Oxidative stress-induced temporal activation of ERK1/2 phosphorylates coreceptor of Wnt/ß-catenin for myofibroblast formation in human lens epithelial cells.

Purpose: Posterior capsular opacification (PCO) is the most common complication postcataract surgery, and its underlying mechanisms involve epithelial-mesenchymal transition (EMT) of remnant lens epithelial cells (LECs) in response to drastic changes in stimuli in the intraocular environment, such as oxidative stress and growth factors. Wnt/ß-catenin signaling is a major pathway mediating oxidative stress-induced EMT in LECs, but its interplay with other transduction pathways remains little known in the development of PCO. ERK1/2 signaling is the downstream component of a phosphorelay pathway in response to extracellular stimuli (e.g., reactive oxygen species), and its activation regulates multiple cellular processes, including proliferation and EMT. Thus, this study aimed to investigate how ERK1/2 signaling and Wnt/ß-catenin pathway crosstalk in oxidative stress-induced EMT in LECs. Methods: Hydrogen peroxide (H2O2) at 50 µM treatment for 48 h was used to establish a moderate oxidative stress-induced EMT model in LECs. ERK1/2 signaling was inhibited using MEK1/2 inhibitor U0126 at 20 µM. Western blotting was used to quantify protein expression of various biomarkers of EMT and phosphorylated components in ERK1/2 and Wnt/ß-catenin signaling. LEC proliferation was determined using an EdU staining assay and expression of proliferating cellular nuclear antigen (PCNA). Subcellular localization of biomarker proteins was visualized with immunofluorescent staining. Results: Under the moderate level of H2O2-induced EMT in LECs, ERK1/2 signaling was activated, as evidenced by a marked increase in the ratio of phosphorylated ERK1/2 to total ERK1/2 at early (i.e., 5-15 min) and late time points (i.e., 12 h); the canonical Wnt/ß-catenin pathway was activated by H2O2 at 48 h. LECs exposed to H2O2 exhibited hyperproliferation and EMT; however, these were restored by inhibition of ERK1/2 signaling demonstrated by reduced DNA synthesis and PCNA expression for cellular proliferation and altered expression of various EMT protein markers, including E-cadherin, α-SMA, and vimentin. More importantly, inhibition of ERK1/2 signaling reduced ß-catenin accumulation in the activated Wnt/ß-catenin signaling cascade. Specifically, there was significant downregulation in the phosphorylation level of LRP6 at Ser 1490 and GSK-3ß at Ser 9, the key coreceptor of Wnt and regulator of ß-catenin, respectively. Conclusions: ERK1/2 signaling plays a crucial role in the moderate level of oxidative stress-induced EMT in LECs. Pharmacologically blocking ERK1/2 signaling significantly inhibited LEC proliferation and EMT. Mechanistically, ERK1/2 signaling regulated Wnt/ß-catenin cascade by phosphorylating Wnt coreceptor LRP6 at Ser 1490 in the plasma membrane. These results shed light on a potential molecular switch of ERK1/2 and Wnt/ß-catenin crosstalk underlying the development of PCO.

Anti-fatigue effects of fermented soybean protein peptides in mice.

BACKGROUND: Bioactive protein hydrolysates and peptides are believed to help counteract and ameliorate physical fatigue. Fermented soybean protein peptides (FSPPs) were prepared by protease hydrolysis and microbial fermentation. The present study aimed to evaluate the anti-fatigue properties of FSPPs. RESULTS: The forced swimming time in the FSPP group was 35.78% longer than the control group, the oxygen-resistant survival time of the FSPP group was significantly prolonged and the prolongation rate was 31.00%. In addition, FSPPs decreased the lactic acid (LD), blood urea nitrogen (BUN) and creatine kinase (CK) concentration by 27.47%, 25.93% and 21.70%, respectively, after treatment, while increasing the levels of liver glycogen and muscle glycogen by 93.35% and 67.31%, respectively. FSPPs can significantly increase gut microbiota diversity and regulate the species richness of gut microbiota. The results of real-time polymerase chain reaction (RT-PCR) and western blotting showed that FSPPs activate p-AMPK/PGC1-α and PI3K/Akt/mTOR signaling pathways. CONCLUSION: These results indicate that treatment with FSPPs induces anti-fatigue effects, which may be due to the mediating muscle protein synthesis and participation in skeletal muscle hypertrophy, providing energy for muscle cells. FSPPs may have potential applications in the food industry as functional material additives. © 2021 Society of Chemical Industry.

