Association of Human Whole-blood NAD + Levels with Nabothian Cyst.

Objective: Little is known about the association between whole-blood nicotinamide adenine dinucleotide (NAD +) levels and nabothian cysts. This study aimed to assess the association between NAD + levels and nabothian cysts in healthy Chinese women. Methods: Multivariate logistic regression analysis was performed to analyze the association between NAD + levels and nabothian cysts. Results: The mean age was 43.0 ± 11.5 years, and the mean level of NAD + was 31.3 ± 5.3 µmol/L. Nabothian cysts occurred in 184 (27.7%) participants, with single and multiple cysts in 100 (15.0%) and 84 (12.6%) participants, respectively. The total nabothian cyst prevalence gradually decreased from 37.4% to 21.6% from Q1 to Q4 of NAD + and the prevalence of single and multiple nabothian cysts also decreased across the NAD + quartiles. As compared with the highest NAD + quartile (≥ 34.4 µmol/L), the adjusted odds ratios with 95% confidence interval of the NAD + Q1 was 1.89 (1.14-3.14) for total nabothian cysts. The risk of total and single nabothian cysts linearly decreased with increasing NAD + levels, while the risk of multiple nabothian cysts decreased more rapidly at NAD + levels of 28.0 to 35.0 µmol/L. Conclusion: Low NAD + levels were associated with an increased risk of total and multiple nabothian cysts.

Peptide targeting improves the delivery and therapeutic index of glucocorticoids to treat rheumatoid arthritis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by excessive inflammation in the joints. Glucocorticoid drugs are used clinically to manage RA symptoms, while their dosage and duration need to be tightly controlled due to severe adverse effects. Using dexamethasone (DEX) as a model drug, we explored here whether peptide-guided delivery could increase the safety and therapeutic index of glucocorticoids for RA treatment. Using multiple murine RA models such as collagen-induced arthritis (CIA), we found that CRV, a macrophage-targeting peptide, can selectively home to the inflammatory synovium of RA joints upon intravenous injection. The expression of the CRV receptor, retinoid X receptor beta (RXRB), was also elevated in the inflammatory synovium, likely being the basis of CRV targeting. CRV-conjugated DEX increased the accumulation of DEX in the inflamed synovium but not in healthy organs of CIA mice. Therefore, CRV-DEX demonstrated a stronger efficacy to suppress synovial inflammation and alleviate cartilage/bone destruction. Meanwhile, CRV conjugation reduced immune-related adverse effects of DEX even after a long-term use. Last, we found that RXRB expression was significantly elevated in human patient samples, demonstrating the potential of clinical translation. Taken together, we provide a novel, peptide-targeted strategy to improve the therapeutic efficacy and safety of glucocorticoids for RA treatment.

Mechanism of analgesic effect of fire needle on peripheral sensitization in rats with neuropathic pain induced by chemotherapy. / ç«é’ˆå¯¹åŒ–ç–—æ‰€è‡´ç¥žç»ç— ç†æ€§ç–¼ç—›å¤§é¼ å¤–å‘¨æ•åŒ–çš„é•‡ç—›ä½œç”¨æœºåˆ¶.

