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Peng Guo,1,* Chi Huang,2,* Qin Yang,1 Guofeng Zhong,1 Junbo Zhang,1 Mengyu Qiu,1 Rui Zeng,3 Kaijun Gou,3 Chen Zhang,1 Yan Qu1 1State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China; 2Department of Pharmacy, Jiang’an Hospital of Traditional Chinese Medicine, Yibin, 644200, People’s Republic of China; 3Institute of Tibetan Plateau, Southwest Minzu University, Chengdu, 610225, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Qu; Chen Zhang, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China, Email quyan028@126.com; chenzhang_1990@126.comAbstract: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation, eventually leading to severe disability and premature death. At present, the treatment of RA is mainly to reduce inflammation, swelling, and pain. Commonly used drugs are non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying anti-rheumatic drugs (DMARDs). These drugs lack specificity and require long-term, high-dose administration, which can cause serious adverse effects. In addition, the oral, intravenous, and intra-articular injections will reduce patient compliance, resulting in high cost and low bioavailability. Due to these limitations, microneedles (MNs) have emerged as a new strategy to efficiently localize the drugs in inflamed joints for the treatment of RA. MNs can overcome the cuticle barrier of the skin without stimulating nerves and blood vessels. Which can increase patient compliance, improve bioavailability, and avoid systemic circulation. This review summarizes and evaluates the application of MNs in RA, especially dissolving MNs (DMNs). We encourage the use of MNs to treat RA, by describing the general properties of MNs, materials, preparation technology, drug release mechanism, and advantages. Furthermore, we discussed the biological safety, development prospects, and future challenges of MNs, hoping to provide a new strategy for the treatment of RA. Keywords: rheumatoid arthritis, dissolving microneedles, transdermal delivery system, degradability, biosafety

Guo P, Huang C, Yang Q, et al. Int J Nanomedicine. 2023;18:7759-7784. The authors have advised the correspondence section on page 7759 is incorrect. The correct correspondence address is as follows. Correspondence: Yan Qu, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China, Email quyan028@126.com The authors apologize for this error.

Wang H, Zhou C, Su Y, Gou K, Geng X, Qiu X. Drug Des Devel Ther. 2021;15:4865–4873. The authors have informed the journal that ripretinib was used in this study, not erdafitinib as indicated in parts of the paper. Namely, on page 4865, Abstract, Results section; page 4868, Animal Experiments and Pharmacokinetics Study sections; page 4872, Pharmacokinetics Effects and Conclusions sections. The authors have also advised on page 4867, Materials and Methods, Chemicals Materials section, third line from the bottom, the text “Itraconazole” should read “voriconazole”. The authors apologize for any confusion this may have caused.

Hui-jun Wang,1 Chun-yan Zhou,1 Yan-ding Su,1 Kai-feng Gou,1 Xiao-nan Geng,1 Xiang-jun Qiu1,2 1Department of Pharmacy, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of China; 2Functional Experiment Teaching Center, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuFunctional Experiment Teaching Center, School of Basic Medical Sciences, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, People’s Republic of ChinaTel +8613698882699Fax +86379-64830346Email lyxiangjun@126.comBackground: A new UPLC-MS/MS technique for the determination of ripretinib in beagle dog plasma was developed, and the pharmacokinetic effects of voriconazole and itraconazole on ripretinib in beagle dogs were studied.Methods: After extraction with ethyl acetate under alkaline conditions, ripretinib was detected using avapritinib as the internal standard (IS). The mobile phases were 0.1% formic acid-acetonitrile. The scanning method was multi-reaction monitoring using ESI+ source, and the ion pairs for ripretinib and IS were m/z 509.93→ 416.85 and 499.1→ 482.09, respectively. This animal experiment adopted a three period self-control experimental design. In the first period, ripretinib was orally administered to six beagle dogs at a dose of 5 mg/kg. In the second period, the same six beagle dogs were orally given itraconazole at a dose of 7 mg/kg, after 30 min, ripretinib was orally given. In the third period, voriconazole at a dose of 7 mg/kg was given orally, and then ripretinib was orally given. At different time points, the blood samples were collected. The concentration of ripretinib was detected, and the pharmacokinetic parameters of ripretinib were calculated.Results: Ripretinib had a good linear relationship in the range of 1– 1000 ng/mL. The precision, accuracy, recovery, matrix effect and stability met the requirements of the guiding principles. After erdafitinib combined with itraconazole, the Cmax and AUC0→t of ripretinib increased by 38.35% and 36.36%, respectively, and the t1/2 was prolonged to 7.53 h. After ripretinib combined with voriconazole, the Cmax and AUC0→t of ripretinib increased by 37.44% and 25.52%, respectively, and the t1/2 was prolonged to 7.33 h.Conclusion: A new and reliable UPLC-MS/MS technique was fully optimized and developed to detect the concentration of ripretinib in beagle dog plasma. Itraconazole and voriconazole could inhibit the metabolism of ripretinib in beagle dogs and increase the plasma exposure of ripretinib.Keywords: itraconazole, voriconazole, ripretinib, UPLC-MS/MS, pharmacokinetics, beagle dog

