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Although it is well established that Huntington's disease (HD) is mainly caused by polyglutamine-expanded mutant huntingtin (mHTT), the molecular mechanism of mHTT-mediated actions is not fully understood. Here, we showed that expression of the N-terminal fragment containing the expanded polyglutamine (HTTQ94) of mHTT is able to promote both the ACSL4-dependent and the ACSL4-independent ferroptosis. Surprisingly, inactivation of the ACSL4-dependent ferroptosis fails to show any effect on the life span of Huntington's disease mice. Moreover, by using RNAi-mediated screening, we identified ALOX5 as a major factor required for the ACSL4-independent ferroptosis induced by HTTQ94. Although ALOX5 is not required for the ferroptotic responses triggered by common ferroptosis inducers such as erastin, loss of ALOX5 expression abolishes HTTQ94-mediated ferroptosis upon reactive oxygen species (ROS)-induced stress. Interestingly, ALOX5 is also required for HTTQ94-mediated ferroptosis in neuronal cells upon high levels of glutamate. Mechanistically, HTTQ94 activates ALOX5-mediated ferroptosis by stabilizing FLAP, an essential cofactor of ALOX5-mediated lipoxygenase activity. Notably, inactivation of theAlox5gene abrogates the ferroptosis activity in the striatal neurons from the HD mice; more importantly, loss of ALOX5 significantly ameliorates the pathological phenotypes and extends the life spans of these HD mice. Taken together, these results demonstrate that ALOX5 is critical for mHTT-mediated ferroptosis and suggest that ALOX5 is a potential new target for Huntington's disease.

BACKGROUND: High-speed health trains are important tools and guarantees in major accidents, epidemic pandemics, disasters, and warfare health care, and the health trains currently developed for common train platforms have more functional defects. OBJECTIVE: The purpose of this study is to analyze the relationship between the medical transfer system and the medical system, and to obtain a better medical transfer train formation through the established model. METHODS: Based on the case study of medical transport tools, this paper analyzes the components and interrelationships of the medical transport system and the medical system, and then analyzes the medical transport task process of the health train by using the hierarchical task analysis (HTA) method. Combined with the Chinese standard EMU, a medical transport task model of the high-speed health train is established. Through this model, the functional compartment unit of the high-speed health train and the marshaling scheme of the high-speed health train are obtained. RESULTS: The expert system is used to evaluate the scheme. The results show that the train formation scheme formulated by the model in this paper is superior to other train formation schemes in three indicators, meeting the requirements of large medical transfer tasks. CONCLUSION: The results of this study can improve the ability of on-site treatment of patients, and can provide a basis for the research and development of a high-speed health train, which has a certain practical application value.

The fall armyworm (FAW) Spodoptera frugiperda Smith (Lepidoptera: Noctuidae) invaded Myanmar and China in 2018 and greatly impacted agricultural production and ecosystem balance in these areas. FAW is a migratory insect, but its seasonal migration pattern between the two countries has been largely unknown. From 2019 to 2021, we monitored the seasonal migration of FAW in the China-Myanmar border area using a searchlight trap, assessed the reproductive development status of female migrants and traced the migratory routes by trajectory simulation.FAW moths were trapped by the searchlight trap in Lancang County (Yunnan, China) all year, with obvious seasonal differences in the number caught. There were small-scale persistent trapping peaks in spring and summer, and obvious peaks in autumn; only a small number of moths were trapped in winter. Examination of the ovaries of female moths collected in different seasons showed that most females had matured, indicating that the moths were migrating and did not take off from the local area. In the migration trajectory simulation, FAW mainly migrated from Myanmar to Southwest China in spring and summer and back to Myanmar in autumn.Our findings indicate that FAW migrates between China and Myanmar according to the monsoon circulation, which will help guide cross-border regional monitoring and management strategies against this pest. © 2022 Society of Chemical Industry.