OBJECTIVES: This study aims to explore the analgesic mechanism of fire needle on peripheral sensitization in rats with neuropathic pain(NP) induced by oxaliplatin, so as to investigate its mechanism in improving peri-pheral sensitization. METHODS: Male SD rats aged 8 weeks were randomly divided into 4 groups：normal group(n=6), model group(n=6), fire needle group(n=6), and medication group(n=6). NP rat model was established by intraperitoneal injection of oxaliplatin(4 mg/kg) on days 1, 2, 8, 9, 15, 16, 22, and 23. For rats in the fire needle group, fire needle treatment was performed at the "Jiaji"(EX-B2) acupoints of the L4-L6 segments on days 24, 26, and 28, ie. 1 day, 3 and 5 days after modeling. The medication group received intraperitoneal injection of pregabalin(100 mg/kg). Mechanical pain thresholds of the rats were measured before modeling, after modeling and intervention. Serum contents of tumor necrosis factor-α(TNF-α), interleukin-6(IL-6) and chemokine ligand 12(CXCL12) were detected by ELISA. Skin histopathology changes in the acupoint area were observed using HE staining. The number of mast cells in the skin of the acupoints was observed using toluidine blue staining. Immunohistochemical staining was performed to detect the postive expressions of transient receptor potential vanilloid 1(TRPV1), protease-activated receptor 2(PAR2) and tryptase(TPS) in the skin of the acupoint area. Western blot was used to detect the protein expressions of TRPV1 and PAR2 in the dorsal root ganglia(DRG). RESULTS: Compared with the normal group, the model group had decreased paw withdrawal threshold(PWT) after modeling(P<0.05), increased serum contents of IL-6, TNF-α, and CXCL12(P<0.05), increased number of mast cells in the acupoint area(P<0.05), and increased positive protein expressions of TPS, TRPV1, and PAR2 in the skin of the acupoint area(P<0.05). Compared with the model group, the fire needle group and medication group had increased PWT after intervention(P<0.05), decreased serum contents of IL-6, TNF-α, and CXCL12, and postive protein expressions of TPS, TRPV1, and PAR2 in the skin of the acupoint area(P<0.05)；while the medication group had decreased protein expressions of TRPV1 and PAR2 in DRG(P<0.05). HE staining showed thickened epidermis, disordered cellular arrangement, significant intercellular edema, and inflammatory cell infiltration in the model group. In the medication and fire needle groups, the epidermis was thinner, cellular arrangement was clearer, and the extent of tissue edema and inflammatory cell infiltration was reduced compared to the model group. CONCLUSIONS: Fire needle can improve mechanical pain threshold and reduce the contents of peripheral inflammatory factors in rats with oxaliplatin-induced NP. This effect may be related to the inhibition of mast cell activation and the inhibition of TPS, TRPV1 and PAR2 protein expressions, in the local areas of acupoints.

Curcumin Alleviates Singapore Grouper Iridovirus-Induced Intestine Injury in Orange-Spotted Grouper (Epinephelus coioides).

Singapore grouper iridovirus (SGIV) is a new ranavirus species in the Iridoviridae family, whose high lethality and rapid spread have resulted in enormous economic losses for the aquaculture industry. Curcumin, a polyphenolic compound, has been proven to possess multiple biological activities, including antibacterial, antioxidant, and antiviral properties. This study was conducted to determine whether curcumin protected orange-spotted grouper (Epinephelus coioides) from SGIV-induced intestinal damage by affecting the inflammatory response, cell apoptosis, oxidative stress, and intestinal microbiota. Random distribution of healthy orange-spotted groupers (8.0 ± 1.0 cm and 9.0 ± 1.0 g) into six experimental groups (each group with 90 groupers): Control, DMSO, curcumin, SGIV, DMSO + SGIV, and curcumin + SGIV. The fish administered gavage received DMSO dilution solution or 640 mg/L curcumin every day for 15 days and then were injected intraperitoneally with SGIV 24 h after the last gavage. When more than half of the groupers in the SGIV group perished, samples from each group were collected for intestinal health evaluation. Our results showed that curcumin significantly alleviated intestine damage and repaired intestinal barrier dysfunction, which was identified by decreased intestine permeability and serum diamine oxidase (DAO) activity and increased expressions of tight junction proteins during SGIV infection. Moreover, curcumin treatment suppressed intestinal cells apoptosis and inflammatory response caused by SGIV and protected intestinal cells from oxidative injury by enhancing the activity of antioxidant enzymes, which was related to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Moreover, we found that curcumin treatment restored the disruption of the intestinal microbiota caused by SGIV infection. Our study provided a theoretical basis for the functional development of curcumin in aquaculture by highlighting the protective effect of curcumin against SGIV-induced intestinal injury.

The Efficacy and Cognitive Impact of Perampanel Monotherapy in Patients with Self-Limited Epilepsy with Centrotemporal Spikes: A Retrospective Analysis.