Perspectives of nursing directors on emergency nurse deployment during the pandemic of COVID-19: A nationwide cross-sectional survey in mainland China.

AIMS: The aim of this study is to investigate the situation and perceptions of nursing directors about emergency nursing staff deployment in designated hospitals during the pandemic of COVID-19 in mainland China. BACKGROUND: The pandemic of COVID-19 has significantly depleted health care resources, leading to increased burden of nursing care and staffing and exacerbating the crisis in health care facilities. Currently, how to effectively plan and schedule nursing staffing in the pandemic still remains unknown. METHODS: From 14 July 2020 to 8 September 2020, 62 nursing directors of designated hospitals in mainland China were invited to participate in a cross-sectional online survey for their perceptions of nursing human-resource allocation during the pandemic of COVID-19. RESULTS: A total of 55 valid questionnaires were collected, showing that 96.36% of the hospitals had emergency nursing organizations and management systems during the pandemic, 96.36% had well-established scheduling principles for nursing human resources and 54.55% of hospitals had human-resource scheduling platforms. All the hospitals had trained emergency nursing staff in infection control (55, 100%), work process (51, 92.73%) and emergency skills (50, 90.91%). Most of the participants were satisfied with the nursing staffing deployments at their institutions (52, 94.55%). However, more than two thirds of them believed that their human-resource deployment plans need further improvements (39, 70.91%). CONCLUSIONS: Most of the designated hospitals investigated had established emergency nursing organizations, and management systems, and related regulations for the epidemic. However, the contents mentioned above still need to be further standardized. IMPLICATIONS FOR NURSING MANAGEMENT: The surge of patients in the epidemic was considerable challenge for the emergency capacity of hospitals. In the future, we should pay more attention to the following aspects: building emergency nursing staffing platforms, increasing emergency human-resource reserves, establishing reliable communication channels for emergency response teams, improving the rules and regulations of emergency human-resource management, offering more training and drills for emergency-related knowledge and skills and giving more focus on bio-psycho-social wellbeing of nurses.

[Towards Academician Wang Qi's academic thought and medication philosophy in the treatment of secondary erectile dysfunction].

Professor Wang Qi, an academician of the Chinese Academy of Engineering and the founder of andrology of traditional Chinese medicine (TCM), has been engaged in theoretical and clinical researches on andrology of TCM for many years. Erudite and well-experienced, he advanced the idea of "treating impotence from the liver" and unique theories of TCM therapies for male diseases, with ingenuity and originality in clinical medication, proficient in using small and precise prescriptions to achieve high efficacy. This article summarizes and discusses the authors' experience in Professor Wang Qi's clinic learning from him his academic thought and medication philosophy in the treatment of secondary ED.

The mechanism and structure-activity relationship of amide bond formation by silane derivatives: a computational study.

