Nanomedicines targeting activated immune cells and effector cells for rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation and inflammatory cellular infiltration. Functional cells in the RA microenvironment (RAM) are composed of activated immune cells and effector cells. Activated immune cells, including macrophages, neutrophils, and T cells, can induce RA. Effector cells, including synoviocytes, osteoclasts, and chondrocytes, receiving inflammatory stimuli, exacerbate RA. These functional cells, often associated with the upregulation of surface-specific receptor proteins and significant homing effects, can secrete pro-inflammatory factors and interfere with each other, thereby jointly promoting the progression of RA. Recently, some nanomedicines have alleviated RA by targeting and modulating functional cells with ligand modifications, while other nanoparticles whose surfaces are camouflaged by membranes or extracellular vesicles (EVs) of these functional cells target and attack the lesion site for RA treatment. When ligand-modified nanomaterials target specific functional cells to treat RA, the functional cells are subjected to attack, much like the intended targets. When functional cell membranes or EVs are modified onto nanomaterials to deliver drugs for RA treatment, functional cells become the attackers, similar to arrows. This study summarized how diversified functional cells serve as targets or arrows by engineered nanoparticles to treat RA. Moreover, the key challenges in preparing nanomaterials and their stability, long-term efficacy, safety, and future clinical patient compliance have been discussed here.

Flavonoidal alkaloids: Emerging targets for drug discovery from Nature's bounty.

This paper explores the potential of flavonoid alkaloids, a unique class of compounds that contain both flavonoid and alkaloid structures, as emerging targets for drug discovery. These compounds exhibit diverse biological activities, such as anti-inflammatory, anti-cancer, and anti-diabetic effects, which are attributed to the combination of different flavonoid scaffolds and alkaloid groups. Flavonoid alkaloids have attracted researchers' attention due to their diverse structures and important bio-activities. Therefore, this review summarizes recent advances in the extraction, purification, structural characterization, synthesis pathways and biological activities of flavonoid alkaloids from natural sources. Finally, the potential prospects and challenges associated with this class of compounds in pharmacological research are discussed along with details of a mechanistic investigation and future clinical applications in this research field.

Pushing Forward the DNA Walkers in Connection with Tumor-Derived Extracellular Vesicles.

Extracellular vesicles (EVs) are microparticles released from cells in both physiological and pathological conditions and could be used to monitor the progression of various pathological states, including neoplastic diseases. In various EVs, tumor-derived extracellular vesicles (TEVs) are secreted by different tumor cells and are abundant in many molecular components, such as proteins, nucleic acids, lipids, and carbohydrates. TEVs play a crucial role in forming and advancing various cancer processes. Therefore, TEVs are regarded as promising biomarkers for the early detection of cancer in liquid biopsy. However, the currently developed TEV detection methods still face several key scientific problems that need to be solved, such as low sensitivity, poor specificity, and poor accuracy. To overcome these limitations, DNA walkers have emerged as one of the most popular nanodevices that exhibit better signal amplification capability and enable highly sensitive and specific detection of the analytes. Due to their unique properties of high directionality, flexibility, and efficiency, DNA walkers hold great potential for detecting TEVs. This paper provides an introduction to EVs and DNA walker, additionally, it summarizes recent advances in DNA walker-based detection of TEVs (2018-2024). The review highlights the close relationship between TEVs and DNA walkers, aims to offer valuable insights into TEV detection and to inspire the development of reliable, efficient, simple, and innovative methods for detecting TEVs based on DNA walker in the future.

Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by inflammation of the synovial tissue and joint bone destruction, often leading to significant disability. The main pathological manifestation of joint deformity in RA patients is bone destruction, which occurs due to the differentiation and proliferation of osteoclasts. The transcription factor nuclear factor-activated T cell 1 (NFATc1) plays a crucial role in this process. The regulation of NFATc1 in osteoclast differentiation is influenced by three main factors. Firstly, NFATc1 is activated through the upstream nuclear factor kappa-B ligand (RANKL)/RANK signaling pathway. Secondly, the Ca2+-related co-stimulatory signaling pathway amplifies NFATc1 activity. Finally, negative regulation of NFATc1 occurs through the action of cytokines such as B-cell Lymphoma 6 (Bcl-6), interferon regulatory factor 8 (IRF8), MAF basic leucine zipper transcription factor B (MafB), and LIM homeobox 2 (Lhx2). These three phases collectively govern NFATc1 transcription and subsequently affect the expression of downstream target genes including TRAF6 and NF-κB. Ultimately, this intricate regulatory network mediates osteoclast differentiation, fusion, and the degradation of both organic and inorganic components of the bone matrix. This review provides a comprehensive summary of recent advances in understanding the mechanism of NFATc1 in the context of RA-related bone destruction and discusses potential therapeutic agents that target NFATc1, with the aim of offering valuable insights for future research in the field of RA. To assess their potential as therapeutic agents for RA, we conducted a drug-like analysis of potential drugs with precise structures.

