Design and optimization of a greener sinomenine hydrochloride preparation process considering variations among different batches of the medicinal herb

The current methods used to industrially produce sinomenine hydrochloride involve several issues,including high solvent toxicity,long process flow,and low atomic utilization efficiency,and the greenness scores of the processes are below 65 points.To solve these problems,a new process using anisole as the extractant was proposed.Anisole exhibits high selectivity for sinomenine and can be connected to the subsequent water-washing steps.After alkalization of the medicinal material,heating extraction,water washing,and acidification crystallization were carried out.The process was modeled and optimized.The design space was constructed.The recommended operating ranges for the critical process parameters were 3.0–4.0 h for alkalization time,60.0–80.0℃ for extraction temperature,2.0–3.0(volume ratio)for washing solution amount,and 2.0–2.4 mol·L^(-1) for hydrochloric acid concentration.The new process shows good robustness because different batches of medicinal materials did not greatly impact crystal purity or sinomenine transfer rate.The sinomenine transfer rate was about 20%higher than that of industrial processes.The greenness score increased to 90 points since the novel process proposed in this research solves the problems of long process flow,high solvent toxicity,and poor atomic economy,better aligning with the concept of green chemistry.

Design and optimization of purification process of sinomenine hydrochloride

Sinomenine hydrochloride is generally produced from Caulis Sinomenii. At present, the purification process in industrial production suffers from large amount of solid waste, high solvent toxicity, and low sinomenine hydrochloride yield. In this study, a new purification process for sinomenine hydrochloride was proposed by using the extract obtained from acid extraction of Caulis Sinomenii as the starting material.The process included the following steps: alkalization, extraction, water washing, acid–water stripping,drying, and crystallization. 1-Heptanol was used as the extractant. The distribution coefficients of sinomenine and sinomenine hydrochloride in 1-heptanol–water system were 27.4 and 0.0167, respectively.The dissociation constants of sinomenine hydrochloride were 8.27 and 11.24, respectively. Process parameters of the new purification process were optimized with experimental design. The extractant1-heptanol and sinomenine hydrochloride in the crystallization mother solution can be recycled in the new process. The purity of the obtained sinomenine hydrochloride crystals exceeded 85%, and the yield was about 70%. Compared with current industrial processes, safer extractant, less solid waste, and higher sinomenine hydrochloride yield can be achieved using the new purification process of sinomenine hydrochloride provided in this study.

Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity

Gaining a better understanding of autoprotection against drug-induced liver injury(DILI)may provide new strategies for its prevention and therapy.However,little is known about the underlying mechanisms of this phenomenon.We used single-cell RNA sequencing to characterize the dynamics and functions of hepatic non-parenchymal cells(NPCs)in autoprotection against DILI,using acetaminophen(APAP)as a model drug.Autoprotection was modeled through pretreatment with a mildly hepatotoxic dose of APAP in mice,followed by a higher dose in a secondary challenge.NPC subsets and dynamic changes were identified in the APAP(hepatotoxicity-sensitive)and APAP-resistant(hepatotoxicity-resistant)groups.A chemokine(C-C motif)ligand 2^(+)endothelial cell subset almost disappeared in the APAP-resistant group,and an R-spondin 3^(+)endothelial cell subset promoted hepatocyte proliferation and played an important role in APAP autoprotection.Moreover,the dendritic cell subset DC-3 may protect the liver from APAP hepatotoxicity by inducing low reactivity and suppressing the autoimmune response and occurrence of inflammation.DC-3 cells also promoted angiogenesis through crosstalk with endothelial cells via vascular endothelial growth factor-associated ligand-receptor pairs and facilitated liver tissue repair in the APAP-resistant group.In addition,the natural killer cell subsets NK-3 and NK-4 and the Sca-1^(-)CD62L^(+)natural killer T cell subset may promote autoprotection through interferon-γ-dependent pathways.Furthermore,macrophage and neutrophil subpopulations with anti-inflammatory phenotypes promoted tolerance to APAP hepatotoxicity.Overall,this study reveals the dynamics of NPCs in the resistance to APAP hepatotoxicity and provides novel insights into the mechanism of autoprotection against DILI at a high resolution.

