugated to the polymer through the formation of a Schiff base. At the same time, an iodinated boron dipyrromethene (BDPI) photosensitizer with high singlet oxygen generation efficacy and near infrared (NIR) fluorescence was encapsulated by the nanoparticles, which makes it a potential pH-sensitive NIR imaging-guided chemotherapy/PDT agent. In vitro and in vivo studies reveal that in a tumor acidic environment, the protonation of the tertiary amine group destroyed the nanostructure of the nanoparticles, resulting in increased BDPI release. Meanwhile, the bond cleavage of the Schiff base led to the release of conjugated mannose and synergistic inhibition of tumor cell growth with the PDT effect was realized. The combination of these two kinds of tumor suppression effects and photodynamic therapy made this pH-sensitive polypeptide delivery system show great potential for further cancer therapy.
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http://dx.doi.org/10.1039/c9tb01527bDOI Listing
November 2019

Effect of Particle Size Refinement on the Leaching Behavior of Mixed Rare-Earth Concentrate Using Hydrochloric Acid.

ACS Omega 2019 Jun 4;4(6):9813-9822. Epub 2019 Jun 4.

Key Laboratory of Green Extraction and Efficient Utilization of Light Rare Earth Resources and Mining Research Institute, Inner Mongolia University of Science and Technology, Baotou 014010, China.

The effects of particle size, temperature, and leaching time on the leaching behavior of rare-earth elements were studied. The leaching efficiency of the rare earth reached 39.24% under leaching conditions of hydrochloric acid concentration of 8.00 mol/L, particle size 95% distributed below 1.5 μm, leaching time of 120 min, and temperature of 90 °C. According to the scanning electron microscopy and X-ray diffraction analysis of the residue, the mechanism of the leaching process was also investigated. Actually, the phase of REFCO transformed into that of RECl and REF but there was an existing intermediate transition, where the phase of REFCO on reacting with hydrochloric acid generated that of REO F and this process also released RE into the solution. REO F continued reacting with hydrochloric acid to release a lot of F, which on combining with RE formed REF precipitation. The leaching kinetics of rare earths follows a shrinking core model that can be expressed as 1 - 3(1 - ) + 2(1 - ) = . The activation energies are 62.1, 54.8, 35.1, and 34.9 kJ/mol, respectively.
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http://dx.doi.org/10.1021/acsomega.9b01141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648474PMC
June 2019

Chlorogenic acid attenuates cadmium-induced intestinal injury in Sprague-Dawley rats.

Food Chem Toxicol 2019 11 4;133:110751. Epub 2019 Aug 4.

State Key Lab of Food Science and Technology, Institute of Nutrition and College of Food Science and Technology, Nanchang University, Nanchang, 330047, China. Electronic address:

Chronic exposure to cadmium (Cd) causes remarkable damage to the liver and gastrointestinal tract. Previous studies have revealed that chlorogenic acid (CGA) could improve the intestinal barrier integrity for weaned rats. Hence, this study sought to investigate the protective effects of CGA from pure reagent and sunflower seed extract (SSE) on growth performance, antioxidant indicators, inflammatory biomarkers and intestinal barrier function in Cd treated rats. A total of 32 Sprague-Dawley female rats with similar weights were randomly allotted to four treatments: control, CdCl (6 mg/kg BW), co-treatment of Cd (6 mg/kg BW) and pure CGA (50 mg/kg BW), and co-treatment of Cd (6 mg/kg BW) and SSE (50 mg/kg BW) for 14 days. The data indicated that, CGA or SSE with Cd sequestration and good antioxidative ability decreased Cd absorption and accumulation in the jejunum and increased fecal Cd levels in Cd-exposed rats. Compared with the Cd group, co-treatment with CGA or SSE also alleviated inflammation, ameliorated the villus damage, reversed the disruption of tight junctions, and recovered weight gain of rats. These results suggest that CGA or SSE can protect the intestinal barrier, which is related to the alleviation of Cd-induced oxidative stress and growth decrease.
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http://dx.doi.org/10.1016/j.fct.2019.110751DOI Listing
November 2019

Angiotensin-converting enzyme 2 regulates autophagy in acute lung injury through AMPK/mTOR signaling.

Arch Biochem Biophys 2019 09 26;672:108061. Epub 2019 Jul 26.