Objective: The third generation of antiepileptic medication (ASM) perampanel (PER), is mostly used as an add-on treatment for refractory epilepsy patients, and rarely used as a monotherapy. This study aims to observe the efficacy and assess the cognitive effects of PER monotherapy in patients with self-limited epilepsy with centrotemporal spikes (SeLECTS). Patients and Methods: Through screening, 86 patients who were first diagnosed with SeLECTS and treated with PER monotherapy were included in this study. All patients were followed up at least 12 months, and Evaluated the efficacy and safety of PER by observing the seizures of patients. At the same time, we used the P300 event-related potential (ERP) component and Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) to evaluate the cognitive changes in children before and after treatment with PER. Results: Ten percent of the children experienced adverse effects, such as dizziness, gait instability, and irritability. The drug retention rate at the last follow-up was 98.83%. Further more, the P300 ERP component and WISC-IV tests were performed no significant difference before and 12 months after PER monotherapy in SeLECTS children. Conclusion: The third-generation of ASM PER monotherapy had a clear effect in children with SeLECTS. A small dose of PER can control seizures well and has no obvious effect on cognitive development.

Measuring psychiatric symptoms online: A systematic review of the use of inventories on Amazon Mechanical Turk (mTurk).

Symptom measurement in psychiatric research increasingly uses digitized self-report inventories and is turning to crowdsourcing platforms for recruitment, e.g., Amazon Mechanical Turk (mTurk). The impact of digitizing pencil-and-paper inventories on the psychometric properties is underexplored in mental health research. Against this background, numerous studies report high prevalence estimates of psychiatric symptoms in mTurk samples. Here we develop a framework to evaluate the online implementation of psychiatric symptom inventories relative to two domains, that is, the adherence to (i) validated scoring and (ii) standardized administration. We apply this new framework to the online use of the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Alcohol Use Disorder Identification Test (AUDIT). Our systematic review of the literature identified 36 implementations of these three inventories on mTurk across 27 publications. We also evaluated methodological approaches to enhance data quality, e.g., the use of bot detection and attention check items. Of the 36 implementations, 23 reported the applied diagnostic scoring criteria and only 18 reported the specified symptom timeframe. None of the 36 implementations reported adaptations made in their digitization of the inventories. While recent reports attribute higher rates of mood, anxiety, and alcohol use disorders on mTurk to data quality, our findings indicate that this inflation may also relate to the assessment methods. We provide recommendations to enhance both data quality and fidelity to validated administration and scoring methods.

Physical dual-network photothermal antibacterial multifunctional hydrogel adhesive for wound healing of drug-resistant bacterial infections synthesized from natural polysaccharides.

Wound-healing of drug-resistant bacterial infections has always been a clinical challenge. The design and development of effective and economically safe wound dressings with antimicrobial activity and healing-promoting properties is highly desirable, especially in the context of wound-infections. Herein, we designed a physical dual-network multifunctional hydrogel adhesive based on polysaccharide material for the treatment of full-thickness skin defects infected with multidrug-resistant bacteria. The hydrogel utilized ureido-pyrimidinone (UPy)-modified Bletilla striata polysaccharide (BSP) as the first physical interpenetrating network for providing some brittleness and rigidity; and then branched macromolecules formed after cross-linking Fe3+ with dopamine-conjugated di-aldehyde-hyaluronic acid as the second physical interpenetrating network for providing some flexibility and elasticity. In this system, BSP and hyaluronic acid (HA) are used as synthetic matrix materials to provide strong biocompatibility and wound-healing ability. In addition, ligand cross-linking of catechol-Fe3+ and quadrupole hydrogen-bonding cross-linking of UPy-dimer can form a highly dynamic physical dual-network structure, which imparts good rapid self-healing, injectability, shape-adaptation, NIR/pH responsiveness, high tissue-adhesion and mechanical properties of this hydrogel. Meanwhile, bioactivity experiments demonstrated that the hydrogel also possesses powerful antioxidant, hemostatic, photothermal-antibacterial and wound-healing effects. In conclusion, this functionalized hydrogel is a promising candidate for clinical treatment of full-thickness bacteria-stained wound dressing materials.

Chitinase Is Involved in the Fruiting Body Development of Medicinal Fungus Cordyceps militaris.