Xuetongsu attenuates bone destruction in collagen-induced arthritis mice by inhibiting osteoclast differentiation and promoting osteoclast apoptosis.

Tujia ethnomedicine Xuetong (the stems of Kadsura heteroclita) have been widely used in folk for rheumatoid arthritis (RA), which can alleviate rheumatic pain through liquor soaking in folk. In this study, we aimed to evaluate the pharmacological effects and underlying mechanism of Xuetongsu (a key chemical component of Xuetong) on bone destruction. In our previous study, it was found that Xuetong extract can reduce adjuvant arthritic rats paw swelling and inhibit inflammatory factors in serum. Furthermore, Xuetongsu has been demonstrated to inhibit the proliferation of fibroblast-like synoviocytes, but its potential to inhibit bone destruction has not been explored. To address this, we employed the STRING database to predict protein interactions and utilized Autodock software to simulate the binding of Xuetongsu to target proteins. In this study, administration of Xuetongsu significantly alleviated paw swelling and bone destruction in C57BL/6 mice with collagen-induced arthritis (CIA). Mechanistic studies have indicated that Xuetongsu promotes apoptosis of mature osteoclasts in joint tissues by activating Caspase-3 and Bax, while inhibiting Bcl-2. Additionally, Xuetongsu inhibits osteoclast differentiation by suppressing RANKL, RANK, P-NF-κB, and NFATc1, and reduces bone resorption activity by inhibiting MMP-9, CTSK, and TRAP. Importantly, Xuetongsu exhibits good biocompatibility in major organs of mice. In summary, Xuetongsu has the potential to treat bone destruction by promoting apoptosis of mature osteoclasts, inhibiting osteoclast differentiation, and reducing bone resorption. This study reveals the pharmacological effects of Xuetongsu and its mechanism of action, which may contribute to the development of novel approaches for treating RA.

Design, Synthesis, and Antitumor Activity Evaluation of Artemisinin Bivalent Ligands.

Five artemisinin bivalent ligands molecules 4a-4e were designed, synthesized, and confirmed by 1H NMR, 13C NMR, and low-resolution mass spectrometry, and the bioactivities of the target compounds were investigated against four human tumor cell lines in vitro, including BGC-823, HepG-2, MCF-7, and HCT-116. The results showed 4a, 4d, and 4e exhibited significantly tumor cell inhibitory activity compared with the artemisinin and dihydroartemisinin; compound 4e has good biological activity inhibiting BGC-823 with an IC50 value of 8.30 µmol/L. Then, the good correlations with biological results were validated by molecular docking through the established bivalent ligands multi-target model, which showed that 4e could bind well with the antitumor protein MMP-9.

Glycosides from the leaves of Fraxinus Hubeiensis.

Fraxinus hubeiensis is a plant endemic to China and widely used as folk medicine to treat various diseases. However, its chemical constituents have never been reported sufficiently. Thus, the primary objective of this study was to investigate the phytochemical constituents and biological activities of F. hubeiensis leaves. Hence, combined column chromatographic and spectroscopic techniques were used to identify and characterize the secondary metabolites such as a pair of 3-keto-glycoside epimers (1) and (2), along with five known compounds (3 ~ 7). The results of α-glucosidase inhibitory activity exhibited that 1 and 2 had moderate activity with IC50 values of 359.50 and 468.43 µM, respectively, compared to a positive control acarbose with the IC50 value of 164.08 µM. However, Compounds 1-6 were shown to be inactive against the tested microbes.

Hybrid channel coding for OAM division multiplexing free space optical communication systems.