Wei Xin,1,2 Yumei Wang,3 Xianmou Guo,3 Kaijun Gou,3 Jing Li,3 Sanming Li,3 Lin Zhao,1 Heran Li1 1School of Pharmacy, China Medical University, Shenyang 110122, People’s Republic of China; 2The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 3School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of ChinaCorrespondence: Heran Li; Lin ZhaoSchool of Pharmacy, China Medical University, 77 Puhe Road, Shenyang North New Area, Shenyang 110122, People’s Republic of ChinaTel +8613897945866; +8618900911856Email liheranmm@163.com; zl_cmu@163.comPurpose: The aim of this study was to improve the oral bioavailability and anti-inflammatory activity of the poorly soluble drug ibuprofen (IBU) by employing a new kind of poly(ethyleneimine)s (PEIs)-based mesocellular siliceous foam (MSF) called B-BMSF@PEI as drug carrier.Methods: B-BMSF@PEI was biomimetically synthesized by using PEIs as templates, catalysts and scaffolds under ambient conditions, and the structural characteristics, including size, morphology, mesoscopic structure and pore properties, were estimated by TEM, SEM, FTIR and N2 desorption/adsorption measurement. Then, IBU was incorporated into B-BMSF@PEI at the drug:carrier weight ratio of 1:1. The structural features of IBU before and after drug loading were systemically characterized. IBU and B-BMSF@PEI were then subject to in vitro drug release study and wettability analysis. Finally, in vivo pharmacokinetics and anti-inflammatory pharmacodynamics studies were carried out to evaluate the efficacy of B-BMSF@PEI on improving the oral adsorption of IBU.Results: The results demonstrated that B-BMSF@PEI was a meso–meso porous silica material with foam appearance. It consisted of uniform spherical cells (40 nm) with interconnected pore networks. IBU can be successfully loaded into B-BMSF@PEI with high efficiency (as high as 39.53%), and crystal IBU was effectively converted to an amorphous state during this process. Benefiting from the great architectures of B-BMSF@PEI, IBU/B-BMSF@PEI performed good wetting property and significantly improved the dissolution rate in both simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Notably, IBU exhibited very satisfactory relative bioavailability (681.4%) and anti-inflammatory effects (the inhibition rates were between the ranges of 113.5% to 1504.3%).Conclusion: B-BMSF@PEI with bimodal mesoporous system and interconnected nanopores was obtained owing to the dynamic self-assembly functions of PEIs. It had superiority in drug loading and could improve the oral adsorption of ibuprofen to a satisfactory level.Keywords: biomimetic synthesis, MSF, bimodal mesostructured, bioavailability, ibuprofen

Photooxidative damage causes early leaf senescence and plant cell death. In this study, a light-sensitive rice cultivar, 812HS, and a non-light-sensitive cultivar, 812S, were used to investigate early leaf photooxidation. Leaf tips of 812HS exhibited yellowing under a light intensity of 720 µmol(photon) m-2 s-1, accompanied by a decrease in chlorophyll and carotenoids, but 812S was unaffected. The photosynthetic performance of 812HS was also poorer than that of 812S. The H2O2, O2*-, and malondialdehyde content increased sharply in 812HS, and associated antioxidant enzymes were inhibited. The degradation of core proteins in both PSI and PSII, as well as other photosynthesis-related proteins, was accelerated in 812HS. When shaded [180 µmol(photon) m-2 s-1], 812HS recovered to normal. Therefore, our findings suggested excess light disturbed the balance of ROS metabolism, leading to the destruction of the antioxidant system and photosynthetic organs, and thus triggering the senescence of rice leaves. [ABSTRACT FROM AUTHOR]

Mixed infectious vaginitis poses a serious threat to female reproductive health due to complex pathogenic factors, a long course and easy recurrence. Currently, antibiotic-based treatment methods are facing a crisis of drug resistance and secondary dysbiosis. Exploring effective drugs for the treatment of mixed vaginitis from Paeonia suffruticosa Andr., a natural traditional Chinese medicine with a long history of medicinal use, is a feasible treatment strategy. P. suffruticosa Andr. leaf extract (PLE) has significant anti-bacterial effects due to its rich content of polyphenols and flavonoids. The polyphenols in peony leaves have the potential to make carboxymethyl chitosan form in situ gel. In the current study, PLE and carboxymethyl chitosan were combined to develop another type of natural anti-bacterial anti-oxidant hydrogel for the treatment of mixed infectious vaginitis. Through a series of characterisations, CP had a three-dimensional network porous structure with good mechanical properties, high water absorption, long retention and a slow-release drug effect. The mixed infectious vaginitis mouse model induced by a mixture of pathogenic bacteria was used to investigate the therapeutic effects of CP in vivo. The appearance of the vagina, H&E colouring of the tissue and inflammatory factors (TNF-α, IL-6) confirm the good anti-vaginal effect of CP. Therefore, CP was expected to become an ideal effective strategy to improve mixed infection vaginitis due to its excellent hydrogel performance and remarkable ability to regulate flora., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: β-Arbutin, a hydroquinone glucoside found in pears, bearberry leaves, and various plants, exhibits antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. β-Arbutin has wide applications in the pharmaceutical and cosmetic industries. However, the limited availability of high-performance strains limits the biobased production of β-arbutin., Results: This study established the β-arbutin biosynthetic pathway in C. glutamicum ATCC13032 by introducing codon-optimized ubiC, MNX1, and AS. Additionally, the production titer of β-arbutin was increased by further inactivation of csm and trpE to impede the competitive metabolic pathway. Further modification of the upstream metabolic pathway and supplementation of UDP-glucose resulted in the final engineered strain, C. glutamicum AR11, which achieved a β-arbutin production titer of 7.94 g/L in the optimized fermentation medium., Conclusions: This study represents the first successful instance of de novo β-arbutin production in C. glutamicum, offering a chassis cell for β-arbutin biosynthesis., (© 2024. The Author(s).)

Wounds in harsh environments can face long-term inflammation and persistent infection, which can slow healing. Wound spray is a product that can be rapidly applied to large and irregularly dynamic wounds, and can quickly form a protective film in situ to inhibit external environmental infection. In this study, a biodegradable A and B combined multi-functional spray hydrogel is developed with methacrylate-modified chitosan (CSMA 1st ) and ferulic acid (FA) as type A raw materials and oxidized Bletilla striata polysaccharide (OBSP) as type B raw materials. The precursor CSMA 1st -FA/OBSP (CSOB-FA 1st ) hydrogel is formed by the self-cross-linking of dynamic Schiff base bonds, the CSMA-FA/OBSP (CSOB-FA) hydrogel is formed quickly after UV-vis light, so that the hydrogel fits with the wound. Rapid spraying and curing provide sufficient flexibility and rapidity for wounds and the hydrogel has good injectability, adhesive, and mechanical strength. In rats and miniature pigs, the A and B combined spray hydrogel can shrink wounds and promote healing of infected wounds, and promote the enrichment of fibrocyte populations. Therefore, the multifunctional spray hydrogel combined with A and B can protect irregular dynamic wounds, prevent wound infection and secondary injury, and be used for safe and effective wound treatment, which has a good prospect for development., (© 2024 Wiley‐VCH GmbH.)