Cordyceps militaris is a famous traditional edible and medicinal fungus in Asia, and its fruiting body has rich medicinal value. The molecular mechanism of fruiting body development is still not well understood in C. militaris. In this study, phylogenetically analysis and protein domains prediction of the 14 putative chitinases were performed. The transcription level and enzyme activity of chitinase were significant increased during fruiting body development of C. militaris. Then, two chitinase genes (Chi1 and Chi4) were selected to construct gene silencing strain by RNA interference. When Chi1 and Chi4 genes were knockdown, the differentiation of the primordium was blocked, and the number of fruiting body was significantly decreased approximately by 50% compared to wild-type (WT) strain. The length of the single mature fruiting body was shortened by 27% and 38% in Chi1- and Chi4-silenced strains, respectively. In addition, the chitin content and cell wall thickness were significantly increased in Chi1- and Chi4-silenced strains. These results provide new insights into the biological functions of chitinase in fruiting body development of C. militaris.

Entropically Driven Fabrication of Binary Superlattices Assembled from Polymer-Tethered Nanocubes and Nanospheres.

The spontaneous organization of two types of nanoparticles (NPs) with different shapes or properties into binary nanoparticle superlattices (BNSLs) with different configurations has recently attracted significant attention due to the coupling or synergistic effect of the two types of NPs, providing an efficient and general route for designing new functional materials and devices. Here, this work reports the co-assembly of polystyrene (PS) tethered anisotropic gold nanocubes (AuNCs@PS) and isotropic gold NPs (AuNPs@PS) via an emulsion-interface self-assembly strategy. The distributions and arrangements of the AuNCs and spherical AuNPs in the BNSLs can be precisely controlled by adjusting the effective size ratio (λeff ) of the effective diameter (deff ) of the embedded spherical AuNPs to the polymer gap size (L) between the neighboring AuNCs. λeff determines not only the change of the conformational entropy of the grafted polymer chains (∆Scon ) but also the mixing entropy (∆Smix ) of the two types of NPs. During the co-assembly process, ∆Smix tends to be as high as possible, and the -∆Scon tends to be as low as possible, leading to free energy minimization. As a result, well-defined BNSLs with controllable distributions of spherical and cubic NPs can be obtained by tuning λeff . This strategy can also be applied for other NPs with different shapes and atomic properties, thus largely enriching the BNSL library and enabling the fabrication of multifunctional BNSLs, which have potential applications in photothermal therapy, surface-enhanced Raman scattering, and catalysis.

Fabrication and characterization of PVA@PLA electrospinning nanofibers embedded with Bletilla striata polysaccharide and Rosmarinic acid to promote wound healing.

In this study, a novel nanofiber material with Polylactic acid (PLA), natural plant polysaccharides-Bletilla striata polysaccharide (BSP) and Rosmarinic acid (RA) as the raw materials to facilitate wound healing was well prepared through coaxial electrospinning. The morphology of RA-BSP-PVA@PLA nanofibers was characterized through scanning electron microscopy (SEM), and the successful formation of core-shell structure was verified under confocal laser microscopy (CLSM) and Fourier transform infrared spectroscopy (FTIR). RA-BSP-PVA@PLA exhibited suitable air permeability for wound healing, as indicated by the result of the water vapor permeability (WVTR) study. The results of tension test results indicated the RA-BSP-PVA@PLA nanofiber exhibited excellent flexibility and better accommodates wounds. Moreover, the biocompatibility of RA-BSP-PVA@PLA was examined through MTT assay. Lastly, RA-BSP-PVA@PLA nanofibers can induce wound tissue growth, as verified by the rat dorsal skin wound models and tissue sections. Furthermore, RA-BSP-PVA@PLA can facilitate the proliferation and transformation of early wound macrophages, and down-regulate MPO+ expression of on the wound, thus facilitating wound healing, as confirmed by the result of immunohistochemical. Thus, RA-BSP-PVA@PLA nanofibers show great potential as wound dressings in wound healing.

Identification of an ALK-2 inhibitor as an agonist for intercellular exchange and tumor delivery of nanomaterial.