The condensation of carboxylic acids and amines mediated by silane derivatives provided a straightforward and sustainable method for amide bond formation with minimal waste. However, the detailed mechanism and structure-activity relationship of substrates, the topics that are of interest for both academic and industrial applications, were not clear. Herein, a systematic computational study was conducted to solve the two questions. We found that the two previously proposed mechanisms involving intramolecular acyl transfer or silanolate were less likely because the associated silanone intermediate and zwitterion adducts were too unstable with higher overall energy barriers. By comparison, the mechanism involving deprotonation of carboxylic acids, addition of carboxylates on silane reagents, dihydrogen formation to afford an acyloxysilane intermediate, carboxylic-acid-assisted addition of amines, and concerted proton transfer/amide formation, was found to be more favorable with overall energy barriers varying between 24 and 28 kcal mol-1 for the different calculated cases. Meanwhile, the dihydrogen formation and amide formation processes are both potential rate-determining steps. Energy composition, atomic charge, and distortion-interaction analyses indicated that the steric effect of silane reagents was more important than the electronic effect, making less bulky silane reagents more reactive. On the other hand, the dihydrogen formation process was mainly controlled by the electronic effect of the substituents of carboxylic acids and amines while the amide formation process was mainly influenced by their steric effect. As a result, less bulky, less acidic alkyl carboxylic acids are more reactive than unsaturated carboxylic acids, and less bulky, medium basic primary alkyl amines are more reactive than secondary alkyl amines and primary aryl amines. The related results provided deeper mechanistic insights into the amide bond formation mediated by silane derivatives and can act as a reference for further experimental design.

[Fibrillin-2 gene mutations associated with hereditary connective tissue diseases].

Fibrillin-2 (FBN2) is an important component of microfibers which are involved in the formation of elastic fibers in connective tissue throughout the human body. Hereditary connective tissue diseases may result from genetic mutations of FBN2 causing heterogeneity of fibrin. Genetic mutations of FBN2 are associated with a variety of hereditary connective tissue diseases including Congenital Contractural Arachnodactyl (CCA), Macular Degeneration (MD), and myopathy. Studies have shown that the FBN2 gene is recognized as the only pathogenic gene related to CCA and that CCA patients have different clinical presentations depending on the identified genetic mutations at different FBN2 sites. In this review, we summarize the roles of FBN2, its mutations and impact on the physiological and pathological processes of many hereditary connective tissue diseases. We include brief descriptions of clinical manifestations of these diseases providing a basis for further exploration of the specific molecular mechanism of FBN2 gene mutation pathogenesis which provides a theoretical basis for the therapy and medications for refractory diseases caused by FBN2 gene mutation.

Mechanism and Rate-Determining Factors of Amide Bond Formation through Acyl Transfer of Mixed Carboxylic-Carbamic Anhydrides: A Computational Study.

Acyl transfer of in situ-generated mixed anhydrides is an important method for amide bond formation from short linkages with the easily removed byproduct CO2. To improve our understanding of the inherently difficult acyl transfer hindered by the large ring strain, a density functional theory study was performed. The calculations indicate that the amidation of activated α-aminoesters and N-protected amino acids is more likely to proceed via the self-catalytic nucleophilic substitution of the two substrates and the subsequent 1,3-acyl transfer. By comparison, the mechanism involving 1,5-acyl transfer is less kinetically favored because of the slow homocoupling of activated α-aminoesters. Furthermore, we found that the detailed mechanism of 1,3-acyl transfer on the mixed carboxylic-carbamic anhydrides depends on the catalysts. Strong acidic catalysts and bifunctional catalysts both lead to stepwise pathways, but their elementary steps are different. Basic catalysts cause a concerted C-N bond formation/decarboxylation pathway. The calculations successfully explain the reported performances of different Brønsted-type catalysts and substrates, which validates the proposed mechanism and reveals the dependence of the reaction rates on the acid-base property of catalysts and the acidity of substrates.

Importance of integrating nanotechnology with pharmacology and physiology for innovative drug delivery and therapy - an illustration with firsthand examples.