Cell shapes in tissues are affected by the biophysical interaction between cells. Tissue forces can influence specific cell features such as cell geometry and cell surface area. Here, we examined the 2-dimensional shape, size, and perimeter of pleural epithelial cells at various lung volumes. We demonstrated a 1.53-fold increase in 2-dimensional cell surface area and a 1.43-fold increase in cell perimeter at total lung capacity compared to residual lung volume. Consistent with previous results, close inspection of the pleura demonstrated wavy folds between pleural epithelial cells at all lung volumes. To investigate a potential explanation for the wavy folds, we developed a physical simulacrum suggested by D'Arcy Thompson in On Growth and Form. The simulacrum suggested that the wavy folds were the result of redundant cell membranes unable to contract. To test this hypothesis, we developed a numerical simulation to evaluate the impact of an increase in 2-dimensional cell surface area and cell perimeter on the shape of the cell-cell interface. Our simulation demonstrated that an increase in cell perimeter, rather than an increase in 2-dimensional cell surface area, had the most direct impact on the presence of wavy folds. We conclude that wavy folds between pleural epithelial cells reflects buckling forces arising from the excess cell perimeter necessary to accommodate visceral organ expansion., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As a positional and geometrical isomer of linoleic acid, trans 10, cis 12 conjugated linoleic acid (t10c12-CLA) reduces white fat by reducing food intake, modulating lipid metabolism, and stimulating energy expenditure. However, the t10c12-CLA products are mostly mixtures, making it difficult to obtain accurate results. Studies are needed to investigate the effects of pure t10c12-CLA on animals and humans. In this study, we used the biallelic transgenic (tg) mice, which could produce t10c12-CLA itself, to investigate the effects of pure t10c12-CLA on female reproductive ability. The results showed that the body and relative ovary weights had no significant difference between tg and wild-type (wt) littermates at ages 3 or 10 weeks. While the fecundity test found that tg mice had a significantly longer first litter time (32.0 ± 4.70 days vs. 21.3 ± 2.31 days, P <0.05), and a significantly lower number of litters (4.75 ± 2.75 vs. 6.67 ± 0.57, P <0.05) when compared with wt mice during continuous mating within seven months. Hormone profiles showed that serum estradiol levels did not change in tg mice; however, significantly ( P <0.05) decreased progesterone and increased prostaglandin E2 levels were observed in tg mice compared with those of wt mice. Hematoxylin-eosin staining showed no pathological characteristics in tg ovaries, except for the increased atresia follicles ( P <0.05). Moreover, the tg mice had a significantly more extended diestrus period than the wt mice (48.4 ± 6.38% vs. 39.6 ± 3.81%, P <0.05). In summary, t10c12-CLA could affect serum progesterone and prostaglandin E2 levels, lead to a disordered estrus cycle, and impact the reproductive performance of female mice. This study provided theoretical and biosafety recommendations for applying t10c12-CLA in female mammals., Competing Interests: Conflicts of interest: The authors have no conflict of interest to declare., (Copyright © The Author(s).)

Wound healing is a dynamic and complex biological process, and traditional biological excipients cannot meet the needs of the wound healing process, and there is an urgent need for a biological dressing with multifunctionality and the ability to participate in all stages of wound healing. This study developed tea polyphenol (TP) incorporated multifunctional hydrogel based on oxidized Bletilla striata polysaccharide (OBSP) and adipic acid dihydrazide modified gelatin (Gel-ADH) with antimicrobial, antioxidant hemostatic, and anti-inflammatory properties to promote wound healing. The composite OBSP, Gel-ADH, TP (OBGTP) hydrogels prepared by double crosslinking between OBSP, TP and Gel-ADH via Schiff base bonding and hydrogen bonding had good rheological and swelling properties. The introduction of TP provided the composite hydrogel with excellent antioxidant antibacterial activities against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coil). In the rat liver hemorrhage model and skin injury model, the OBGTP composite hydrogel had significant (p < 0.001) hemostatic ability, and had the ability to accelerate collagen deposition, reduce the expression of inflammatory factors, and promote rapid wound healing. In addition, OBGTP hydrogels had adhesive properties and good biocompatibility. In conclusion, OBGTP multifunctional composite hydrogels have great potential for wound healing applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Perovskite solar cells (PSCs) have become a new photovoltaic technology with great commercial potential because of their excellent photovoltaic performance. However, the toxicity and poor environmental stability of Pb in Pb-based perovskites limit its large-scale application. Exploring alternatives to Pb is an available approach to develop environmentally friendly PSCs. As an adjacent element of Pb, Bi shows many similar physical and chemical properties; therefore, it is commonly applied for B site substitution in Pb-based PSCs. CsBiSCl 2 , a new Pb-free perovskite system, was synthesized for the first time as a light absorber. By preparing DMABiS 2 as an intermediate, Cs-Bi-based CsBiSCl 2 perovskite films with a band gap over 2.012 eV were prepared by introducing CsCl, and the optimal annealing temperature, time, and stoichiometric ratio of the film were explored in this work. The conventional structure of CsBiSCl 2 PSCs achieved a power conversion efficiency (PCE) of 10.38%, and the efficiency declined by only 3% after aging in air for 150 days, showing excellent stability, which is one of the most stable devices in inorganic PSCs. This work opens up a new road for the future development of environmentally friendly and commercially stable lead-free PSCs.