High-throughput transcriptional profiling of perturbations by Panax ginseng saponins and Panax notoginseng saponins using TCM-seq

Panax ginseng(PG)and Panax notoginseng(PN)are highly valuable Chinese medicines(CM).Although both CMs have similar active constituents,their clinical applications are clearly different.Over the past decade,RNA sequencing(RNA-seq)analysis has been employed to investigate the molecular mechanisms of extracts or monomers.However,owing to the limited number of samples in standard RNA-seq,few studies have systematically compared the effects of PG and PN spanning multiple conditions at the transcriptomic level.Here,we developed an approach that simultaneously profiles transcriptome changes for multiplexed samples using RNA-seq(TCM-seq),a high-throughput,low-cost workflow to molecularly evaluate CM perturbations.A species-mixing experiment was conducted to illustrate the accuracy of sample multiplexing in TCM-seq.Transcriptomes from repeated samples were used to verify the robustness of TCM-seq.We then focused on the primary active components,Panax notoginseng saponins(PNS)and Panax ginseng saponins(PGS)extracted from PN and PG,respectively.We also characterized the transcriptome changes of 10 cell lines,treated with four different doses of PNS and PGS,using TCM-seq to compare the differences in their perturbing effects on genes,functional pathways,gene modules,and molecular networks.The results of transcriptional data analysis showed that the transcriptional patterns of various cell lines were significantly distinct.PGS exhibited a stronger regulatory effect on genes involved in cardiovascular disease,whereas PNS resulted in a greater coagulation effect on vascular endothelial cells.This study proposes a paradigm to comprehensively explore the differences in mechanisms of action between CMs based on transcriptome readouts.

Scalable Electrophysiology of Millimeter-Scale Animals with Electrode Devices

Millimeter-scale animals such as Caenorhabditis elegans,Drosophila larvae,zebrafish,and bees serve as powerful model organisms in the fields of neurobiology and neuroethology.Various methods exist for recording large-scale electrophysiological signals from these animals.Existing approaches often lack,however,real-time,uninterrupted investigations due to their rigid constructs,geometric constraints,and mechanical mismatch in integration with soft organisms.The recent research establishes the foundations for 3-dimensional flexible bioelectronic interfaces that incorporate microfabricated components and nanoelectronic function with adjustable mechanical properties and multidimensional variability,offering unique capabilities for chronic,stable interrogation and stimulation of millimeter-scale animals and miniature tissue constructs.This review summarizes the most advanced technologies for electrophysiological studies,based on methods of 3-dimensional flexible bioelectronics.A concluding section addresses the challenges of these devices in achieving freestanding,robust,and multifunctional biointerfaces.

Functionalized lipid nanoparticles modulate the blood-brain barrier and eliminate α-synuclein to repair dopamine neurons

The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3β expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3β pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.

Multimodal integrated strategy for the discovery and identification of quality markers in traditional Chinese medicine

With the modernization and internationalization of traditional Chinese medicine(TCM),the requirement for quality control has increased.The quality marker(Q-marker)is an important standard in this field and has been implemented with remarkable success in recent years.However,the establishment of Qmarkers remains fragmented and the process lacks systematicity,resulting in inconsistent quality control and insufficient correlation with clinical efficacy and safety of TCM.This review introduces four multimodal integrated approaches that contribute to the discovery of more comprehensive and accurate Qmarkers,thus aiding in the establishment of new quality control patterns based on the characteristics and principles of TCM.These include the whole-process quality control strategy,chemical-activity-based screening method,efficacy,safety,and consistent combination strategy,and TCM theory-guided approach.Furthermore,methodologies and representative examples of these strategies are described,and important future directions and questions in this field are also proposed.

Two-Dimensional Thermal Regulation Based on Non-Hermitian Skin Effect

The non-Hermitian skin effect has been applied in multiple fields.However,there are relatively few models in the field of thermal diffusion that utilize the non-Hermitian skin effect for achieving thermal regulation.Here,we propose two non-Hermitian Su-Schrieffer-Heeger(SSH)models for thermal regulation:one capable of achieving edge states,and the other capable of achieving corner states within the thermal field.By analyzing the energy band structures and the generalized Brillouin zone,we predict the appearance of the non-Hermitian skin effect in these two models.Furthermore,we analyze the time-dependent evolution results and assess the robustness of the models.The results indicate that the localized thermal effects of the models align with our predictions.In a word,this work presents two models based on the non-Hermitian skin effect for regulating the thermal field,injecting vitality into the design of non-Hermitian thermal diffusion systems.