Nanotechnology has been applied extensively in drug delivery to improve the therapeutic outcomes of various diseases. Tremendous efforts have been focused on the development of novel nanoparticles and delineation of the physicochemical properties of nanoparticles in relation to their biological fate and functions. However, in the design and evaluation of these nanotechnology-based drug delivery systems, the pharmacology of delivered drugs and the (patho-)physiology of the host have received less attention. In this review, we discuss important pharmacological mechanisms, physiological characteristics, and pathological factors that have been integrated into the design of nanotechnology-enabled drug delivery systems and therapies. Firsthand examples are presented to illustrate the principles and advantages of such integrative design strategies for cancer treatment by exploiting 1) intracellular synergistic interactions of drug-drug and drug-nanomaterial combinations to overcome multidrug-resistant cancer, 2) the blood flow direction of the circulatory system to maximize drug delivery to the tumor neovasculature and cells overexpressing integrin receptors for lung metastases, 3) endogenous lipoproteins to decorate nanocarriers and transport them across the blood-brain barrier for brain metastases, and 4) distinct pathological factors in the tumor microenvironment to develop pH- and oxidative stress-responsive hybrid manganese dioxide nanoparticles for enhanced radiotherapy. Regarding the application in diabetes management, a nanotechnology-enabled closed-loop insulin delivery system was devised to provide dynamic insulin release at a physiologically relevant time scale and glucose levels. These examples, together with other research results, suggest that utilization of the interplay of pharmacology, (patho-)physiology and nanotechnology is a facile approach to develop innovative drug delivery systems and therapies with high efficiency and translational potential.

Polymer-lipid hybrid nanoparticles synchronize pharmacokinetics of co-encapsulated doxorubicin-mitomycin C and enable their spatiotemporal co-delivery and local bioavailability in breast tumor.

UNLABELLED: Effective combination chemotherapy requires the delivery of drugs of synergism to tumor sites while sparing normal tissues. Herein we investigated whether coencapsulation of doxorubicin and mitomycin C within polymer-lipid hybrid nanoparticles (DMPLN) achieved this goal via ratiometric drugs in an orthotopic murine breast tumor model with nanocarrier-modified biodistribution, pharmacokinetics, local bioavailability and toxicity. Fluorescence imaging revealed quickened and extended tumor uptake but reduced cardiac accumulation of DMPLN. Quantitative drug analysis demonstrated prolonged systemic circulation, increased tumor accumulation and sustained synergistic ratios of doxorubicin and mitomycin C delivered by DMPLN over 24h. Higher levels of tumor cell apoptosis and reduced organ toxicity were obtained with DMPLN compared to free drug cocktails. DMPLN released DOX in tumors more efficiently than that from liposomal doxorubicin, as evidenced by a higher extent of the metabolite, doxorubicinol. These findings substantiate the importance of rational design of nanoparticles for synergistic drug combination therapy. FROM THE CLINICAL EDITOR: The treatment of cancer usually involves using combination chemotherapeutic agents. In adopting a nanomedicine approach, one can in theory design combination therapy consisting of drugs of synergistic activities, with the aim to target tumor specifically while minimizing systemic toxicity. The authors in this study provided evidence for this rational design by co-encapsulation of doxorubicin and mitomycin C within polymer-lipid hybrid nanoparticles (DMPLN) in a breast cancer model.

YAP and TAZ Take Center Stage in Cancer.

The Hippo pathway was originally identified and named through screening for mutations in Drosophila, and the core components of the Hippo pathway are highly conserved in mammals. In the Hippo pathway, MST1/2 and LATS1/2 regulate downstream transcription coactivators YAP and TAZ, which mainly interact with TEAD family transcription factors to promote tissue proliferation, self-renewal of normal and cancer stem cells, migration, and carcinogenesis. The Hippo pathway was initially thought to be quite straightforward; however, recent studies have revealed that YAP/TAZ is an integral part and a nexus of a network composed of multiple signaling pathways. Therefore, in this review, we will summarize the latest findings on events upstream and downstream of YAP/TAZ and the ways of regulation of YAP/TAZ. In addition, we also focus on the crosstalk between the Hippo pathway and other tumor-related pathways and discuss their potential as therapeutic targets.

Synergistic nanoparticulate drug combination overcomes multidrug resistance, increases efficacy, and reduces cardiotoxicity in a nonimmunocompromised breast tumor model.