Produced gas re-injection is an effective and eco-friendly approach for enhancing oil recovery from shale oil reservoirs. However, the interactions between different gas phase components, and the oil phase and rocks are still unclear during the re-injection process. This study aims to investigate the potential of produced gas re-injection, particularly focusing on the effects of methane (CH 4 ) content in the produced gas on shale oil displacement. Molecular dynamics simulations were employed to analyze the interactions between gas, oil, and matrix phases with different CH 4 proportions (0%, 25%, 50%, and 100%), alkanes and under various burial depth. Results show that a 25% CH 4 content in the produced gas achieves almost the same displacement effect as pure carbon dioxide (CO 2 ) injection. However, when the CH 4 content increases to 50% and 100%, the interaction between gas and quartz becomes insufficient to effectively isolate oil from quartz, causing only expansion and slight dispersion. Interestingly, the presence of CH 4 has a synergistic effect on CO 2 , facilitating the diffusion of CO 2 into the oil film. During the gas stripping process, CO 2 is the main factor separating oil from quartz, while CH 4 mainly contributes to oil expansion. In addition, for crude oil containing a large amount of light alkanes, extracting light components through mixed gas may be more effective than pure CO 2 . This study offers valuable insights for applications of produced gas re-injection to promote shale oil recovery., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The expeditious healing of chronic wounds with bacterial infections poses a formidable challenge in clinical practice because of the persistent bacterial presence, excessive inflammation, and the accumulation of reactive oxygen species (ROS) in clinical practice. Thus, in this study, natural antimicrobial material microneedles (MNs) with multifunctional properties were prepared by adding peony leaf extract (PLE) into a matrix of methacrylated Bletilla striata polysaccharide (BSPMA) and methacrylated chitosan (CSMA) via cross-linking under ultra-violet light to accelerate the rapid healing of chronic wounds with bacterial infections. Results showed that BCP-MNs effectively inhibited the growth of Escherichia coli, Staphylococcus aureus, and methicillin-resistant S. aureus (MRSA) by disrupting bacterial cell membranes and accelerated the healing of infected wounds by enhancing cell migration, epidermal regeneration, pro-collagen deposition, and angiogenesis and reducing inflammation. Furthermore, BCP-MNs not only possessed good mechanical properties, stability, and biocompatibility but also showed potent antioxidant effects to eliminate excessive ROS accumulation in the wound bed. In conclusion, BCP-MNs possess multifunctional wound-healing properties and can serve as excellent wound dressing in to treat infected wounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Ulcerative colitis (UC) is a chronic disease with diffuse mucosal inflammation limited to the colon. A topical drug delivery system that could be facilely performed and efficiently retained at colon are attractive for clinical ulcerative colitis treatment. Herein, a novel platform for rectal administration of thermosensitive hydrogel co-loaded with nanoparticles to treat ulcerative colitis was developed. Thiolated-hyaluronic acid was synthesized, and prepared nanoparticles with zein and Puerarin. And the Bletilla striata polysaccharide with colonic mucosa repair effect was oxidized, and mixed with chitosan and β-sodium glycerophosphate to prepare thermosensitive hydrogel. Thermosensitive hydrogels were combined with nanoparticles to investigate their mucosal adhesion, retention, and permeability, as well as their therapeutic effects on ulcerative colitis. Thiolated-hyaluronic acid nanoparticles had good stability, and could be quickly converted into hydrogel at body temperature when combined with thermosensitive hydrogel. The nanoparticles-loaded thermosensitive hydrogel also was excellent at mucosal penetration, enhancing the retention time of drugs in colon, and effectively controlling drug release. In vivo ulcerative colitis treatment revealed that the nanoparticles-loaded hydrogel significantly repaired the colonic mucosa and inhibit colonic inflammation. Therefore, the thermosensitive hydrogel co-loaded nanoparticles will have a promising application in effective treatment of ulcerative colitis by topical administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Bletilla striata polysaccharide (BSP) is a naturally occurring polysaccharide that demonstrates notable biocompatibility and biodegradability. Additionally, BSP possesses therapeutic attributes, including anti-inflammatory and reparative actions. Herein, we report a novel BSP hydrogel prepared using 1,4-butanediol diglycidyl ether (BDDE) as a cross-linking agent. The hydrogel was synthesized via condensation of the hydroxyl group in the BSP molecule with the epoxy group in BDDE. This technique of preparation preserves BSP's natural properties while avoiding any potentially hazardous or adverse effects that may occur during the chemical alteration. Compared with BSP before crosslinking, BSP hydrogel has distinct advantages, such as a three-dimensional network structure, improved water retention, enhanced swelling capacity, greater thermal stability, and superior mechanical properties. Experiments on in vitro cytotoxicity, hemolysis, and degradation revealed that BSP hydrogel had good biocompatibility and biodegradability. Finally, we evaluated the in vivo wound repair effect of BSP hydrogel, and the results showed that BSP hydrogel had a significant wound-healing effect. Furthermore, the BSP hydrogel promoted the polarization of M1-type macrophages towards the M2-type and reduced the inflammatory response during the wound healing phase. Because of its ease of production, safety, efficacy, and environmental friendliness, BSP hydrogel is considered a highly promising material for wound dressings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that might have influenced the work reported herein., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Inspired by the unique pharmacological effects of chiral drugs in the asymmetrical body environments, it is assumed that the chirality of nanocarriers is also a key factor to determine their oral adsorption efficiency, apart from their size, shape, etc. Herein, l/d-tartaric acid modified mesoporous silica nanoparticles (l/d-CMSNs) are fabricated via a one-pot cocondensation method, and focused on whether the oral adsorption of nanocarriers will be benefited from their chirality. It is found that l-CMSN performed better in the sequential oral absorption processes, including mucus permeation, mucosa bio-adhesion, cellular uptake, intestinal transport and gastrointestinal tract (GIT) retention, than those of the d-chiral (d-CMSN), racemic (dl-CMSN), and achiral (MSN) counterparts. The multiple chiral recognition mechanisms are experimentally and theoretically demonstrated following simple differential adsorption on biointerfaces, wherein electrostatic interaction is the dominant energy. During the oral delivery task, l-CMSN, which is proven to be stable, nonirritative, biocompatible, and biodegradable, is efficiently absorbed into the blood (1.72-2.05-fold higher than other nanocarriers), and helps the loaded doxorubicin (DOX) to achieve better intestinal transport (2.32-27.03-times higher than other samples), satisfactory bioavailability (449.73%) and stronger antitumor effect (up to 95.43%). These findings validated the dominant role of chirality in determining the biological fate of nanocarriers., (© 2023 Wiley-VCH GmbH.)