Inefficient extravasation and penetration in solid tissues hinder the clinical outcome of nanoparticles (NPs). Recent studies have shown that the extravasation and penetration of NPs in solid tumor was mostly achieved via an active transcellular route. For this transport process, numerous efforts have been devoted to elucidate the endocytosis and subcellular trafficking of NPs. However, how they exit from one cell and re-enter into neighboring ones (termed intercellular exchange) remains poorly understood. We previously developed cellular assays that exclusively quantify the intercellular exchange of NPs in vitro. Our study showed that a significant portion of NPs are transferred inside extracellular vesicles (EVs). Pharmacological inhibition of EV biogenesis significantly reduced the tumor accumulation and vascular penetration of both inorganic and organic NPs in vivo. Intrigued by this result, we performed here a manual chemical screen with our assay, which identified that LDN-214117 (an inhibitor for activin receptor-like kinase-2, ALK-2) is an agonist of NP intercellular exchange. We further showed that LDN-214117 regulates the intercellular exchange by increasing the EV biogenesis. Mechanistic investigation showed that LDN-214117 functions via BMP (bone morphogenetic protein)-MAPK (mitogen-activated protein kinase) signaling pathway to increase EV biogenesis. We further demonstrated that LDN-214117 treatment in vivo enhanced the tumor accumulation and vascular penetration of a variety of NPs in multiple tumor models, which improves their antitumor efficacy. Overall, we showcase here the identification of a novel chemical compound with our intercellular exchange assays to modulate EV biogenesis and EV-mediated transport, thus boosting up the delivery and therapeutic efficacy of nanomaterial.

Chitosan electrospun nanofibers derived from Periplaneta americana residue for promoting infected wound healing.

Periplaneta americana has been used medicinally for years to treat a wide variety of skin lesions or ulcers. However, a sizable portion of the drug residues that are retained after extraction are routinely thrown away, thus posing a hazard to the environment and depleting resources. In this study, low molecular weight Periplaneta americana chitosan (LPCS) and high molecular weight Periplaneta americana chitosan (HPCS) were extracted from Periplaneta americana residue (PAR) based on the conventional acid-base method and two deacetylation methods. Moreover, the physicochemical properties and structural differences between the above two chitosan and commercial chitosan (CS) were compared using different methods. Next, two nanofibers comprising different ratios of Periplaneta americana chitosan (LPCS or HPCS), polyvinyl alcohol (PVA), and polyethylene oxide (PEO) were prepared and optimized. The above nanofibers exhibited excellent mechanical properties, antibacterial properties, and biocompatibility while facilitating wound healing in an infected rat whole-layer wound model by promoting wound closure, epithelialization, collagen deposition, and inflammation reduction. In brief, this study produced an effective and affordable wound dressing and offered a suggestion for the comprehensive utilization of Periplaneta americana residue.

Co-administration of Transportan Peptide Enhances the Cellular Entry of Liposomes in the Bystander Manner Both In Vitro and In Vivo.

Liposomes have been widely used as a drug delivery vector. One way to further improve its therapeutic efficacy is to increase the cell entry efficiency. Covalent conjugation with cell-penetrating peptides (CPPs) and other types of ligands has been the mainstream strategy to tackle this issue. Although efficient, it requires additional chemical modifications on liposomes, which is undesirable for clinical translation. Our previous study showed that the transportan (TP) peptide, an amphiphilic CPP, was able to increase the cellular uptake of co-administered, but not covalently coupled, metallic nanoparticles (NPs). Termed bystander uptake, this process represents a simpler method to increase the cell entry of NPs without chemical modifications. Here, we extended our efforts to liposomes. Our results showed that co-administration with the TP peptide improved the internalization of liposome into a variety of cell lines in vitro. This effect was also observed in primary cells, ex vivo tumor slices, and in vivo tumor tissues. On the other hand, this peptide-assisted liposome internalization did not apply to cationic CPPs, which were the main inducers for bystander uptake in previous studies. We also found that TP-assisted bystander uptake of liposome is receptor dependent, and its activity is more sensitive to the inhibitors of the macropinocytosis pathway, underlining the potential cell entry mechanism. Overall, our study provides a simple strategy based on TP co-administration to increase the cell entry of liposomes, which may open up new avenues to apply TP peptides in nanotherapeutics.

Extraction, purification, structural features and biological activities of longan fruit pulp (Longyan) polysaccharides: A review.

Dimocarpus longan Lour. (also called as longan) is a subtropical and tropical evergreen tree belonging to the Sapindaceae family and is widely distributed in China, Southeast Asia and South Asia. The pulp of longan fruit is a time-honored traditional medicinal and edible raw material in China and some Asian countries. With the advancement of food therapy in modern medicine, longan fruit pulp as an edible medicinal material is expected to usher in its rapid development as a functional nutrient. As one of the main constituents of longan fruit pulp, longan fruit pulp polysaccharides (LPs) play an indispensable role in longan fruit pulp-based functional utilization. This review aims to outline the extraction and purification methods, structural characteristics and biological activities (such as immunoregulatory, anti-tumor, prebiotic, anti-oxidant, anti-inflammatory and inhibition of AChE activity) of LPs. Besides, the structure-activity relationship, application prospect and patent application of LPs were analyzed and summarized. Through the systematic summary, this review attempts to provide a theoretical basis for further research of LPs, and promote the industrial development of this class of polysaccharides.