Nano transdermal system combining mitochondria-targeting cerium oxide nanoparticles with all-trans retinoic acid for psoriasis

Psoriasis is an inflammatory skin disease that is intricately linked to oxidative stress.Antioxidation and inhibition of abnormal proliferation of keratinocytes are pivotal strategies for psoriasis.Delivering drugs with these effects to the site of skin lesions is a challenge that needs to be solved.Herein,we reported a nanotransdermal delivery system composed of all-trans retinoic acid(TRA),triphenylphosphine(TPP)-modified cerium oxide(CeO2)nanoparticles,flexible nanoliposomes and gels(TCeO_(2)-TRA-FNL-Gel).The results revealed that TCeO_(2)synthesized by the anti-micelle method,with a size of approximately 5 nm,possessed excellent mitochondrial targeting ability and valence conversion capability related to scavenging reactive oxygen species(ROS).TCeO_(2)-TRA-FNL prepared by the film dispersion method,with a size of approximately 70 nm,showed high drug encapsulation efficiency(>96%).TCeO_(2)-TRA-FNL-Gel further showed sustained drug release behaviors,great transdermal permeation ability,and greater skin retention than the free TRA.The results of in vitro EGF-induced and H2O2-induced models suggested that TCeO_(2)-TRA-FNL effectively reduced the level of inflammation and alleviated oxidative stress in HaCat cells.The results of in vivo imiquimod(IMQ)-induced model indicated that TCeO_(2)-TRA-FNL-Gel could greatly alleviate the psoriasis symptoms.In summary,the transdermal drug delivery system designed in this study has shown excellent therapeutic effects on psoriasis and is prospective for the safe and accurate therapy of psoriasis.

ROS-responsive nanoparticles targeting inflamed colon for synergistic therapy of inflammatory bowel disease via barrier repair and anti-inflammation

The destruction of the intestinal barrier is likely to cause an increase in intestinal permeability and cause pathological damage.Numerous studies have demonstrated that intestinal barrier function plays an important role in the occurrence and development of inflammatory bowel disease(IBD).Oral administration is the most common route for intestinal diseases.In this study,a synergistic strategy is proposed for IBD management through active barrier repair combined with anti-inflammatory treatment,which can interrupt the pathological process of IBD,resulting in the significantly improved efficacy of existing treatments.Based on the specific pH values and high reactive oxygen species(ROS)levels in inflammatory sites of IBD,an orally administrated ROS-responsive drug delivery system targeting inflamed colon has been designed,and confirmed in vitro and in vivo.The anti-inflammatory drug dexamethasone acetate(Dex)and the barrier function regulator LY294002 are delivered by the synthesized nanocarrier to treat IBD synergistically by inhibiting inflammation and actively repairing the intestinal barrier through tight junctions(TJs).The accumulation of nanocarriers in the inflamed colon and synergistic efficacy has been validated in mice with colitis.In brief,a drug delivery system and a therapeutic strategy for IBD are successfully developed.

Advances of nanoparticles in transmucosal drug delivery

Transmucosal drug administration represents a potential strategy for enhancing treatment efficacy and reducing side effects by avoiding the first-pass effect into the systemic circulation and delivering therapeutics directly to the target disease site.However,many challenges still remain in its clinical application,including low drug availability and limited retention time in the mucosa.The burgeoning advancement of nanotechnologies offers great potential to overcome the above limitations,leveraging their distinct advantages of high drug-loading capacity and strong permeability.In this review,the latest developments of nanoparticles(NPs)in transmucosal drug delivery as well as their clinical applications are discussed.

MOF负载Weel抑制剂实现p53突变胆囊癌的合成致死靶向治疗

Adavosertib(ADA)is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer(GBC).However,drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications.Herein,estrone-targeted ADA-encapsulated metal–organic frameworks(ADA@MOF-EPL)for GBC synthetic lethal treatment by inducing conditional factors are developed.The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment.Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species(ROS),which leads to a further increase in DNA damage,resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality.The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity.Moreover,ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors,revealing its potential as a broad-spectrum antitumor drug.

