Marine-Derived Bisindoles for Potent Selective Cancer Drug Discovery and Development.

Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.

Cedrol-loaded dissolvable microneedles based on flexible backing for promoting hair growth.

OBJECTIVES: The dissolvable microneedles loaded with cedrol based on flexible backing were developed to deliver cedrol directly and continuously to the dermis, where the drug concentration in the hair follicle can be increased locally. METHODS: The tip-layer matrix solution was prepared by mixing cedrol and polyvinylpyrrolidone K25 (PVP K25), and the pedestal matrix solution was prepared with aqueous hyaluronic acid. The cedrol-loaded dissolvable microneedles (cedrol-DMNs) were prepared under vacuum conditions. The mechanical properties, pig skin penetration efficiency, in vitro cutaneous permeation test, and the amount of drug in the skin and receptor chamber were evaluated. Pharmacodynamical studies were performed with C57BL/6 mice. RESULTS: The mechanical properties of cedrol-DMNs were good. In vitro cutaneous permeation tests and pharmacodynamical studies demonstrated that cedrol-DMN could efficiently deliver the drug to the deep dermis and effectively promote hair growth. CONCLUSIONS: The cedrol-DMNs offer a promising strategy for treating patients suffering from hair loss.

Thiol-modified hyaluronic acid improves the physical stability of curcumin-zein nanoparticles by forming disulfide bonds with zein.

Zein-based nanoparticles have been developed in the food industry. However, their poor pH stability and unfavorable ionic strength stability remain a challenge even with the use of polysaccharides (such as hyaluronic acid) as stabilizers. To address this shortcoming, an improved strategy based on the disulfide bonds between thiol-modified hyaluronic acid (HASH) and zein was proposed. In this study, curcumin-zein nanoparticles (ZNs-HASH) were prepared with HASH as a stabilizer. The ZNs-HASH displayed similar particle sizes and spherical structures with ZNs and ZNs-HA (HA as a stabilizer). The Fourier transform infrared spectroscopy demonstrated the formation of disulfide bonds between zein and HASH. Among the three formulations tested, ZNs-HASH exhibited the highest pH and salt ion stability and the strongest antioxidant capacity. This study provided new insights for the improvement of physical stability of zein nanoparticles and the development of oral bioactive substances by chemical modification of natural polysaccharides.

Programmed pH-responsive core-shell nanoparticles for precisely targeted therapy of ulcerative colitis.

pH-Responsive nanotherapeutics were recently developed for the treatment of ulcerative colitis (UC). However, they target the entire colon rather than the UC site, which leads to insufficient accumulation in inflamed colon lesions and causes side effects. Core-shell nanoparticles exhibit unique advantages in improving the precision of targeted delivery. In this study, Eudragit® EPO and L100, two pH-sensitive materials, were coated on nano-sized curcumin to fabricate core-shell nanoparticles. The developed CNs@EPO@L100 exhibited programmed pH-responsive drug release behavior, improved in vitro anti-inflammatory ability, and enhanced accumulation at the site of inflammation in the colon. Furthermore, after oral administration, CNs@EPO@L100 significantly ameliorated the inflammatory symptoms in mice. Taken together, this study provides insights into programmed release through the rational application of pH-sensitive materials and offers strategies for a precisely targeted therapy of UC using core-shell nanoparticles.

Recrystallization Mediates the Gelation of Amorphous Drugs: The Case of Acemetacin.

Amorphization is widely used as an effective method of increasing the solubility of insoluble drugs. However, some amorphous drugs exhibit a much lower dissolution rate than their corresponding crystalline form due to their gelation. In this study, we reported the gels formed from amorphous acemetacin (ACM) for the first time. Gelation was promoted at conditions of lower pH, higher temperature and lower ionic strength. Solid-state characterizations suggested that ACM gels may be formed by recrystallization. This mechanism provides a new direction in facilitating the elimination of gelation for amorphous drugs. Moreover, it also provides the basis for the development of sustained-release formulations using the gelation properties.

Roles of effective stabilizers in improving oral bioavailability of naringenin nanocrystals: Maintenance of supersaturation generated upon dissolution by inhibition of drug dimerization.