As a global health threat, NASH has been confirmed to be a chronic progressive liver disease that is strongly associated with obesity. However, no approved drugs or efficient therapeutic strategies are valid, mainly because its complicated pathological processes is underestimated.We identified the RING-type E3 ubiquitin transferase-tripartite motif-containing protein 31 (TRIM31), a member of the E3 ubiquitin ligases family, as an efficient endogenous inhibitor of transforming growth factor-beta-activated kinase 1 (mitogen-activated protein kinase kinase kinase 7; MAP3K7), and we further confirmed that TRIM31 is an MAP3K7-interacting protein and promotes MAP3K7 degradation by enhancing ubiquitination of K48 linkage in hepatocytes. Hepatocyte-specific Trim31 deletion blocks hepatic metabolism homeostasis, concomitant with glucose metabolic syndrome, lipid accumulation, up-regulated inflammation, and dramatically facilitates NASH progression. Inversely, transgenic overexpression, lentivirus, or adeno-associated virus-mediated Trim31 gene therapy restrain NASH in three dietary mice models. Mechanistically, in response to metabolic insults, TRIM31 interacts with MAP3K7 and conjugates K48-linked ubiquitination chains to promote MAP3K7 degradation, thus blocking MAP3K7 abundance and its downstream signaling cascade activation in hepatocytes.TRIM31 may serve as a promising therapeutic target for NASH treatment and associated metabolic disorders.

PDF file - 179KB, Sequence of oligonucleotides used in this study.

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PDF file - 2673KB, MiR-30s target BCL9 in MM cells.

Supplementary Figure S3. Changes in PUMA mRNA expression induced by V-miR-221-222-GFP and V-as-miR-221-222-GFP.

Supplementary Figure S2. AGO2/RNA immunoprecipitation assay in MM1S cells.

PDF file - 1392KB, BMSCs decrease miR-30s levels, and enforced expression of miR-30s inhibits CAM-DR in MM cells.

Supplementary Figure Legends. Legend for Supplementary Figures S1-S4.

PDF file - 2071KB, MiR-30s treatment does not have a negative impact on bone disease in MM1S-Luc-Neo bearing mice.

Supplementary Figure S4. Increased drug resistance to apoptosis in V-miR-221-222-GFP stable transduced MM1S cells.

The G protein–coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver–bile acid–microbiota–organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non–small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for β-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR–β-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.

The H-bond and ionic bond of the well-defined PSMA hydrolysates induce the TSI-n–π of carbonyl clusters to emit fluorescence and RTP.

Wuhai is a typical coking industrial base including three industrial parks within its jurisdiction. The emission amount of air pollutants is considerable here, and O

Sesquiterpenes are one of the most diverse groups of secondary metabolites that have mainly been observed in terpenoids. It is a natural terpene containing 15 carbon atoms in the molecule and three isoprene units with chain, ring, and other skeleton structures. Sesquiterpenes have been shown to display multiple biological activities such as anti-inflammatory, anti-feedant, anti-microbial, anti-tumor, anti-malarial, and immunomodulatory properties; therefore, their therapeutic effects are essential. In order to overcome the problem of low-yielding sesquiterpene content in natural plants, regulating their biosynthetic pathways has become the focus of many researchers. In plant and microbial systems, many genetic engineering strategies have been used to elucidate biosynthetic pathways and high-level production of sesquiterpenes. Here, we will introduce the research progress and prospects of the biosynthesis of artemisinin, costunolide, parthenolide, and dendrobine. Furthermore, we explore the biosynthesis of dendrobine by evaluating whether the biosynthetic strategies of these sesquiterpene compounds can be applied to the formation of dendrobine and its intermediate compounds. KEY POINTS: • The development of synthetic biology has promoted the study of terpenoid metabolism and provided an engineering platform for the production of high-value terpenoid products. • Some possible intermediate compounds of dendrobine were screened out and the possible pathway of dendrobine biosynthesis was speculated. • The possible methods of dendrobine biosynthesis were explored and speculated.

The fall armyworm (FAW, Spodoptera frugiperda Smith) is an important invasive pest of maize crops in Africa, Asia and the Middle East. To enable timely and effective pest management, accurate monitoring and forecasting of S. frugiperda populations is essential. In this study, we used food attractants to assess seasonal abundance of S. frugiperda in southern Yunnan (China) and determined adult age based upon ovarian development or testes size. During 2020–2021, the seasonal abundance of trapping S. frugiperda males with food attractants and sex pheromones were approximately the same at two field sites. Both trapping methods yielded S. frugiperda males of different ages – with an identical age structure for both trap types. The proportion of females trapped with food attractants was about 80%, which was significantly higher than that of males. S. frugiperda populations at two field sites were composed of immigrants that either originated in central Yunnan or in eastern Myanmar. Based upon field-level recordings of adult reproductive state, models reliably anticipated S. frugiperda fecundity dynamics. Next, drawing upon meteorological data and FAW adult age, migration trajectories were established for S. frugiperda immigrant populations. Overall, these novel (food-based) monitoring and forecasting tools can improve integrated pest management (IPM) of S. frugiperda in China and abroad.