An orbital angular momentum division multiplexing free space optical communication (OAM-DM FSO) system with channel coding can compensate atmospheric channel fading and improve system performance. An OAM-DM FSO system based on hybrid channel coding is proposed in this paper. The coding gain is improved by taking into account mode dependent channel fading difference caused by atmospheric turbulence. Simulation results show that compared with single channel coding, the coding gain is increased by 1.85 dB under Cn2=1E-14, BER=1E-5 with non-uniform LDPC code (0.7 code rate) for an OAM1/OAM3 multiplexing system. In addition, for four OAM modes (+1,+3,+5,+7) multiplexing systems, the coding gain is increased by more than 3.8 dB under Cn2=1E-14 and BER=1E-5.

Three new constituents from the Tujia ethnomedicine Swertia punicea Hemsl.

Three new constituents: 1,5R-dihydroxy-3,8S-dimethoxy-5,6,7,8-tetrahydroxanthone (1), (3S,4R,16S,17R)-3,16,23-trihydroxyoleana-11,13(18)-dien-28-aldehyde-3-O-ß-D-glucopyranoside (2), and new natural product (S)-gentiandiol (3), along with 41 known compounds were isolated from Tujia ethnomedicine Shuihuanglian, namely, the whole plant of Swertia punicea. Structures of all these compounds were established through extensive spectroscopic techniques, namely 1D, 2D-NMR spectroscopy, HRESIMS analysis, and the absolute configuration of the new compounds was discerned by circular dichroism (CD) spectroscopy. Antioxidative effects of these compounds were evaluated by using the DPPH radical scavenging method, compounds 7, 9 and 14 showed antioxidant activities with IC50 values of 68.9, 50.8 and 48.2 µM, respectively.

The traditional ethnic herb Tadehagi triquetrum from China: a review of its phytochemistry and pharmacological activities.

CONTEXT: Tadehagi triquetrum (Linn.) Ohashi (Fabaceae) (TT), is a traditional herbal medicine used especially in China's ethnic-minority communities, such as the Zhuang, Dai, Li and Wa aeras. As an ethnic medicine, it has long been used to treat various diseases. OBJECTIVE: This review summarised the phytochemical and pharmacological progress on TT from 1979 to October, 2021 by highlighting its chemical classification, structural features, pharmacological applications and folk applications to provide inspirations and suggestions for accelerating further research of this traditional phytomedicine. METHODS: The information on TT in this article has been obtained using these multiple scientific databases including Scifinder, Web of Science, ScienceDirect, Wiley, ACS publications, Springer, PubMed, China Knowledge Resource Integrated Database from the China National Knowledge Infrastructure (CNKI), Google Scholar and Baidu Scholar. Some information was also collected from classic literature on traditional Chinese medicines. RESULTS: More than 70 compounds have been isolated and reported from TT to date by the comprehensive analysis of the current literature. A large number of traditional uses and pharmacological studies have exhibited diversified bioactivities of various TT extracts and its metabolites, including anti-inflammatory, antimicrobial, anti-hepatitis B virus, hepatoprotective, insecticidal, etc. CONCLUSIONS: As a famous traditional medicine with a long history, TT has various medicinal uses and some of them have been supported by modern pharmacological researches. Further detailed studies on the action mechanisms, pharmacodynamics and structure-function relationships of single compounds or active constituents from TT are also required.