Nanocrystals (NCs), a colloidal dispersion system formulated with stabilizers, have attracted widespread interest due to their ability to effectively improve the oral bioavailability of poorly water-soluble drugs. The stabilizer plays a key role because it can affect the physical stability and even the oral bioavailability of NCs. However, how stabilizers affect the bioavailability of NCs remains unknown. In this study, F68, F127, HPMC, and PVP were each used as a stabilizer to formulate naringenin NCs. The NCs formulated with PVP exhibited excellent release behaviors, cellular uptake, permeability, oral bioavailability, and anti-inflammatory effects. The underlying mechanism is that PVP effectively inhibits the formation of naringenin dimer, which in turn improves the physical stability of the supersaturated solution generated when NC is dissolved. This finding provides insights into the effects of stabilizers on the in vivo performances of NCs and supplies valuable knowledge for the development of poorly water-soluble drugs.

A unique two-phase heterostructure with cubic NiSe2 and orthorhombic NiSe2 for enhanced lithium ion storage and electrocatalysis.

Two-phase heterostructures have received tremendous attention in energy-related fields as high-performance electrode materials. However, heterogeneous interfaces are usually constructed by introducing foreign elements, which disturbs the investigation of the intrinsic effect of the two-phase heterostructure. Herein, unique heterostructures constructed with orthorhombic NiSe2 and cubic NiSe2 phases are developed, which are embedded in in situ formed porous carbon from metal-organic frameworks (MOFs) (O/C-NiSe2@C). Precisely-controlled selenylation of MOFs is crucial for the formation of the O/C-NiSe2 heterostructure. The heterogeneous interfaces with lattice dislocations and charge distribution are conducive to the high-speed transfer of electrons and ions during electrochemical processes, so as to improve the electrochemical reaction kinetics for lithium-ion storage and the hydrogen evolution reaction (HER). When used as the anode of lithium-ion batteries (LIBs), O/C-NiSe2@C shows a superior electrochemical performance to the counterparts with only the cubic phase (C-NiSe2@C), in view of the cycling performance (719.3 mA h g-1 at 0.1 A g-1 for 100 cycles; 456.3 mA h g-1 at 1 A g-1 for 1000 cycles) and rate capabilities (344.8 mA h g-1 at 4 A g-1). Furthermore, O/C-NiSe2@C also exhibits better HER properties than C-NiSe2@C, that is, much lower overpotentials of 154 mV and 205 mV in 0.5 M H2SO4 and 1 M KOH, respectively, at 10 mA cm-2, a smaller Tafel slope as well as stable electrocatalytic activities for 2000 cycles/10 h. Preliminary observations indicate that the unique orthorhombic/cubic two-phase heterostructure could significantly improve the electrochemical performance of NiSe2 without additional modifications such as doping, suggesting the O/C-NiSe2 heterostructure as a promising bifunctional electrode for energy conversion and storage applications.

An evaluating system for wetland ecological risk: Case study in coastal mainland China.

Coastal wetland degradation and fragmentation contribute to habitat and biodiversity loss. We construct wetland ecological risk assessment framework to evaluate the risk posed to 35 coastal wetland national nature reserves (NNRs) in China for the years 2000 and 2020. Our wetland ecological risk index (WRI) is based on an external hazard sub-index (EHI) and an internal vulnerability sub-index. Most NNRs have low EHI values in both 2000 and 2020. Ratios of change in EHI range from -22.76% to 52.15% (a negative value indicates a decrease, a positive value an increase), and the EHI for 20 of 35 NNRs (57.1%) decreases over time. Variation in the internal vulnerability index ranges -44.78% to 88.97%, and increases at 18 NNRs (51.4%) over time. WRI variation ranges between -48.13% and 82.91%, and increases at 19 NNRs (54.3%). Most NNRs are ranked as being at low, medium risk in both 2000 and 2020. Notably, the number of high-risk NNRs increases from 3 to 10 (for which WRI values also increase). Expansion of built-up land, cropland occupation (in 2020), road disturbance, and water quality are all significantly associated WRI. Intensified management of the 10 NNRs ranked at high risk is necessary to prevent further deterioration.

Hydrologic-induced concentrated soil nutrients and improved plant growth increased carbon storage in a floodplain wetland over wet-dry alternating zones.