Ferroptosis is an iron-dependent regulated cell death marked by excessive oxidative phospholipids (PLs). The polyunsaturated fatty acids-containing phospholipids (PUFA-PLs) are highly susceptible to lipid peroxidation under oxidative stress. Numerous pulmonary diseases occurrences and degenerative pathologies are driven by ferroptosis. This review discusses the role of ferroptosis in the pathogenesis of pulmonary diseases including asthma, lung injury, lung cancer, fibrotic lung diseases, and pulmonary infection. Additionally, it is proposed that targeting ferroptosis is a potential treatment for pulmonary diseases, particularly drug-resistant lung cancer or antibiotic-resistant pulmonary infection, and reduces treatment-related adverse events.

Purpose: Spinal cord injury (SCI) has a damaging impact on patients, amid being a worldwide problem with no effective treatment. Herein, we reported a method for functional therapy of SCI in rats, wherein we combined thermo-sensitive hydrogel with Sonic Hedgehog (SHH) expressed in rat bone-marrow derived mesenchymal stem cells (RMSCs).Methods: Bone marrow-derived mesenchymal stem cells (BMSCs) were isolated from Sprague-Dawley (SD) female rats. The SHH was optimized and transferred into RMSCs via cationic liposomes, while thermo-sensitive hydrogel was reformed with hyaluronate (HA) and Pluronic F127. Then, a rat model with SCI was established accordingly by male SD rats and randomized into sham, model, RMSCs with hydrogel and SHH-RMSCs with hydrogel. The evaluation of SCI repair based on Basso, Beattie Bresnahanlocomotor rating scale (BBB scale) and inclined plate score. Immunofluorescence, immunohistochemistry and hematoxylin-eosin were utilized to explore the expression of protein (GFAP, GAP43, NF200 and MBP) and histopathology.Results: It was demonstrated that transfection of SHH with cationic liposomes exhibited more effect in RMSCs than lipofectamine 2000. As shown in SEM, 3.5% HA-F127 demonstrated porous structure. In the MTT and dead/live assay, 3.5% HA-F127 showed good biocompatibility for RMSCs. Both RMSCs and SHH-RMSCs groups could significantly promote BBB and inclined plate scores (p < 0.01) compared with the model. Furthermore, the SHH-RMSC group was significantly improved than RMSC with the expression of related proteins, where NF200, MBP, and GAP43 were principally enhanced with the GFAP expression being virtually down-regulated.Conclusion: All in all, the results suggested that transplantation of RMSCs with SHH could improve the function of SCI and promote nerve regeneration.

Single-molecule white-light emission (SMWLE) has many advantages in practical applications; however, the fabrication of SMWLE from nonconjugated luminescent polymers, namely, clusteroluminogens (CLgens), is still a big challenge. Herein, the first example of linear nonconjugated polyesters with SMWLE is reported. Twenty-four kinds of nonconjugated aliphatic polyesters with tunable clusteroluminescence (CL) colors and efficiency were synthesized by the copolymerization of six epoxides and four anhydrides. Experimental and calculation results prove that, at the primary structure level, the balance of structural flexibility and rigidity via adjusting the side-chain length significantly enhances the efficiency of CL without wavelength change. However, altering the chemical structures of the monomer from succinic anhydride to

We report a transparent display based on a metasurface of silver nanoparticles (Ag NPs), consisting of a transparent substrate and a layer of Ag NPs deposited by a dielectric film. The Ag NPs metasurface is prepared by a simple and direct annealing process. It presents a deep transmission valley at the wavelength of λ = 468 nm and enables desired transparent display by projecting the monochromatic image onto the metasurface. We also demonstrate that the formed Ag NPs can be approximated as truncated nanospheres, which have obvious directional scattering properties, and can radiate most of the scattered energy into the backward hemisphere with a relatively large angular beamwidth (the full width at half maximum of the scattered intensity) of ∼90°. Therefore, the fabricated displays possess wide viewing angles and high brightness characteristics. Additionally, the transmission modes can be red-shifted to the wavelength of λ = 527 nm by controlling the thickness of the deposited dielectric film. This approach using traditional thin film deposition and moderate annealing processing techniques enables simple, low-cost, and scalable fabrication in large areas for transparent displays.