Anthracyclines, commonly employed for cancer chemotherapy, suffer from dose-limiting cardiotoxicity and poor efficacy due to multidrug resistance (MDR). We previously demonstrated that simultaneous delivery of the synergistic drugs doxorubicin (DOX) and mitomycin C (MMC) by polymer-lipid hybrid nanoparticles (PLN) circumvented MDR, increased efficacy, and reduced cardiotoxicity in immuncompromised mice superior to poly(ethylene glycol)-coated (PEGylated) lipososmal DOX (PLD). Herein it is shown that the DOX-MMC combination was also synergistic in MDR EMT6/AR1 murine breast cancer cells and that their nanoparticle formulations were able to overcome the MDR phenotype. In contrast PLD exhibited little or no effect on the MDR cells. For the first time, these differences in in vitro efficacy are shown to be strongly correlated with cellular uptake and intracellular distribution of DOX brought about by DOX formulations (e.g., free solution, PLN vs PLD). To take into consideration the role of an intact immune system and tumor stroma in the response of host and tumor to chemotherapy, use was made of nonimmunocomprised mouse models to study the dose tolerance, cardiotoxicity, and efficacy of DOX-MMC coloaded PLN (DMsPLN) compared to PLD. DMsPLN treatment at 50 mg/m(2) DOX and 17 mg/m(2) of MMC singly or once every 4 days for 4 cycles were well tolerated by the mice without elevated systemic toxicity blood markers or myocardial damage. In contrast, PLD was limited to a single treatment due to significant total weight loss. The DMsPLN treatment delayed tumor growth up to 312% and 28% in EMT6/WT and EMT6/AR1 models, respectively. This work supports the translational value of DMsPLN for the aggressive management of either naïve or anthracycline-resistant tumors.

Protocadherin-7 induces bone metastasis of breast cancer.

Breast cancer had a propensity to metastasize to bone, resulting in serious skeletal complications associated with poor outcome. Previous study showed that Protocadherin-7 (PCDH7) play an important role in brain metastatic breast cancer, however, the role of PCDH7 in bone metastatic breast cancer has never been explored. In the present study, we found that PCDH7 expression was up-regulation in bone metastatic breast cancer tissues by real-time PCR and immunohistochemistry assays. Furthermore, suppression of PCDH7 inhibits breast cancer cell proliferation, migration, and invasion in vitro by MTT, scratch, and transwell assays. Most importantly, overexpression of PCDH7 promotes breast cancer cell proliferation and invasion in vitro, and formation of bone metastasis in vivo. These data provide an important insight into the role of PCDH7 in bone metastasis of breast cancer.

Oxidative stress, epigenetic regulation and pathological processes of lens epithelial cells underlying diabetic cataract.

Background: Cataract is a blinding disease worldwide. It is an age-related disease that mainly occurs in people over 65 years old. Cataract is also prevalent in patients with diabetes mellites (DM). The pathological mechanisms underlying diabetic cataract (DC) are more complex than that of age-related cataract. Studies have identified that polyol pathway, advanced glycation end products (AGEs) and oxidative stress are the primary pathogenesis of DC. In recent years, molecular-level regulations and pathological processes of lens epithelial cells (LECs) have been confirmed to play roles in the initiation and progression of DC. A comprehensive understanding and elucidation of how chronic hyperglycemia drives molecular-level regulations and cytopathological processes in the lens will shed lights on the prevention, delay and treatment of DC. Main text: Excessive glucose in the lens enhances polyol pathway and AGEs formation. Polyol pathway causes imbalance in the ratio of NADPH/NADP+ and NADH/NAD+. Decrease in NADPH/NADP+ ratio compromises antioxidant enzymes, while increase in NADH/NAD+ ratio promotes reactive oxygen species (ROS) overproduction in mitochondria, resulting in oxidative stress. Oxidative stress in the lens causes oxidation of DNA, proteins and lipids, leading to abnormalities in their structure and functions. Glycation of proteins by AGEs decreases solubility of proteins. High glucose triggered epigenetic regulations directly or indirectly affect expressions of genes and proteins in LECs. Changes in autophagic activity, increases in fibrosis and apoptosis of LECs destroy the morphological structure and physiological functions of the lens epithelium, disrupting lens homeostasis. Conclusions: In both diabetic animal models and diabetics, oxidative stress plays crucial roles in the formation of cataract. Epigenetic regulations, include lncRNA, circRNA, microRNA, methylation of RNA and DNA, histone acetylation and pathological processes, include autophagy, fibrosis and apoptosis of LECs also involved in DC.