Cyclocarya paliurus (Batalin) Iljinskaja: Botany, Ethnopharmacology, phytochemistry and pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Cyclocarya paliurus (Batalin) Iljinskaja (C. paliurus) also known as Sweet tea tree, Money tree, Money willow, green money plum, mountain willow and shanhua tree, is a native rare monocotyledonous plant in Southern China. It possesses numerous traditional benefits, including clearing heat, detoxification, producing saliva, slake thirst, anti-inflammatory, insecticidal, dispelling wind and relieving itching. It is also effective in preventing and treating diabetes, hypertension, hyperlipidemia, dizziness and swelling and pain, as well as reducing cholesterol, and modulating the functions of the immune system. The stem, leaves and bark of this plant are all medicinal parts, but the leaves have the highest research value. AIM OF THE STUDY: This article summarized the plant's botanical description, distribution, ethnopharmacology, phytochemical profiles and pharmacological for the first time, to provide possible directions for future development and research in brief. MATERIAL AND METHODS: The literature for this current manuscript was obtained from reports published from 1992 to May 2021 in diverse databases such as the China Knowledge Resource Integrated databases (CNKI), SciFinder, Google Scholar, Baidu Scholar, Elsevier and Pub-Med. The domestic and foreign references published about C. paliurus over recent years were collected, analyzed and summarized. RESULTS: The botanical characteristics of the fruits of C. paliurus are unique in having a central nutlet surrounded by a circular wing to distinguish the living genera of Juglandaceae. In traditional medicine, C. paliurus leaves are used by the local people of Southern China to make tea to prevent diabetes. More than 210 compounds have been isolated from C. paliurus. Among them, the characteristic 3,4-seco-dammaranes accounted for the most. Other compounds include dammarane tetracyclic triterpenoids, various pentacyclic triterpenoids, flavonoids, isosclerones, phenolic derivatives and polysaccharides. The plant extracts and compounds have been reported to exert various pharmacological activities, such as anti-hyperglycemic, anti-hyperlipidemic, anti-cancer, cytotoxic, anti-oxidative, anti-inflammatory, hepatoprotective, and anti-microbial activities. CONCLUSIONS: Comprehensive literature analysis shows that C. paliurus extract and its compounds have a variety of biological activities for the treatment of various diseases. The current modern pharmacology research is mostly related to the records of ethnic pharmacology, mainly in vitro research, relatively few in vivo research. Therefore, future studies should focus on this aspect. In addition, we also would like to recommend further research should concentrate on toxicity studies and quality control of C. paliurus to fill the study gap, as well as to provide theoretical support for the further development of the potential functions and clinical applications of the plant.

Flavonoid glycosides from the rhizomes of Pronephrium penangianum.

Six flavonoid glycosides jixueqisus A-F, together with nine known flavonoids, were isolated from the rhizomes of the fern Pronephrium penangianum. Among them, two red pigments jixueqisus A and B possess the same rare 6,8-dimethyl-2-phenyl-7H-1-benzopyran-7-one skeleton (a long conjugated system). Jixueqisu Cwas a dihydrochalcone glycoside, jixueqisu D was a chalcone glycoside, jixueqisu E was an aurone glycoside, and jixueqisu F was a flavonone glycoside. Interestingly, jixueqisus D-F, (2S)-5,2',5'-trihydroxy-7-methoxyflavanone and 5,2',5'-trihydroxy-7-methoxyflavone possessed a 2,5-dihydroxy substituted benzene ring (B-ring). Their structures were elucidated by various spectroscopic and chemical methods. Furthermore, the plausible biosynthetic pathways of jixueqisus A-F were discussed, respectively. All isolated compounds were evaluated for their activities against the proliferation of MCF-7, HepG-2, HCT-116 and BGC-823 tumor cell lines, four known flavane-4-ol glycosides, abacopterins A and C, eruberin B and triphyllin A, exhibited moderate activities to various cell lines.

Development of a nanodrug-delivery system camouflaged by erythrocyte membranes for the chemo/phototherapy of cancer.

Aim: Development of a new drug-delivery system using a compound derived from Pronephrium penangianum (J5) for the treatment of cervical cancer. Materials & methods: The delivery system was developed using Prussian blue nanoparticles, camouflaged by red blood cell membrane and with folic acid surface modifications. Results: Our results showed the successful development of a nanodrug-delivery system, which increases the half-life and immune evasion ability of the drug. The mechanism of this system was through suppressing B-cell lymphoma 2 and increasing B-cell lymphoma 2-associated X protein and the cleaved caspase level. An in vivo study also confirmed good antitumor activity without any side effects to normal tissue. Conclusion: This drug-delivery system provides a good alternative for the treatment of cervical cancer using J5.

Endogenous Cys-Assisted GSH@AgNCs-rGO Nanoprobe for Real-Time Monitoring of Dynamic Change in GSH Levels Regulated by Natural Drug.