Serum albumin is the most abundant protein in mammalian plasma and is often used as a model to understand the adhesion behavior of proteins on surfaces. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) is used to non-destructively and dynamically detect the chemical change information between the protein and the surface during the adhesion process, which is especially suitable for in-situ measurement of samples in water. Therefore, the adhesion of bovine serum albumin (BSA) on the surface in H2O and D2O is investigated by ATR-FTIR technology, which effectively avoids the interference of the characteristic peak of deformation vibration of liquid H2O (1645 cm−1) on the amide I band of BSA. Sodium alginate, a polysaccharide widely present in the ocean, is introduced into the BSA solution to explore the changes in the adhesion process of proteins on the surface of ZnSe, and polarized ATR-FTIR spectra are also collected to study the adhesion orientation of BSA. Sodium alginate presents a negative effect on the adhesion of BSA on the surface and there is no specific orientation of BSA on the surface.

The study of non-conjugated luminescent polymers (NCLPs) with fluorescence and long-lived room-temperature phosphorescence is of great significance for revealing the essence of NCLPs luminescence, which has gradually attracted the attention of researchers in recent years. Herein, polymethylol (PMO) and poly(3-butene-1,2-diol) (PBD) with polyhydroxyl structures were prepared and their luminescence behaviors were investigated to further reveal the clusteroluminescence (CL) mechanism. Compared with the weak or even non-luminescent behavior of polyvinyl alcohol, PMO and PBD exhibit cyan-blue fluorescence with quantum yields of ca. 12% and green room-temperature phosphorescence with lifetimes of ca. 89 ms in the solid state. Both fluorescence and phosphorescence exhibit typical excitation-dependent CL behavior. Experimental and theoretical analyses show that the strong hydrogen-bonding interaction of PMO and PBD greatly promotes the formation of oxygen clusters and the through-space n-n interaction of oxygen atoms, enabling fluorescence and phosphorescence emission. The results of this work have important implications for understanding the clusteroluminescence mechanism of NCLPs and provide a new polymer design strategy for the rational design of novel NCLPs materials.

It is well established that ferroptosis is primarily induced by peroxidation of long-chain poly-unsaturated fatty acid (PUFA) through nonenzymatic oxidation by free radicals or enzymatic stimulation of lipoxygenase. Although there is emerging evidence that long-chain saturated fatty acid (SFA) might be implicated in ferroptosis, it remains unclear whether and how SFA participates in the process of ferroptosis. Using endogenous metabolites and genome-wide CRISPR screening, we have identified FAR1 as a critical factor for SFA-mediated ferroptosis. FAR1 catalyzes the reduction of C16 or C18 saturated fatty acid to fatty alcohol, which is required for the synthesis of alkyl-ether lipids and plasmalogens. Inactivation of FAR1 diminishes SFA-dependent ferroptosis. Furthermore, FAR1-mediated ferroptosis is dependent on peroxisome-driven ether phospholipid biosynthesis. Strikingly, TMEM189, a newly identified gene which introduces vinyl-ether double bond into alkyl-ether lipids to generate plasmalogens abrogates FAR1-alkyl-ether lipids axis induced ferroptosis. Our study reveals a new FAR1-ether lipids-TMEM189 axis dependent ferroptosis pathway and suggests TMEM189 as a promising druggable target for anticancer therapy.

Carbonized polymer dots (CPDs) have received great interest from researchers in recent years. However, the solid-state photoluminescence quenching of CPDs is a big challenge owing to the resonance energy transfer or π–π* interaction. Herein, we report a new type of carbon dioxide (CO2) derived CPD exhibiting quantum yields of 46.2% in solution and 11.3% as a solid. These CPDs were prepared using ethylenediamine and trimethylolpropane tri(cyclic carbonate)ether synthesized from the reaction of carbon dioxide (CO2) and trimethylolpropane triglycidyl ether as precursors in ethanol. Gel permeation chromatography results revealed that the formation of CPDs involved the polymerization of small molecules and then the transformation of the polymers to CPDs. The solid-state fluorescence is attributed to the self-passivation of poly(hydroxyurethane) chains on the surface of the carbon core. Particularly, the synthesis of CPDs consumed nearly 26.7 wt% CO2, thus providing a new method for fixing CO2 to functional carbon materials. We have also demonstrated the application of CO2-derived CPDs by the fabrication of multicolor light-emitting diodes (LEDs), and a warm white LED is obtained when CPDs are applied as single phosphors by changing the amount of CPDs and the type of chip.