Synthesis, Characterization, and Bioactivities of Polysaccharide Metal Complexes: A Review.

Natural polysaccharides are critical to a wide range of fields (e.g., medicine, food production, and cosmetics) for their various remarkable physical properties and biological activities. However, the bioactivities of naturally acquired polysaccharides may be unsatisfactory and limit their further applications. It is generally known that the chemical structure exhibited by polysaccharides lays the material basis for their biological activities. Accordingly, possible structural modifications should be conducted on polysaccharides for their enhancement. Recently, polysaccharides complexed with metal ions (e.g., Fe, Zn, Mg, Cr, and Pt) have been reported to be possibly used to improve their bioactivities. Moreover, since the properties exhibited by metal ions are normally conserved, polysaccharides may be endowed with new applications. In this review, the synthesis methods, characterization methods, and bioactivities of polysaccharide metal complexes are summarized specifically. Then, the application prospects and limitations of these complexes are analyzed and discussed.

Synergistic Entry of Individual Nanoparticles into Mammalian Cells Driven by Free Energy Decline and Regulated by Their Sizes.

Cell entry is one of the common prerequisites for nanomaterial applications. Despite extensive studies on a homogeneous group of nanoparticles (NPs), fewer studies have been performed when two or more types of NPs were coadministrated. We previously described a synergistic cell entry process for two heterogeneous groups of NPs, where NPs functionalized with TAT (transactivator of transcription) peptide (T-NPs) stimulate the cellular uptake of coadministered unfunctionalized NPs (bystander NPs, B-NPs). Here, we show that the synergistic cell entry of NPs is driven by free energy decline and depends on B-NP sizes. Simulations showed that when separately placed initially, two NPs first move toward each other instead of initiating cell entry individually. Only T-NP invokes an inward bending of membrane mimicking endocytosis, which attracts the nearby NPs into the same "vesicle". A two-phase free energy decline of the entire system occurred as two NPs get closer until contact, which is likely the thermodynamic driver for synergistic NP coentry. Experimentally, we found that T-NPs increase the apparent affinity of B-NPs to plasma membrane, suggesting that T-NPs help B-NPs "trapped" in the endocytic vesicles. Next, we varied the sizes of B-NPs and found that bystander activity peaks around 50 nm. Simulations also showed that the size of B-NPs influences the free energy decline, and thus the tendency and dynamics of NP coentry. These efforts provide a system to further understand the synergistic cell entry among individual NPs or multiple NP types on a biophysical basis and shed light on the future design of nanostructures for intracellular delivery.

Design, Semisynthesis, Insecticidal and Antibacterial Activities of a Series of Marine-Derived Geodin Derivatives and Their Preliminary Structure-Activity Relationships.

To enhance the biological activity of the natural product geodin (1), isolated from the marine-derived fungus Aspergillus sp., a series of new ether derivatives (2-37) was designed and semisynthesized using a high-yielding one-step reaction. In addition, the insecticidal and antibacterial activities of all geodin congeners were evaluated systematically. Most of these derivatives showed better insecticidal activities against Helicoverpa armigera Hübner than 1. In particular, 15 showed potent insecticidal activity with an IC50 value of 89 µM, comparable to the positive control azadirachtin (IC50 = 70 µM). Additionally, 5, 12, 13, 16, 30 and 33 showed strong antibacterial activity against Staphylococcus aureus and Aeromonas salmonicida with MIC values in the range of 1.15-4.93 µM. The preliminary structure-activity relationships indicated that the introduction of halogenated benzyl especially fluorobenzyl, into 1 and substitution of 4-OH could be key factors in increasing the insecticidal and antibacterial activities of geodin.

Structure modification, antialgal, antiplasmodial, and toxic evaluations of a series of new marine-derived 14-membered resorcylic acid lactone derivatives.