Phase-Locking Diffusive Skin Effect

We explore the exceptional point(EP)induced phase transition and amplitude/phase modulation in thermal diffusion systems.We start from the asymmetric coupling double-channel model,where the temperature field is unbalanced in the amplitude and locked in the symmetric phase.By extending into the one-dimensional tight-binding non-Hermitian lattice,we study the convection-driven phase locking and the asymmetric-couplinginduced diffusive skin effect with the high-order EPs in static systems.Combining convection and asymmetric couplings,we further show the phase-locking diffusive skin effect.Our work reveals the mechanism of controlling both the amplitude and phase of temperature fields in thermal coupling systems and has potential applications in non-Hermitian topology in thermal diffusion.

Recent advances of bioresponsive polymeric nanomedicine for cancer therapy

A bioresponsive polymeric nanocarrier for drug delivery is able to alter its physical and physicochemical properties in response to a variety of biological signals and pathological changes,and can exert its therapeutic efficacy within a confined space.These nanosystems can optimize the biodistribution and subcellular location of therapeutics by exploiting the differences in biochemical properties between tumors and normal tissues.Moreover,bioresponsive polymer-based nanosystems could be rationally designed as precision therapeutic platforms by optimizing the combination of responsive elements and therapeutic components according to the patient-specific disease type and stage.In this review,recent advances in smart bioresponsive polymeric nanosystems for cancer chemotherapy and immunotherapy will be summarized.We mainly discuss three categories,including acidity-sensitive,redox-responsive,and enzyme-triggered polymeric nanosystems.The important issues regarding clinical translation such as reproducibility,manufacture,and probable toxicity,are also commented.

Revealing the Transformation Invariance of Full-Parameter Omnidirectional Invisibility Cloaks

Searching for an optimal solution among many nonunique answers provided by transformation optics is critical for many branches of research,such as the burgeoning research on invisibility cloaks.The past decades have witnessed rapid development of transformation optics,and different kinds of invisibility cloaks have been designed and implemented.However,the available cloaks realized thus far have been mostly demonstrated with reduced parameters,which greatly impact the predefined cloaking performance.Here,we report a general design strategy to realize full-parameter omnidirectional cloaks that can hide arbitrarily shaped objects in free space.Our approach combines a singular transformation with transformation-invariant metamaterials.The cloaking device with extreme parameters is implemented using a metallic array structure.In the experiment,two cloak samples are designed and fabricated,one with nondiscrete cloaking regions and the other with separated hidden regions.Near-unit transmission of electromagnetic waves with arbitrary incident angles is experimentally demonstrated along with significantly suppressed scattering.Our work challenges the prevailing paradigms of invisibility cloaks and provides deep insight into how transformation optics could be harnessed to obtain easily-accessible metadevices.

Breakdown of effective-medium theory by a photonic spin Hall effect

Effective-medium theory pertains to the theoretical modelling of homogenization,which aims to replace an inhomogeneous structure of subwavelength-scale constituents with a homogeneous effective medium.The effective-medium theory is fundamental to various realms,including electromagnetics and material science,since it can largely decrease the complexity in the exploration of light-matter interactions by providing simple acceptable approximation.Generally,the effective-medium theory is thought to be applicable to any all-dielectric system with deep-subwavelength constituents,under the condition that the effective medium does not have a critical angle,at which the total internal reflection occurs.Here we reveal a fundamental breakdown of the effective-medium theory that can be applied in very general conditions:showing it for deep-subwavelength all-dielectric multilayers even without a critical angle.Our finding relies on an exotic photonic spin Hall effect,which is shown to be ultrasensitive to the stacking order of deep-subwavelength dielectric layers,since the spin-orbit interaction of light is dependent on slight phase accumulations during the wave propagation.Our results indicate that the photonic spin Hall effect could provide a promising and powerful tool for measuring structural defects for all-dielectric systems even in the extreme nanometer scale.