The oral delivery of nano-drug delivery systems (Nano-DDS) remains a challenge. Taking inspirations from viruses, here we construct core-shell mesoporous silica nanoparticles (NPs, ~80 nm) with virus-like nanospikes (VSN) to simulate viral morphology, and further modified VSN with L-alanine (CVSN) to enable chiral recognition for functional bionics. By comparing with the solid silica NPs, mesoporous silica NPs and VSN, we demonstrate the delivery advantages of CVSN on overcoming intestinal sequential barriers in both animals and human via multiple biological processes. Subsequently, we encapsulate indomethacin (IMC) into the nanopores of NPs to mimic gene package, wherein the payloads are isolated from bio-environments and exist in an amorphous form to increase their stability and solubility, while the chiral nanospikes multi-sited anchor and chiral recognize on the intestinal mucosa to enhance the penetrability and ultimately improve the oral adsorption of IMC. Encouragingly, we also prove the versatility of CVSN as oral Nano-DDS., (© 2023. The Author(s).)

Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively active in ovarian cancer (OC) with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other DNA repair pathway members. We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. Here, we demonstrate that lysine-specific demethylase 1 (LSD1) is an important regulator for OC. Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials., (© 2023. The Author(s).)

To investigate the fluorescein angiography (FA) findings and compare the extent of retinal vascularization in retinopathy of prematurity (ROP), recovered after intravitreal ranibizumab (IVR) monotherapy and those regressed spontaneously. Infants with a history of ROP who underwent FA between April 2018 and November 2021 were retrospectively included. The patients were divided into two groups based on whether they had received IVR (IVR group) or had ROP that regressed spontaneously without treatment (untreated group). The differences between the two groups in zone II ROP were also compared, to equalize the subgroups as much as possible in terms of disease severity. FA findings were recorded. The extent of vascularization was measured by the ratio of the distance from the center of the disk to the border of the vascularized zone (DB) and the distance from the center of the disk to the center of the fovea (DF). The width of the persistent avascular retina (PAR) was counted by disc diameters (DD). One hundred and ten eyes of 55 infants were included in the IVR group and 76 eyes of 38 babies in the untreated group. The ratio of abnormal shape of vessels was significantly higher in the IVR group than in the untreated group (50.9% vs. 35.5%; P = 0.038), while the linear choroidal filling pattern, tortuosity of vessels over the posterior pole, dye leakage, anomalous branching of vessels, circumferential vessels, arteriovenous shunt, abnormal capillary bed, and macular abnormalities were similarly. There was a smaller temporal DB/DF ratio (4.48 vs. 4.63; P = 0.003) and greater PAR (2.63 vs. 1.76; P < 0.001) in the IVR group compared to the untreated group. In zone II ROP, the progression of retinal vascularization was significantly larger in the IVR group than that in the untreated group (P = 0.003), while no statistical differences were observed in FA features, the DB/DF ratio, and PAR between the two subgroups. The residual vascular abnormalities and PAR may be common results of ROP regression. The DB/DF ratio of 4.0 temporally and 3.3 nasally could be used as the preliminary indicators for safe retinal vascularization in the completion of ROP regression., (© 2023. The Author(s).)

As a key rate-limiting enzyme in the de novo synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase ( h DHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1 H -pyrazolo[3,4- b ]pyridine scaffold was identified as an h DHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine ( w2) , which was found to be the most promising and drug-like compound with potent inhibitory activity against h DHODH (IC 50 = 173.4 nM). Compound w2 demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, w2 exerted better therapeutic effects on ulcerative colitis than h DHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising h DHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.

Targeting mitochondrial complex I (CI) is emerging as an attractive anticancer strategy, and CI inhibitor IACS-010759 has achieved breakthrough success. However, the narrow therapeutic index of IACS-010759 seriously hinders its further application. In this study, a series of novel pyrazole amides were designed and optimized based on IACS-010759, and their potential CI inhibitory effects were biologically evaluated. Among them, the maximum tolerated dose (MTD) values of SCAL-255 (compound 5q) and SCAL-266 (compound 6f) were 68 mg/kg, which was nearly 10 times that of IACS-010759 (6 mg/kg), showing good safety. In addition, SCAL-255 and SCAL-266 significantly inhibited the proliferation of HCT116 and KG-1 cells in vitro and exerted satisfactory inhibitory activity against KG-1 cells in vivo. These results suggested that the optimized compounds might serve as promising CI inhibitors against oxidative phosphorylation (OXPHOS)-dependent cancer, which merits further study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Conventional wound dressings fail to satisfy the requirements and needs of wounds in various stages. It is challenging to develop a multifunctional dressing that is hemostatic, antibacterial, anti-inflammatory, and promotes wound healing. Therefore, this study aimed to develop a multifunctional sponge dressing for the full-stage wound healing based on copper and two natural products, Bletilla striata polysaccharide (BSP) and peony leaf extract (PLE). The developed BSP-Cu-PLE sponges were characterized by SEM, XRD, FTIR, and XPS to assess micromorphology and elemental composition. Their properties and bioactivities were also verified by the further experiments, whereby the findings revealed that the BSP-Cu-PLE sponges had improved water absorption and porosity while exhibiting excellent antioxidative, biocompatible, and biodegradable properties. Moreover, the antibacterial test revealed that BSP-Cu-PLE sponges had superior antibacterial activity against S. aureus and E. coli. Furthermore, the hemostatic activity of BSP-Cu-PLE sponges was significantly enhanced in a rat liver trauma model. Most notably, further studies have demonstrated that the BSP-Cu-PLE sponges could significantly (p < 0.05) accelerate the healing process of skin wounds by stimulating collagen deposition, promoting angiogenesis, and decreasing inflammatory cells. In summary, the BSP-Cu-PLE sponges could provide a new strategy for application in clinical setting for full-stage wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The decellularized human umbilical artery (HUA) is considered as a promising option for small-diameter, tissue-engineered vascular grafts (TEVGs). Our previous study showed that the HUA bears a thin, watertight lining on its outermost abluminal surface. Removal of this abluminal lining layer improves efficacy of the perfusion-assisted decellularization of the HUA and increases its compliance. As stress across the wall is believed to affect growth and remodeling of the TEVG, it is imperative to mechanically characterize the HUA using thick-walled models. Combining inflation experiments and computational methods, we investigate the mechanical properties of the HUA before and after the abluminal lining removal to examine the HUA's wall mechanics. The inflation tests of five HUAs were performed to obtain the mechanical and geometrical response of the vessel wall before and after the lining layer removal. Using nonlinear hyperelastic models, the same responses are obtained computationally using the thick-walled models. The experimental data are incorporated into the computational models to estimate the mechanical and orientation parameters of the fibers and isotropic matrix of different layers in the HUAs. The parameter fitting of both thick-walled models (before and after the abluminal lining removal) results in most of the R-squared values for measuring the goodness of fitting to be over 0.90 for all samples. The compliance of the HUA increases from a mean value of 2.60% per 100 mmHg before the removal of the lining to a mean value of 4.21% per 100 mmHg after the removal. The results reveal that, although the abluminal lining is thin, it is stiff and capable of supporting majority of the high luminal pressure, and that the inner layer is far less stressed than the abluminal lining. Computational simulations also show that removal of the abluminal lining increases the circumferential wall stress by up to 280 kPa under the in vivo luminal pressure. The integrated computational and experimental approaches provide more accurate estimates of the material behaviors of HUAs employed in grafts and, in turn, the study enhances our understanding of interactions between the graft and the native vessel on vascular growth and remodeling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Lysine-specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell-derived and patient-derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage-inducible gene 45beta ( GADD45B ) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B , a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co-administration of ZY0511 and DTP3, which specifically enhanced the pro-apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