Glutathione (GSH) levels are closely related to the homeostasis of redox state which directly affects human disease occurrence by regulating cell apoptosis. Hence, real-time monitoring of dynamic changes in intracellular GSH levels is urgently needed for disease early diagnosis and evaluation of therapy efficiency. In this study, an endogenous cysteine (Cys)-assisted detection system based on GSH@AgNCs and reduced graphene oxide (rGO) with high sensitivity and specificity was developed for GSH detection. Compared with GSH, GSH@AgNCs with weaker affinity and bonding force was quite easier to extrude from the rGO surface when competing against GSH, leading to the obvious change in fluorescence signal. This phenomenon was termed as "a crowding out effect". Furthermore, the presence of Cys can improve GSH assay sensitivity by enhancing the quenching efficiency of rGO on the GSH@AgNCs. In vitro assay indicated that the efficiency of fluorescence recovery was positively related with GSH concentration in the range from 0 to 10 mM. In addition, the method was employed for real-time monitoring of the dynamic changes in GSH levels regulated by natural drugs. The imaging results showed that the natural compound 3 (C3) can downregulate GSH levels in HepG2 cells, which was accompanied by reactive oxygen species (ROS) release and apoptosis induction. Finally, the method was used to monitor the change of GSH levels in serum samples with chronic hepatitis B (CHB) infection. The results demonstrated that the occurrence and development of CHB may be positively correlated with GSH levels to some extent. Overall, the above results demonstrate the potential application of this new nanosystem in anticancer natural drug screening and clinical assay regarding GSH levels.

Triterpenoids from stems of Kadsura heteroclita.

In the present work, we reported the triterpenoids isolated from n-butanol fraction of Kadsura heteroclita which is a Tujia ethnomedicine with trivial name "Xuetong". This effort resulted in the isolation of six unpresented triterpenoids xuetongsu A-F (1-6), along with five known triterpenoids (7-11). The structures of the reported compounds were established on the 1D, and 2D NMR and HRESIMS spectra, along with CD spectroscopic analysis. Moreover, the absolute stereochemistry of compound 7 was determined by X-ray diffraction analysis. Antioxidant and cytotoxic activities were evaluated for all isolated compounds, compound 7 shown weak cytotoxic activity against HL-60 with IC50 value of 50.0 µM.

Schinortriterpenoids from Tujia ethnomedicine Xuetong-The stems of Kadsura heteroclita.

In the present work, we take advantage of the characteristic NMR signal (δC-10 = 96.0-99.9) for guiding the isolation of schinortriterpenoids (SNTs) from n-butanol fraction of stems of Kadsura heteroclita which is a Tujia ethnomedicine with trivial name "Xuetong". This effort resulted in the identification of three unreported 3,4:9,10-disecocycloartane triterpenoids xuetongdilactones A-C and three undescribed SNTs xuetongdilactones D-F, along with two known SNTs, namely, wuweizidilactone B and micrandilactone B. The structures of the unreported compounds were established based on 1D, and 2D NMR, HRESIMS, and ECD spectroscopic data analysis. The absolute stereochemistry of xuetongdilactone A was determined by X-ray diffraction analysis along with ECD calculation. The antioxidant and cytotoxic activities were evaluated for all the isolated compounds.

New Cadinane Sesquiterpenes from the Stems of Kadsura heteroclita.

As part of our continual efforts to exploit 'Tujia Ethnomedicine' for their pharmacophoric functionalities, we herein investigated Kadsura heteroclita collected from a deep Wulin mountain area in northern Hunan province. The current study resulted in the isolation of three new sesquiterpenes: 6α,9α,15-trihydroxycadinan-4-en-3-one (1), (+)-3,11,12-trihydroxycalamenene (2), (-)-3,10,11,12-tetrahydroxy-calamenene (3), along with four known sesquiterpenes (4-7), and a cytochalasin H (8). Their chemical structures were elucidated by 1D-, and 2D-NMR spectroscopy, and HRESI-MS, CD spectrometry. The antioxidant, and cytotoxic activities of the compounds were evaluated. Compound 8 exhibited a strong antioxidant effect with an IC50 value of 3.67 µM on isolated human polymorphonuclear cells or neutrophils.

Designing multi-targeted agents: An emerging anticancer drug discovery paradigm.

The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compounds with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents.

Metal-free synthesis of oxindoles via (NH4)2S2O8-mediated halocarbocyclization of alkenes in water.

A metal-free synthesis of oxindoles was achieved through the (NH4)2S2O8-mediated halocarbocyclization of alkenes. This protocol provides a practical and environmentally benign method for the construction of halo-containing oxindoles in water. The advantages of this reaction are its good functional group tolerance and mild reaction conditions. On the basis of experimental observations, a plausible reaction mechanism is proposed.