Microfluidics-based PLGA nanoparticles of ratiometric multidrug: From encapsulation and release rates to cytotoxicity in human lens epithelial cells.

Multidrug nanomedicine is an effective therapeutic approach for the treatment of chronic diseases and cancers. However, co-encapsulation and release of drug combination at a fixed ratio by nanoparticles, particularly for long acting ocular formulations, remains challenging. Herein, poly (lactic-co-glycolic acid) nanoparticles ratiometrically co-encapsulating hydrophilic dual drugs, mitomycin C and doxorubicin, was obtained (D/M PLGANPs) by combining microfluidics and the Design of Experiments approaches. The formulation variable of lactide-to-glycolide ratios (L/G 50:50, 75:15 and 85:15) was used to achieve fast, medium and slow drug release rates of D/M PLGANPs. The dissolution of D/M PLGANPs in simulated intraocular fluid exhibited sustained release of dual drugs at the fixed ratio over 7 days, and analysis using the Korsmeyer-Peppas model showed mechanism of drug release to be governed by diffusion. More importantly, in human lens epithelial cells, the drug release rate was negatively correlated with drug potency. The slower drug release from D/M PLGANPs led to lower efficacy of drug combination against pathogenesis of cellular migration and proliferation, the key pathogenic processes of capsular opacification after cataract surgery. Compared to fast (L/G 50:50) and medium (L/G 75:15) drug release rate of D/M PLGANPs, the slow release formulation (L/G 85:15) exhibited the least cellular uptake of the dual drugs and the ratio of drug combination was not maintained intracellularly. The present study implicates the potential of using microfluidics for synthesizing polymeric nanoparticles of ratiometric drug combination and highlights the drug release rate as the critical determinant of efficacy for the long-acting nanomedicine design.

Clinical Translation of Long-Acting Drug Delivery Systems for Posterior Capsule Opacification Prophylaxis.

Posterior capsule opacification (PCO) remains the most common cause of vision loss post cataract surgery. The clinical management of PCO formation is limited to either physical impedance of residual lens epithelial cells (LECs) by implantation of specially designed intraocular lenses (IOL) or laser ablation of the opaque posterior capsular tissues; however, these strategies cannot fully eradicate PCO and are associated with other ocular complications. In this review, we critically appraise recent advances in conventional and nanotechnology-based drug delivery approaches to PCO prophylaxis. We focus on long-acting dosage forms, including drug-eluting IOL, injectable hydrogels, nanoparticles and implants, highlighting analysis of their controlled drug-release properties (e.g., release duration, maximum drug release, drug-release half-life). The rational design of drug delivery systems by considering the intraocular environment, issues of initial burst release, drug loading content, delivery of drug combination and long-term ocular safety holds promise for the development of safe and effective pharmacological applications in anti-PCO therapies.

Numerical Simulation and Experimental Analysis on Seam Feature Size and Deformation for T-Joint Laser-GMAW Hybrid Welding.