The purpose of this study was to develop a nano-drug delivery system with intelligent stimuli-responsive drug delivery in tumor microenvironment (TME). Based on chiral mesoporous silica nanoparticles (CMSN) with a chiral recognition function in our previous research, a pH-responsive CMSN (CS-CMSN) was successfully prepared by chemical modification of chitosan (CS), and the related physicochemical properties, drug release performance, potential anti-tumor effect, and biological safety were studied. The results showed that the CS-CMSN were successfully modified by CS. Moreover, CS-CMSN displayed superior encapsulation ability for doxorubicin (DOX) and exhibited controllable pH-responsive drug release properties. In particular, in a physiological environment (pH 7.4/6.5), CS shielded the nanopores, prevented DOX release, and minimized side effects on normal cells. Once the CS-CMSN was exposed to the TME (pH 5.0), the pH-sensitive moiety of CS was cleaved in an acidic environment, along with the rapid release of DOX. In vitro cell experiments further proved that DOX@CS-CMSN was more strongly taken up by 4T1 cells and could enhance the toxicity to 4T1 tumor cells as well as promote cell apoptosis. More importantly, CS-CMSN were shown to have good biosafety in vitro and in vivo. Overall, the delivery of DOX by CS-CMSN nanocarriers is a promising strategy for tumor-targeted therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Blocking the de novo biosynthesis of pyrimidine by inhibiting human dihydroorotate dehydrogenase (hDHODH) is an effective way to suppress the proliferation of cancer cells and activated lymphocytes. Herein, eighteen teriflunomide derivatives and four ASLAN003 derivatives were designed and synthesized as novel hDHODH inhibitors based on a benzophenone scaffold. The optimal compound 7d showed a potent hDHODH inhibitory activity with an IC 50 value of 10.9 nM, and displayed promising antiproliferative activities against multiple human cancer cells with IC 50 values of 0.1-0.8 μM. Supplementation of exogenous uridine rescued the cell viability of 7d-treated Raji and HCT116 cells. Meanwhile, 7d significantly induced cell cycle S-phase arrest in Raji and HCT116 cells. Furthermore, 7d exhibited favorable safety profiles in mice and displayed effective antitumor activities with tumor growth inhibition (TGI) rates of 58.3% and 42.1% at an oral dosage of 30 mg/kg in Raji and HCT116 cells xenograft models, respectively. Taken together, these findings provide a promising hDHODH inhibitor 7d with potential activities against some tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Hydrogen sulfide (H 2 S) is a small reducing gas molecule with various biological functions such as anti-oxidative, anti-apoptotic and anti-inflammatory activities. In this study, we investigated the therapeutic effects of exogenous H 2 S in the experimental models of retinal photodamage in vivo and in vitro. Methods: Rats with open eyelids were pretreated with H 2 S (80~120 μmol/kg) for 10 days and then continuously exposed to blue light (435~445nm, 11.2W/m2) for 8 h to establish in vivo experimental model. ARPE-19 cells were pretreated with H 2 S and then exposed to blue light to establish in vitro experimental model. Results: In vivo experiments, H 2 S significantly ameliorated blue light-induced retinal oxidative stress, apoptosis and degeneration. Moreover, H 2 S inhibited the activation of blue light-induced endoplasmic reticulum (ER) stress CHOP apoptotic signaling. In vitro experiments, H 2 S improved blue light-induced oxidative stress and oxidative damage. H 2 S inhibited ROS-mediated activation of ER stress CHOP apoptotic signaling. H 2 S alleviated blue light-induced apoptosis and increases cell viability. The ER stress inhibitor 4-PBA alleviated blue light-induced apoptosis and increases cell viability. Conclusion: Taken together, these results indicate that H 2 S can inhibit ROS-mediated ER stress-CHOP apoptosis signal, thereby alleviating blue light-triggered retinal apoptosis and degeneration.

Considering the problem of food perishability and the environmental pollution of plastic packaging, the natural active packaging prepared by incorporating plant leaf (e.g. peony leaf) extract into biodegradable food packaging materials may be a key to addressing these issues. In the study, a novel green bioactive composite film (CS-PLE) with antioxidant and antibacterial propertiese was developed by blending peony leaf extract (PLE) into chitosan (CS) film through the solution casting method. The physical properties and biological activities of a series of films, including CS film and CS-PLEs incorporated with different concentrations of PLE, were studied by appropriate experimental protocols. The results demonstrated that addition of PLE improved thermal stability, the barrier performance of UV-A and total phenolic content of CS film, and the antioxidant activities of CS-PLEs increased by 60.6 % ~ 73.2 % with the appending proportion of PLE from 0.1 wt% ~ 0.7 wt% compared to CS film. Furthermore, CS-PLEs had better inhibiting effect on bacteria. Notably, CS-PLE (0.7 wt%) wrapping apples showed the least degree of browning among all the groups. Hence, the study of CS-PLEs can provide a new strategy for the preparation of food packaging materials that are green alternatives and reduce environmental pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