Marine natural products play critical roles in the chemical defense of many marine organisms and are essential, reputable sources of successful drug leads. Sixty-seven 14-membered resorcylic acid lactone derivatives 3-27 and 30-71 of the natural product zeaenol (1) isolated from the marine-derived fungus Cochliobolus lunatus were semisynthesized by chlorination, acylation, esterification, and acetalization in one to three steps. The structures of these new derivatives were established by HRESIMS and NMR techniques. All the compounds (1-71) were evaluated for their antialgal and antiplasmodial activities. Among them, 14 compounds displayed antifouling activities against adhesion of the fouling diatoms. In particular, 9 and 34 exhibited strong and selective inhibitory effects against the diatoms Navicula laevissima and Navicula exigua (EC50 = 6.67 and 8.55 µmol/L), respectively, which were similar in efficacy to those of the positive control SeaNine 211 (EC50 = 2.90 and 9.74 µmol/L). More importantly, 38, 39, and 69-71 showed potent antiplasmodial activities against Plasmodium falciparum with IC50 values ranging from 3.54 to 9.72 µmol/L. Very interestingly, the five antiplasmodial derivatives displayed non-toxicity in the cytotoxicity assays and the zebrafish embryos model, thus, representing potential promising antiplasmodial drug agents. The preliminary structure-activity relationships indicated that biphenyl substituent at C-2, acetonide at positions C-5' and C-6', and tri- or tetra-substituted of acyl groups increased the antiplasmodial activity. Therefore, combining evaluation of chemical ecology with pharmacological models will be implemented as a systematic strategy, not only for environmentally friendly antifoulants but also for structurally novel drugs. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-021-00103-0.

Preparation of Oral Core-Shell Zein Nanoparticles to Improve the Bioavailability of Glycyrrhizic Acid for the Treatment of Ulcerative Colitis.

In this study, oral colon-targeted adhesion core-shell nanoparticles were designed by applying FA-Zein as the core and using pectin as the shell to enhance the low bioavailability exhibited by glycyrrhizic acid (GA) and the anti-inflammatory effect in specific parts of the intestine. As indicated by the results, the nanoparticles (NPs) remained stable in the stomach and small intestine, while pectins began to degrade and release GA in considerable amounts in the colon with the abundant flora. Subsequently, folate-acid targeting was further assessed with Raw 264.7 and NCM 460 cells. Lastly, NPs were reported to exhibit high adhesion on the colon by using the DSS-induced ulcerative colitis mouse model. Moreover, as indicated by in vitro and in vivo studies, nanoparticles could decrease the levels of MPO and TNF-α by reducing macrophages and neutrophils. In brief, this study provides an ideal loaded natural anti-inflammatory drug delivery system to treat ulcerative colitis.

Strategy for osteoarthritis therapy: Improved the delivery of triptolide using liposome-loaded dissolving microneedle arrays.

Osteoarthritis (OA) is a chronic disease that seriously impairs people's physical function and quality of life. Triptolide (TP), as a promising anti-inflammatory drug for the treatment of OA, has limited clinical application due to its severe systemic toxicity, poor solubility and rapid elimination in the body. To extend its application prospect for OA treatment. We have developed a liposome-loaded dissolving microneedle (DMN) system, which can effectively deliver poorly water-soluble TP and improve OA symptoms. To incorporate TP into DMNs, triptolide liposome (TP-Lipo) with entrapment efficiency of 90.25% was prepared by ethanol injection. Subsequently, TP-Lipo was concentrated by ultrafiltration tube and mixed with hyaluronic acid solution to prepare DMNs, TP-Lipo-loaded DMNs (TP-Lipo@DMNs) showed sufficient mechanical and insertion properties to penetrate about 200 µm of rat skin. The drug distribution in vivo showed that TP-Lipo@DMNs had a slow-release effect compared with intra-articular injection. In vivo pharmacodynamic research showed that TP-Lipo@DMNs significantly reduced knee joint swelling and the level of inflammatory cytokines (TNF-α, IL-1ß, IL-6). Micro-CT and histological evaluation showed that TP-Lipo@DMNs effectively reduced cartilage destruction and alleviated OA symptoms. These results support that TP@Lipo@DMNs may be a promising option for OA treatment.