Despite the administration of new effective drugs in recent years, relapse and drug resistance are still the main obstacles in multiple myeloma (MM) treatment, making MM an incurable disease. To overcome drug resistance in MM, it is critical to understand the underlying mechanisms of malfunctioning gene expression and develop novel targeted therapies. During the past few decades, with the discovery and characterization of noncoding RNAs (ncRNAs), the landscape of dysregulated ncRNAs of cancers as well as their biological and pathobiological functions in tumorigenesis and drug resistance have been recognized. Studies about ncRNAs improved the understanding of variations of drug response among individuals at a level distinguished from genetic polymorphism, and provided with new orientations for targeted therapies. In this review, we will summarize the emerging impact and underlying molecular mechanisms of the most relevant classes of ncRNAs in drug resistance of MM, and discuss the potential as well as strategies of treating ncRNAs as therapeutic targets.

Coal and gas outburst is a potentially fatal risk during the mining of gassy coal seams, which seriously threatens the safe mining of collieries. To understand the outburst mechanism and evolution rules, a new apparatus (LSTT) was developed to conduct simulated experiment. In the context of an outburst accident in Dingji coal mine, the authors launched an authentic outburst experiment to replay the outburst accident. Experimental apparatus, similar criterion, coal‐like materials and gas sources, and experimental design were discussed systematically in this paper. Experimentally, the study analyzed the geo‐stress has significant influence on the outburst evolution. At the driving face, the stress concentration possibly caused gas outburst, under the influence of mining‐induced stress. After the outburst occurred, the stress balance of the coal changed, resulting in the instability of the coal. Furthermore, the elastic energy, gas enthalpy, and gravitational potential energy were released rapidly. The experimental result stated that outburst coal has the sorting characteristics, in line with the field outburst law. The intensity prediction model has been built based on the energy model. Moreover, the factors that impact outburst intensity were analyzed. In the process of coal and gas outburst, the gas enthalpy of gas and the elastic potential of coal are the main energy sources. This study provides guidance for the development of the outburst mechanism and outburst mine management.

Background The tea leafhopper, Empoasca onukii Matsuda (Hemiptera: Cicadellidae), is a major pest of tea plants in China. Here, we evaluated the repellent properties of eight volatile chemicals alone and in various combinations as tools for the management of this pest in tea gardens. These chemicals were from the Alliaceae and other aromatic plants, and are known to repel various insect species. Results Among the eight volatile compounds, dimethyl disulfide (DMDS), 1,8-cineole and allyl methyl sulfide were significantly repellent towards E. onukii adults. DMDS and 1,8-cineole were mixed to formulate a binary repellent. Under field conditions, spraying and slow-release applications of the mixture significantly decreased the density of E. onukii adults. The repelling effect after spraying was very short, only ∼ 2 days, but the slow-release mixture had a longer term repelling effect on E. onukii adults. High emission of the slow-release mixture, which was achieved by increasing the number of slow-release bottles, had a stronger repellent effect than low emission. Moreover, when the amount emitted was sufficient, the slow-release mixture significantly decreased the number of leafhopper nymphs in a treated tea-plant line, and significantly decreased the number of leafhopper adults and nymphs in a tea-plant line adjacent to the treated area. Conclusion This study demonstrates the repellent action of a mixture of DMDS and 1,8-cineole applied by a slow-release method against E. onukii in a tea plantation. This mixture has potential applications in integrated pest management schemes. © 2019 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Preparation of non-conjugated polymers with long-wavelength emission and high quantum yield (QY) is still a huge challenge. Herein, we report the first example of linear non-conjugated polyester exhibiting yellow-green clusteroluminescence (CL) and a high QY of 38 %. We discovered that the polyester P3 with balanced flexibility and rigidity showed the longest CL wavelength and highest QY. Systematically photophysical characterization unravel the key role of ester cluster in the CL and the cluster formation via the aggregate of ester units was visualized. Moreover, P3 was demonstrated to be a highly selective, quick-responsive (ca. 1.2 min) and sensitive detector (detection limit is 0.78 μM) for irons owing to the fast disassociation of clusters by irons. This work not only gains further mechanistic insight into CL but also provides a new strategy to design high-efficiency and long-wavelength CL, meanwhile, enlightens the glorious application prospect of luminescent polyester.