In agricultural production with small farmers as the main body, the service scale operation is one of the ways to obtain scale operation benefits. This paper constructs a tripartite evolutionary game model of agricultural scale service providers (integrators), demand subjects (farmers), and agriculture-related government departments and analyzes the influencing factors, influencing relations, and evolutionary stable equilibrium results of each participant's strategy choice. The results show that improving rewards and punishments and strengthening supervision by agriculture-related government departments will help integrators provide high-quality services and encourage farmers to actively produce and reduce speculation; when the cost difference between high-quality service and low-quality service is large, the probability of high-quality service provided by integrators will be reduced, and the evolution result of low Pareto efficiency may appear in the system; when the speculative cost of farmers is not high, the lobbying efforts of integrators will increase the speculative behavior of farmers. Finally, MATLAB2018a is used to simulate and analyze the validity of the model results, which provides a theoretical reference for the scale operation of agricultural services., Competing Interests: The authors declare that they have no conflicts of interest regarding this work., (Copyright © 2022 Kaomin Gou and Luyun Wang.)

Human dihydroorotate dehydrogenase (hDHODH) is a key enzyme in the de novo synthesis pathway of pyrimidine nucleotide in cells. The moderate efficiency of teriflunomide, an approved hDHODH inhibitor for the treatment of multiple sclerosis, limited its therapeutic application of malignancy. Herein, thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated. As a result, the optimal compound A37 exhibited a potent hDHODH inhibitory activity with an IC 50 value of 10.2 nM, which was about 40-fold stronger than that of teriflunomide (IC 50  = 407.8 nM), and showed favorable antiproliferative activities against HCT116 cells with an IC 50 value of 0.3 μM. Meanwhile, A37 displayed an acceptable safety profile at an oral dosage of 400 mg/kg in the acute toxicity assay, and exhibited a promising antitumor effect with tumor growth inhibition rate of 54.4% at an oral dosage of 30 mg/kg in HCT116 xenograft model. These results indicate that A37 is an efficacious hDHODH inhibitor with potential in the treatment of colorectal carcinoma., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Casein kinase 1α (CK1α), acting as one member of the β-catenin degradation complex, negatively regulates the Wnt/β-catenin signaling pathway. CK1α knockout usually causes both Wnt/β-catenin and p53 activation. Our results demonstrated that conditional disruption of CK1α in spermatogonia impaired spermatogenesis and resulted in male mouse infertility. The progenitor cell population was dramatically decreased in CK1α conditional knockout (cKO) mice, while the proliferation of spermatogonial stem cells (SSCs) was not affected. Furthermore, our molecular analyses identified that CK1α loss was accompanied by nuclear stability of p53 protein in mouse spermatogonia, and dual-luciferase reporter and chromatin immunoprecipitation assays revealed that p53 directly targeted the Sox3 gene. In addition, the p53 inhibitor pifithrin α (PFTα) partially rescued the phenotype observed in cKO mice. Collectively, our data suggest that CK1α regulates spermatogenesis and male fertility through p53-Sox3 signaling, and they deepen our understanding of the regulatory mechanism underlying the male reproductive system., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Research on the phototoxicity of blue light (BL) to the skin is increasing. Although blue light can induce oxidative stress, inflammation, and inhibition of proliferation in skin cells, the mechanism by which blue light damages the skin is not yet clear. Endoplasmic reticulum (ER) stress and autophagy are two mechanisms by which cells resist external interference factors and maintain cell homeostasis and normal function, and both can affect cell apoptosis. Interestingly, we have found that blue light (435 nm ~ 445 nm, 8000 lx, 6-24 h)-induced oxidative stress triggers the ER stress-CHOP (C/EBP homologous protein) signal and affects the protein levels of B-cell lymphoma-2 (Bcl-2) and Bcl2-associated X (Bax), thereby promoting apoptosis. In addition, blue light activates autophagy in skin cells, which intensifies cell death. When ER stress is inhibited, autophagy is subsequently inhibited, suggesting that blue light-induced autophagy is influenced by ER stress. These evidences suggest that blue light induces activation of reactive oxygen species (ROS)-ER stress-autophagy-apoptosis axis signaling, which further induces skin injury and apoptosis. This is the first report on the relationships among oxidative stress, ER stress, autophagy, and apoptosis in blue light-induced skin injury. Furthermore, we have studied the effect of hydrogen sulfide (H 2 S) on blue light-induced skin damage, and found that exogenous H 2 S can protect skin from blue light-induced damage by regulating the ROS-ER stress-autophagy-apoptosis axis. Our data shows that when we are exposed to blue light, such as sunbathing and jaundice treatment, H 2 S may be developed as a protective agent., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The host response to COVID-19 pathophysiology over the first few days of infection remains largely unclear, especially the mechanisms in the blood compartment. We report on a longitudinal proteomic analysis of acute-phase COVID-19 patients, for which we used blood plasma, multiple reaction monitoring with internal standards, and data-independent acquisition. We measured samples on admission for 49 patients, of which 21 had additional samples on days 2, 4, 7, and 14 after admission. We also measured 30 externally obtained samples from healthy individuals for comparison at baseline. The 31 proteins differentiated in abundance between acute COVID-19 patients and healthy controls belonged to acute inflammatory response, complement activation, regulation of inflammatory response, and regulation of protein activation cascade. The longitudinal analysis showed distinct profiles revealing increased levels of multiple lipid-associated functions, a rapid decrease followed by recovery for complement activation, humoral immune response, and acute inflammatory response-related proteins, and level fluctuation in the regulation of smooth muscle cell proliferation, secretory mechanisms, and platelet degranulation. Three proteins were differentiated between survivors and nonsurvivors. Finally, increased levels of fructose-bisphosphate aldolase B were determined in patients with exposure to angiotensin receptor blockers versus decreased levels in those exposed to angiotensin-converting enzyme inhibitors. Data are available via ProteomeXchange PXD029437.