受自体材料启发的药物递送系统

随着个性化医疗理念的深入研究,基于自体来源材料的药物递送系统受到越来越多的关注并快速发展.自体来源材料具有保留其体内天然生理学特性和优良的生物相容性等特点,这为其在材料功能化和药物递送方面开辟了广泛的研究空间,也为疾病治疗提供了坚实的基础.借助这些优势,受自体来源材料启发的药物递送系统有望在疾病治疗方面实现减毒增效.本文对基于人源蛋白、细胞材料及细胞外基质支架的药物递送系统的最新研究进行了全面回顾,重点关注了这类药物递送系统的载药策略和应用场景,深入分析了它们在疾病治疗中的优势和限制.此外,本文还探讨了受自体来源材料启发的药物递送系统在临床转化过程中面临的潜在机遇和挑战.

Rationally designed approaches to augment CAR-T therapy for solid tumor treatment

Chimeric antigen receptor T cell denoted as CAR-T therapy has realized incredible therapeutic advancements for B cell malignancy treatment.However,its therapeutic validity has yet to be successfully achieved in solid tumors.Different from hematological cancers,solid tumors are characterized by dysregulated blood vessels,dense extracellular matrix,and filled with immunosuppressive signals,which together result in CAR-T cells’insufficient infiltration and rapid dysfunction.The insufficient recognition of tumor cells and tumor heterogeneity eventually causes cancer reoccurrences.In addition,CAR-T therapy also raises safety concerns,including potential cytokine release storm,on-target/off-tumor toxicities,and neuro-system side effects.Here we comprehensively review various targeting aspects,including CAR-T cell design,tumor modulation,and delivery strategy.We believe it is essential to rationally design a combinatory CAR-T therapy via constructing optimized CAR-T cells,directly manipulating tumor tissue microenvironments,and selecting the most suitable delivery strategy to achieve the optimal outcome in both safety and efficacy.

Autonomous aeroamphibious invisibility cloak with stochastic-evolution learning

Being invisible ad libitum has long captivated the popular imagination,particularly in terms of safeguarding modern high-end instruments from potential threats.Decades ago,the advent of metamaterials and transformation optics sparked considerable interest in invisibility cloaks,which have been mainly demonstrated in ground and waveguide modalities.However,an omnidirectional flying cloak has not been achieved,primarily due to the challenges associated with dynamic synthesis of metasurface dispersion.We demonstrate an autonomous aeroamphibious invisibility cloak that incorporates a suite of perception,decision,and execution modules,capable of maintaining invisibility amidst kaleidoscopic backgrounds and neutralizing external stimuli.The physical breakthrough lies in the spatiotemporal modulation imparted on tunable metasurfaces to sculpt the scattering field in both space and frequency domains.To intelligently control the spatiotemporal metasurfaces,we introduce a stochastic-evolution learning that automatically aligns with the optimal solution through maximum probabilistic inference.In a fully self-driving experiment,we implement this concept on an unmanned drone and showcase adaptive invisibility in three canonical landscapes-sea,land,and air-with a similarity rate of up to 95%.Our work extends the family of invisibility cloaks to flying modality and inspires other research on material discoveries and homeostatic meta-devices.

热扩散系统中非厄米趋肤效应的观测

The paradigm shift of Hermitian systems into the non-Hermitian regime profoundly modifies inherent property of the topological systems, leading to various unprecedented effects such as the nonHermitian skin effect(NHSE). In the past decade, the NHSE has been demonstrated in quantum, optical and acoustic systems. Beside those wave systems, the NHSE in diffusive systems has not yet been observed, despite recent abundant advances in the study of topological thermal diffusion. In this work,we design a thermal diffusion lattice based on a modified Su-Schrieffer-Heeger model and demonstrate the diffusive NHSE. In the proposed model, the asymmetric temperature field coupling inside each unit cell can be judiciously realized by appropriate configurations of structural parameters. We find that the temperature fields trend to concentrate toward the target boundary which is robust against initial excitation conditions. We thus experimentally demonstrated the NHSE in thermal diffusion and verified its robustness against various defects. Our work provides a platform for exploration of non-Hermitian physics in the diffusive systems, which has important applications in efficient heat collection, highly sensitive thermal sensing and others.