Department of pulmonary and critical care medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China. Electronic address:

Autophagy exerts a dual role in promoting cell death or survival. Recent studies have shown that it may play an important role in lipopolysaccharide (LPS)-induced acute lung injury (ALI). It was also suggested that angiotensin converting enzyme 2 (ACE2) may participate in the regulation of autophagy. The present study aims to investigate the role of autophagy in ALI and the involvement of ACE2. The regulation of the APMK/mTOR pathway was explored to clarify the underlying mechanism. The results showed that autophagy played an important role in ALI induced by LPS, as the autophagy inhibitor 3-methyladenine (3-MA) mitigated the severity of ALI. ACE2 activator resorcinolnaphthalein and inhibitor MLN-4760 significantly affected the histological appearance and wet/dry (W/D) ratio of the lung and altered the ACE2 activity of the lung, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) levels in lung tissue. Furthermore, LPS, resorcinolnaphthalein and MLN-4760 significantly affected the expression of autophagy proteins Beclin-1, LC3-I and LC3-II. To explore the mechanism of ACE2 on lung autophagy, we measured the phosphorylation of AMPK/mTOR after mice were treated with LPS and resorcinolnaphthalein or MLN-4760. The results revealed that resorcinolnaphthalein and MLN-4760 both significantly altered the phosphorylation of AMPK/mTOR. Finally, we found that AMPK inhibitor (8-bAMP) and mTOR activator (propranolol) both abolished the effects of ACE2 activator (resorcinolnaphthalein) on the expression of lung autophagy proteins Beclin-1, LC3-I and LC3-II. In conclusion, these findings suggest that ACE2 could alleviate the severity of ALI, inflammation and autophagy in lung tissue through the AMPK/mTOR pathway.
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http://dx.doi.org/10.1016/j.abb.2019.07.026DOI Listing
September 2019

LF4/MOK and a CDK-related kinase regulate the number and length of cilia in Tetrahymena.

PLoS Genet 2019 07 24;15(7):e1008099. Epub 2019 Jul 24.

Department of Cellular Biology, University of Georgia, Athens, Georgia, United States of America.

The length of cilia is controlled by a poorly understood mechanism that involves members of the conserved RCK kinase group, and among them, the LF4/MOK kinases. The multiciliated protist model, Tetrahymena, carries two types of cilia (oral and locomotory) and the length of the locomotory cilia is dependent on their position with the cell. In Tetrahymena, loss of an LF4/MOK ortholog, LF4A, lengthened the locomotory cilia, but also reduced their number. Without LF4A, cilia assembled faster and showed signs of increased intraflagellar transport (IFT). Consistently, overproduced LF4A shortened cilia and downregulated IFT. GFP-tagged LF4A, expressed in the native locus and imaged by total internal reflection microscopy, was enriched at the basal bodies and distributed along the shafts of cilia. Within cilia, most LF4A-GFP particles were immobile and a few either diffused or moved by IFT. We suggest that the distribution of LF4/MOK along the cilium delivers a uniform dose of inhibition to IFT trains that travel from the base to the tip. In a longer cilium, the IFT machinery may experience a higher cumulative dose of inhibition by LF4/MOK. Thus, LF4/MOK activity could be a readout of cilium length that helps to balance the rate of IFT-driven assembly with the rate of disassembly at steady state. We used a forward genetic screen to identify a CDK-related kinase, CDKR1, whose loss-of-function suppressed the shortening of cilia caused by overexpression of LF4A, by reducing its kinase activity. Loss of CDKR1 alone lengthened both the locomotory and oral cilia. CDKR1 resembles other known ciliary CDK-related kinases: LF2 of Chlamydomonas, mammalian CCRK and DYF-18 of C. elegans, in lacking the cyclin-binding motif and acting upstream of RCKs. The new genetic tools we developed here for Tetrahymena have potential for further dissection of the principles of cilia length regulation in multiciliated cells.
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http://dx.doi.org/10.1371/journal.pgen.1008099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682161PMC
July 2019

Uridine dynamic administration affects circadian variations in lipid metabolisms in the liver of high-fat-diet-fed mice.

Chronobiol Int 2019 09 12;36(9):1258-1267. Epub 2019 Jul 12.

a State Laboratory of Food Science and Technology, School of Food Science and Technology, Nanchang University , Nanchang , Jiangxi , China.

Carbohydrate and lipid metabolism in the liver has been reported to follow a certain circadian rhythm. Moreover, uridine supplementation also affected glucose and lipid homeostasis in previous studies; however, the mechanisms remain unclear. Therefore, this study was conducted to investigate whether uridine supplementation at an appropriate time during the day can alleviate obesity in mice. C57BL/6J mice were randomly assigned to four groups (n = 24 per group) with different diets for 2 weeks: (1) HFD group, fed a diet containing 60% fat calories; (2) DUR group, fed with HFD supplemented with 400 mg/kg uridine during zeitgeber time (ZT0) 0 - zeitgeber time 12 ZT12; (3) NUR group, fed HFD supplemented with 400 mg/kg uridine during ZT12 - ZT24. Starting at ZT4, liver samples were collected every 6 h for 24 h. Results showed that uridine supplementation, independent of the time of administration during the day, significantly reduced body weight gain ( < .05). Furthermore, liver weight and ratio showed a strong time dependence ( < .001). Additionally, oral administration of uridine during daytime or nighttime changed the expression levels of genes involved in the metabolism of uridine (SLC29A1, UMPS, UPP, UGT1A1, and DHODH; < .05). Furthermore, uridine affected the levels of 10 fatty acids, lipid and glucose gene (FASN, LCAT, PC, PEPCK, GSK3β, and GLUT2; < .05) depending on the timing of administration ( < .05). In conclusion, oral supplementation with uridine affected the diurnal variations in liver nucleotide and lipid metabolism, which contributed to the weight loss in HFD-fed mice.
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http://dx.doi.org/10.1080/07420528.2019.1637347DOI Listing
September 2019

Dietary l-tryptophan alleviated LPS-induced intestinal barrier injury by regulating tight junctions in a Caco-2 cell monolayer model.