Background: The v-raf-leukemia viral oncogene 1 (RAF1) plays an essential physiological role in reproduction and development through the mediation of steroid hormone synthesis. Follicle-stimulating hormone (FSH) signaling pathway was not involved in the majority of RAF1 studies, whether RAF1 takes part in the signaling events of gonadotropic hormones such as FSH in ovarian tissue is unknown., Methods: The process is blocked by treating granulosa cells (GCs) with the RAF1 inhibitor, RAF709. Inhibition of RAF1 activity by RAF709 decreased extracellular regulated protein kinases (ERK) phosphorylation and suppressed the expression of the cytochrome P450 subfamily 19 member 1 (CYP19A1), which is a major rate-limiting enzyme that participates in the last step of E2 biosynthesis., Results: We found that RAF1, acting as a downstream molecule, mediates FSH signalling to stimulate estradiol (E2) synthesis and secretion in mouse ovarian GCs. Gene expression of RAF1 was induced by FSH and the secretion of E2 increased into the bloodstream of mice and into the supernatant of primary GCs. Our in vitro and in vivo studies clearly illustrate RAF1 plays an important medium adjusting role in the FSH signaling pathway, and RAF1 acting as a downstream molecule to trigger ERK phosphorylation to stimulate GC E2 synthesis and secretion., Conclusions: RAF1 plays a pivotal mediating role in the FSH signaling pathway by inducing the phosphorylation of ERK and promoting E2 synthesis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-393/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

In the microscale, bacteria with helical body shapes have been reported to yield advantages in many bio-processes. In the human society, there are also wisdoms in knowing how to recognize and make use of helical shapes with multi-functionality. Herein, we designed atypical chiral mesoporous silica nano-screws (CMSWs) with ideal topological structures ( e.g. , small section area, relative rough surface, screw-like body with three-dimension chirality) and demonstrated that CMSWs displayed enhanced bio-adhesion, mucus-penetration and cellular uptake (contributed by the macropinocytosis and caveolae-mediated endocytosis pathways) abilities compared to the chiral mesoporous silica nanospheres (CMSSs) and chiral mesoporous silica nanorods (CMSRs), achieving extended retention duration in the gastrointestinal (GI) tract and superior adsorption in the blood circulation (up to 2.61- and 5.65-times in AUC). After doxorubicin (DOX) loading into CMSs, DOX@CMSWs exhibited controlled drug release manners with pH responsiveness in vitro . Orally administered DOX@CMSWs could efficiently overcome the intestinal epithelium barrier (IEB), and resulted in satisfactory oral bioavailability of DOX (up to 348%). CMSWs were also proved to exhibit good biocompatibility and unique biodegradability. These findings displayed superior ability of CMSWs in crossing IEB through multiple topological mechanisms and would provide useful information on the rational design of nano-drug delivery systems., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Embryonic morphogenesis is a biological process which depicts shape forming of tissues and organs during development. Unveiling the roles of mechanical forces generated, transmitted, and regulated in cells and tissues through these processes is key to understanding the biophysical mechanisms governing morphogenesis. To this end, it is imperative to measure, simulate, and predict the regulation and control of these mechanical forces during morphogenesis. This article aims to provide a comprehensive review of the recent advances on mechanical properties of cells and tissues, generation of mechanical forces in cells and tissues, the transmission processes of these generated forces during cells and tissues, the tools and methods used to measure and predict these mechanical forces in vivo, in vitro, or in silico, and to better understand the corresponding regulation and control of generated forces. Understanding the biomechanics and mechanobiology of morphogenesis will not only shed light on the fundamental physical mechanisms underlying these concerted biological processes during normal development, but also uncover new information that will benefit biomedical research in preventing and treating congenital defects or tissue engineering and regeneration., (© 2021 Wiley-VCH GmbH.)

The rate-limiting serine biogenesis enzyme PHGDH is overexpressed in cancers. Both serine withdrawal and genetic/pharmacological inhibition of PHGDH have demonstrated promising tumor-suppressing activities. However, the enzyme properties of PHGDH are not well understood and the discovery of PHGDH inhibitors is still in its infancy. Here, oridonin was identified from a natural product library as a new PHGDH inhibitor. The crystal structure of PHGDH in complex with oridonin revealed a new allosteric site. The binding of oridonin to this site reduced the activity of the enzyme by relocating R54, a residue involved in substrate binding. Mutagenesis studies showed that PHGDH activity was very sensitive to cysteine mutations, especially those in the substrate binding domain. Conjugation of oridonin and other reported covalent PHGDH inhibitors to these sites will therefore inhibit PHGDH. In addition to being inhibited enzymatically, PHGDH can also be inhibited by protein aggregation and proteasome-mediated degradation. Several tested PHGDH cancer mutants showed altered enzymatic activity, which can be explained by protein structure and stability. Overall, the above studies present new biophysical and biochemical insights into PHGDH and may facilitate the future design of PHGDH inhibitors., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Human dihydroorotate dehydrogenase ( h DHODH), as the fourth and rate-limiting enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as h DHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC 50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC 50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited h DHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t . Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of h DHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.

The aim of this study was to build up a novel chiral mesoporous silica called PEIs@TA-CMS through a facile biomimetic strategy and to explore its potential to serve as a drug carrier for improving the delivery efficiency of poorly water-soluble drug. PEIs@TA-CMS was synthesized by using a chiral crystalline complex associated of tartaric acid and polyethyleneimine (PEIs) as templates, scaffolds and catalysts. The structural features including morphology, size, pore structure and texture properties were systematacially studied. The results showed that PEIs@TA-CMS was monodispersed spherical nanoparticles in a uniformed diameter of 120-130 nm with well-developed pore structure (S BET : 1009.94 m 2 /g, pore size <2.21 nm). Then PEIs@TA-CMS was employed as nimodipine (NMP) carrier and compared with the drug carry ability of MCM41. After drug loading, NMP was effectively transformed from the crystalline state to an amorphous state due to the space confinement in mesopores. As expected, PEIs@TA-CMS had superiority in both drug loading and drug release compared to MCM41. It could incorporate NMP with high efficiency, and the dissolution-promoting effect of PEIs@TA-CMS was more obvious because of the unique interconnected curved pore channels. Meanwhile, PEIs@TA-CMS could significantly improve the oral adsorption of NMP to a satisfactory level, which showed approximately 3.26-fold higher in bioavailability, and could effectively prolong the survival time of mice on cerebral anoxia from 10.98 to 17.33 min.