As an innovative technique, laser-GMAW hybrid welding manifests significant superiority in enhancing welding productivity and quality, albeit the optimization of process parameters poses a challenge for practical application. The present manuscript elucidates the influence of process parameters on the dimensional characteristics of the welding seam and the distortion of 8 mm T-joints in the context of laser-GMAW hybrid welding, and channels both simulation and experimentation. The outcomes denote that the dual conical model serves as an efficacious aid for the numerical simulation of T-joint laser-GMAW hybrid welding. Furthermore, the repercussions of process parameters on welding seam dimensional characteristics remain consistently similar in both the simulation and experimental results. From the simulation outcomes, it becomes apparent that the distortion of the base material can be efficiently managed by implementing anti-distortion measures. This inquiry offers both a theoretical and experimental foundation for optimizing process parameters of T-joint laser-GMAW hybrid welding, presenting certain engineering applicability.

Inhibitory Effect of Jinkui Shenqi Pills on Glucocorticoid-Enhanced Axial Length Elongation in Experimentally Myopic Guinea Pigs.

OBJECTIVE: To explore the underlying mechanism of inhibition by Jinkui Shenqi Pills (JKSQP) on glucocorticoid-enhanced axial length elongation in experimental lens-induced myopia (LIM) guinea pigs. METHODS: Sixty 2-week old male guinea pigs were randomly divided into 4 groups with 15 guinea pigs in each group, according to the random numbers generated by SPSS software: control, LIM, saline and JKSQP groups. The control group includes animals with no treatment, while the guinea pigs in the other 3 groups received lens-induced myopization on the right eyes throughout the experiment (for 8 weeks). The saline and JKSQP groups were given daily intraperitoneal injections of 10 mg/kg hydrocortisone for 2 consecutive weeks at the same time, and then orally administered either saline or JKSQP [13.5 g/(kg•d) for 6 consecutive weeks. Body weight, anal temperature and animal appearance were observed and recorded to evaluate the GC-associated symptoms. The ocular parameters, including refraction and axial length, were measured by streak retinoscopy and A-scan ultrasonography, respectively. The levels of plasma hormones associated with the hypothalamic-pituitary-adrenal axis (HPAA), including free triiodothyronine, free thyroxine, estradiol and testosterone, were measured by radioimmunoassay, and cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate were measured by enzyme-linked immunosorbent assay. In addition, the mRNA and protein expressions of retinal amphiregulin (AREG) was measured by quantitative real-time polymerase chain reaction and Western blotting, respectively. RESULTS: JKSQP effectively increased body weight and anal temperature, improved animal appearance and suppressed axial length elongation in glucocorticoid-enhanced myopic guinea pigs with normalization of 4 HPAA-associated plasma hormones (all P<0.05). The plasma level of cAMP was significantly increased, whereas the plasma level of cGMP and the mRNA and protein expressions of retinal AREG were decreased after treatment with JKSQP (all P<0.05). CONCLUSION: JKSQP exhibited a significant inhibitory effect on axial length elongation with decreased expression of AREG in the retina, and normalized 4 HPAA-associated plasma hormones and the expression of cAMP and cGMP in GC-enhanced myopic guinea pigs.

Intravitreal injection of fibrillin 2 (Fbn2) recombinant protein for therapy of retinopathy in a retina-specific Fbn2 knock-down mouse model.