Food Funct 2019 May;10(5):2390-2398

College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.

The intestinal epithelial layer forms a barrier through cell-cell tight junctions and breaking or even slightly disrupting this barrier can lead to serious pathological consequences, including infection and inflammation. Various amino acids have been shown to improve the intestinal tract, but the effect of tryptophan on the intestinal barrier has been controversial. Here, an in vitro Caco-2 cell model was built to investigate the protective and reparative effects of different concentrations of dietary l-Tryptophan (l-Trp) on lipopolysaccharide (LPS)-induced intestinal tight junction injury. Lower concentrations (40 μM) of dietary l-Trp protected and repaired the integrity and permeability injury of the intestinal tight junction induced by LPS, while high concentrations (80 μM) may not have a positive effect. LPS-induced injury led to increased (P < 0.05) mRNA expression of Nuclear factor-kappa B (NFκB) and Myosin light-chain kinase (MLCK), and decreased (P < 0.05) the mRNA expression of extracellular regulated protein kinase 1/2 (ERK1/2) and Mitogen-activated protein (MAP), and the treatment of dietary l-Trp alleviated those regulations in different concentrations, which suggests that dietary l-Trp may attenuate LPS-induced injury to tight junctions via inhibiting the NFκB-MLCK signaling pathway and activating the ERK1/2-MAP signaling pathway. And the mRNA and protein expressions of claudin-1, occludin and ZO-1 in LPS-induced injury were all down-regulated to varying degrees, and dietary l-Trp weakened the down-regulation of claudin-1 (P < 0.05) with no significant regulation of the protein expression of occludin and ZO-1 (P > 0.05).
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http://dx.doi.org/10.1039/c9fo00123aDOI Listing
May 2019

Treatments for Iron Deficiency (ID): Prospective Organic Iron Fortification.

Curr Pharm Des 2019 ;25(3):325-332

State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China.

Iron deficiency, one of the most common nutritional deficient disorders, frequently affects infants, adolescents and pregnant women and impairs growth, development and immune responses. Iron deficiency may also be secondary to gastrointestinal conditions such as gastrectomy and inflammatory bowel disease, as well as cancer and chronic uremia. Iron supplementation is the most commonly selected treatment option for iron deficiency. This review summarizes the iron compounds currently recommended for the iron fortification of foods and for clinical use. Additionally, this review discusses and compares the important aspects of high-quality iron compounds/products and classes of compounds that enhance iron bioavailability. The development of efficient iron fortification methods remains the most cost-effective and long-term approach to the treatment of iron deficiency or related anemia. To date, no orally administered options for iron fortification can sufficiently replace the parenteral administration of iron supplements, which includes the intramuscular injection of iron-dextran to neonatal piglets and intravenous injection of iron supplements to patients with gastrointestinal disorders. Iron bioavailability may be enhanced by encouraging customers to ingest iron-enriched foods together with dietary sources of vitamin C, folic acid and/or oligosaccharides.
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http://dx.doi.org/10.2174/1381612825666190319111437DOI Listing
February 2020

Polypeptide-Conjugated Second Near-Infrared Organic Fluorophore for Image-Guided Photothermal Therapy.

ACS Nano 2019 03 25;13(3):3691-3702. Epub 2019 Feb 25.

CAS Key Laboratory of Soft Matter Chemistry, iChEM, and Department of Chemical Physics , University of Science and Technology of China , Hefei 230026 , China.

Image-guided photothermal therapy (PTT) is an attractive strategy to improve the diagnosis accuracy and treatment outcomes by monitoring the accumulation of photothermal agents in tumors in real-time and determining the best treatment window. Taking advantage of the superior imaging quality of NIR-II fluorescence imaging and remote-controllable phototherapy modality of PTT, we developed a facile macromolecular fluorophore (PF) by conjugating a small-molecule NIR-II fluorophore (Flav7) with an amphiphilic polypeptide. The PF can form uniform micelles in aqueous solution, which exhibit a slight negative charge. In vitro experimental results showed that the PF nanoparticles showed satisfactory photophysical properties, prominent photothermal conversion efficiency (42.3%), excellent photothermal stability, negligible cytotoxicity, and photothermal toxicity. Meanwhile, the PF can visualize and feature the tumors by NIR-II fluorescence imaging owing to prolonged blood circulation time and enhanced accumulation in tumors. Moreover, in vivo studies revealed that the PF nanoparticles achieved an excellent photothermal ablation effect on tumors with a low dose of NIR-II dye and light irradiation, and the process can be traced by NIR fluorescence imaging.
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http://dx.doi.org/10.1021/acsnano.9b00452DOI Listing
March 2019