Red deer (Cervus elaphus) blood is widely used as a health product. Mixed culture fermentation improves the flavor and bioavailability of deer blood (DB), and both DB and its enzymatic hydrolysates exhibit anti-fatigue activities in vivo. To elucidate the bioactive ingredients, enzymatic hydrolysates were fractioned into different peptide groups using reversed phase resin chromatography, and then evaluated using an exhaustive swimming mice model to assess swimming time and biochemical parameters. The structures of the bioactive peptides were elucidated by high performance liquid chromatography with tandem mass detection. Thirty-one compounds were identified as glutamine or branched-chain amino acids containing short peptides, of which Val-Ala-Asn, Val-Val-Ser-Ala, Leu(Ile)-Leu(Ile)-Val-Thr, Pro-His-Pro-Thr-Thr, Glu-Val-Ala-Phe and Val-Leu(Ile)-Asp-Ala-Phe are new peptides. The fractions containing glutamine or valine short peptides, Ala-Gln, Val-Gln, Val-Val-Ser-Ala, Val-Leu(Ile)-Ser improved exercise endurance by increasing hepatic glycogen (HG) storage. The peptides group containing Leu(Ile)-Leu(Ile), Asp-Gln, Phe- Leu(Ile), Val-Val-Tyr-Pro contributed to decreased muscle lactic acid (MLA)accumulation and to an increase in HG. The anti-fatigue activities of DB hydrolysates were attributed to the synergistic effects of different types of peptides.

Red deer (Cervus elaphus) blood is widely used as a health product. Mixed culture fermentation improves the flavor and bioavailability of deer blood (DB), and both DB and its enzymatic hydrolysates exhibit anti-fatigue activities in vivo. To elucidate the bioactive ingredients, enzymatic hydrolysates were fractioned into different peptide groups using reversed phase resin chromatography, and then evaluated using an exhaustive swimming mice model to assess swimming time and biochemical parameters. The structures of the bioactive peptides were elucidated by high performance liquid chromatography with tandem mass detection. Thirty-one compounds were identified as glutamine or branched-chain amino acids containing short peptides, of which Val-Ala-Asn, Val-Val-Ser-Ala, Leu(Ile)-Leu(Ile)-Val-Thr, Pro-His-Pro-Thr-Thr, Glu-Val-Ala-Phe and Val-Leu(Ile)-Asp-Ala-Phe are new peptides. The fractions containing glutamine or valine short peptides, Ala-Gln, Val-Gln, Val-Val-Ser-Ala, Val-Leu(Ile)-Ser improved exercise endurance by increasing hepatic glycogen (HG) storage. The peptides group containing Leu(Ile)-Leu(Ile), Asp-Gln, Phe- Leu(Ile), Val-Val-Tyr-Pro contributed to decreased muscle lactic acid (MLA)accumulation and to an increase in HG. The anti-fatigue activities of DB hydrolysates were attributed to the synergistic effects of different types of peptides.

Mitochondria, as the powerhouse of most cells, are not only responsible for the generation of adenosine triphosphate (ATP) but also play a decisive role in the regulation of apoptotic cell death, especially of cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy are urgently required. In this study, for effective pancreatic cancer therapy, a novel mitochondria-targeted and ROS-triggered drug delivery nanoplatform was developed from the TPP-TK-CPI-613 (TTCI) prodrug, in which the ROS-cleave thioketal functions as a linker connecting mitochondrial targeting ligand TPP and anti-mitochondrial metabolism agent CPI-613. DSPE-PEG2000 was added as an assistant component to increase accumulation in the tumor via the EPR effect. This new nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability, and robust therapeutic performances. With active mitochondrial targeting, the formulated nanoparticles (TTCI NPs) demonstrate much higher accumulation in mitochondria, facilitating the targeted delivery of CPI-613 to its acting site. The results of in vitro antitumor activity and cell apoptosis revealed that the IC50 values of TTCI NPs in three types of pancreatic cancer cells were around 20 ~ 30 µM, which was far lower than those of CPI-613 (200 µM), 50 µM TTCI NPs showed an increase in apoptosis of up to 97.3% in BxPC3 cells. Therefore, this mitochondria-targeted prodrug nanoparticle platform provides a potential strategy for developing safe, targeting and efficient drug delivery systems for pancreatic cancer therapy.