Mutations in the extracellular matrix gene Fibrillin-2 (FBN2) are related to genetic macular degenerative disorders including age-related macular degeneration (AMD) and early-onset macular degeneration (EOMD). It was reported that the retinal protein expression of FBN2 was reduced in patients with AMD and EOMD. The effect of exogenously supplied fbn2 recombinant protein on fbn2-deficiency-related retinopathy was not known. Here we investigated the efficacy and molecular mechanism of intravitreally applied fibrin-2 recombinant protein in mice with fbn2-deficient retinopathy. The experimental study included groups (all n = 9) of adult C57BL/6J male mice which underwent no intervention, intravitreal injection of adeno-associated virus (AAV) empty vector or intravitreal injection of AAV-sh-fbn2 (adeno-associated virus for expressing short hairpin RNA for fibrillin-2) followed by three intravitreal injections of fbn2 recombinant protein, given in intervals of 8 days in doses of 0.30 µg, 0.75 µg, 1.50 µg, and 3.00 µg, respectively. Eyes with intravitreally applied AAV-sh-fbn2 as compared to eyes with injection of AAV-empty vector or developed an exudative retinopathy with involvement of the deep retinal layers, reduction in axial length and reduction in ERG amplitudes. After additional and repeated application of fbn2 recombinant protein, the retinopathy improved with an increase in retinal thickness and ERG amplitude, the mRNA and protein expression of transforming growth factor-beta (TGF-ß1) and TGF-ß binding protein (LTBP-1) increased, and axial length elongated, with the difference most marked for the dose of 0.75 µg of fbn2 recombinant protein. The observations suggest that intravitreally applied fbn2 recombinant protein reversed the retinopathy caused by an fbn2 knockdown.

Oral delivery of decanoic acid conjugated plant protein shell incorporating hybrid nanosystem leverage intestinal absorption of polyphenols.

Polyphenols are potent antioxidants, but their poor oral bioavailability owing to intrinsic insolubility and low permeability significantly hampers their effectiveness for clinical translation. Herein, upper intestinal absorptive polymer-lipid hybrid nanoparticles (PLN) was designed by exploiting the lipidic core for drug encapsulation and the decanoic acid conjugated rapeseed protein as the biopolymeric shell for gastrointestinal stability, retention and permeability. Polyphenol ellagic acid loaded core-shell PLN (EA-PLN(C/S)) was characterized of favorable physicochemical properties in simulated gastric- and intestinal fluids, including high drug loading capacity, slow drug release and prolonged stability. In Caco-2 monolayers, the cellular transport of EA-PLN(C/S) involved dual-paracellular and endocytosis pathways. Compared to drug in suspension or lipidic core nanoparticles, orally administered EA-PLN(C/S) was retained longer and more permeable via the duodenum and jejunum of upper intestine, resulting in up to 5.3-fold and 1.4-fold enhancement in the extent of drug absorption and colonic accumulation, respectively. In an acute colitis murine model, EA-PLN(C/S) at 6 mg/kg low dose markedly reduced colonic lipid peroxidation in contrast to no antioxidant effect in other EA formulations. This work suggests that integration of engineered plant protein biopolymer with lipid nanoparticles created unique oral drug delivery systems enabling intestinal site-specific absorption for effective antioxidant therapeutics.

Pharmaceutical nanoformulation strategies to spatiotemporally manipulate oxidative stress for improving cancer therapies - exemplified by polyunsaturated fatty acids and other ROS-modulating agents.

Chronic oxidative stress and inflammation promote tumorigenesis and tumor progression, while certain chemotherapeutic drugs and radiation are applied to produce free radicals against cancer cells. To reduce tumor-promoting oxidative stress and protect normal tissue from chemotherapy and radiation-associated toxicity, dietary antioxidants, such as omega-3 polyunsaturated fatty acids (PUFA), have been combined with cancer therapies. However, the results of clinical studies are mixed with little to no benefit to therapeutic effect, and even exacerbated adverse effects. PUFA can function as a double-edged sword as an anti- or pro-oxidant depending on when and where it appears. Recent publications indicate that nano-formulations can enhance therapeutic benefit of PUFA and other free-radical generating cytotoxic drugs during chemotherapy by controlling oxidative stress within a nanoscale vicinity. This article critically evaluates the concurrent use of dietary omega-3 PUFA as an adjuvant to cancer therapies, reviews the findings in studies using nanoparticle formulations, and delineates the importance of spatiotemporal manipulation of oxidative stress by pharmaceutical nanotechnology for improving outcomes with cancer therapies using various examples. We hope this review will shed light on rational design of nano-formulations to turn harmful pathological oxidative stress into useful pharmacological modalities by manipulating the location and timing of free-radical generation.