Hydrological gradient variations in wetlands have a vital impact on wetland carbon storage. However, the mechanisms by which hydrological gradient variations affect biomass and carbon storage by regulating the soil nutrient contents and plant diversity remain unclear. This study attempted to explore these influencing mechanisms by studying the relationships between hydrological gradient variations and carbon storage in wetlands. The results showed that the average nutrient content, plant biomass and soil carbon content values in the high-frequency wet-dry alternating zones (HFWA, zones where the frequency of water level occurs between -25 cm and 25 cm greater than 0.5) were 1.4 times, 2.3 times and 0.43 higher, respectively, than those in the low-frequency wet-dry alternating zones (LFWA, zones where the frequency of water level occurs between -25 cm and 25 cm less than 0.3). These results indicated that the HFWA zones had higher soil nutrients, higher plant dominance, higher biomass and higher soil carbon contents than the LFWA zones. The structural equation model revealed a significant positive correlation between wet-dry alternations and the soil nutrient-plant biomass-soil carbon relation in wetlands. Moreover, there was also a significant positive correlation between wet-dry alternations and the plant dominance-plant biomass-soil carbon relation in wetlands. This implied that the concentrated effect of HFWA on soil nutrients promotes plant growth, enhances plant dominance, promotes plant productivity, and enhances the capacities of plants to input carbon to the soil, thereby increasing the soil carbon content. This study closely linked wetland hydrological gradients, plant biodiversity and wetland carbon sequestration and profoundly revealed the mechanisms by which hydrological gradients in wetlands regulate the concentrations of nutrient elements, thereby affecting vegetation growth and carbon sequestration; these results could provide a new cognitive basis for understanding the coupling of carbon and water.

Inflammatory microenvironment-targeted nanotherapies.

Inflammatory microenvironments (IMEs) are common pathological characteristics and drive the development of multiple chronic diseases. Thus, IME-targeted therapies exhibit potential for the treatment of inflammatory diseases. Nanoplatforms have significant advantages in improving the efficiency of anti-inflammatory treatments. Owing to their improved therapeutic effects and reduced side effects, IME-targeted nanotherapies have recently drawn interest from the research community. This review introduces IMEs and discusses the application of IME-targeted nanotherapies for inflammatory diseases. The development of rational targeting strategies tailored to IMEs in damaged tissues can help promote therapies for chronic diseases.

FRET imaging revealed that nanocrystals enhanced drug oral absorption by dissolution rather than endocytosis: A case study of coumarin 6.

Nanocrystals (NCs) exhibit potential in improving oral bioavailability for poorly water-soluble drugs. However, whether NCs improve oral absorption by quick dissolution or by endocytosis remains inconclusive because tracking of dissolved drugs and NCs particles cannot occur simultaneously. In this study, we aim to elucidate how NCs improve oral absorption by using coumarin 6 (C6), an aggregation-caused quenching fluorophore, and 2-((5-(4-(dip-tolylamino)phenyl)thiophen-2-yl)methylene)malononitrile (MeTTMN), an aggregation-induced emission fluorophore. C6 was used as a model drug to prepare NCs and MeTTMN was incorporated to construct fluorescence resonance energy transfer (FRET) pairs. Thus, the molecular absorption can be detected using the fluorescence signal of dissolved C6 and the NCs particles can be tracked simultaneously by monitoring FRET signals. The reliability of this tracking method was validated. Accordingly, in vitro dissolution, gastrointestinal traffic, and biodistribution studies were conducted. The results showed that dissolved C6 molecules were the main absorption mode of C6 NCs. Identification of such pathways bears considerable significance for the broad application of drug NCs in improving the druggability of insoluble drugs.

Naringenin nanocrystals for improving anti-rheumatoid arthritis activity.

Naringenin (NAR) is recognized for its anti-inflammatory activity. However, the clinical application of NAR is limited by low bioavailability, which is attributed to its poor aqueous solubility. In this study, we aimed to improve the therapeutic efficacy of NAR by formulating it into nanocrystals (NCs) via wet milling. The obtained NARNCs exhibited superior dissolution behaviors, increased cellular uptake, and enhanced transcellular diffusion relative to those of bulk NAR. Oral administration of NARNCs also significantly improved bioavailability in rats. In addition, the NARNCs effectively improved rheumatoid arthritis treatment in collagen-induced arthritic rats by reducing inflammatory cell infiltration and synovial damage. These results indicate that NARNCs provides a promising strategy for rheumatoid arthritis treatment.

A carbohydrate polymer is a critical variable in the formulation of drug nanocrystals: a case study of idebenone.

Objective: Stabilizers, especially carbohydrate polymers, have been shown to be necessary for the stabilization of drug nanocrystals. However, the impacts of select stabilizers on the in vitro and in vivo efficacy of therapeutics have rarely been reported. The aim of this study was to evaluate the importance of stabilizers in the formulation of drug nanocrystals.Research design and methods: Idebenone nanocrystals (IDBNC) stabilized by various stabilizers were formulated using a milling method. The in vitro dissolution profiles in water and in situ absoprtion were compared. Finally, an in vivo pharmacokinetic study was performed.Results: The IDBNC profiles were found to have acceptable sizes and similar morphology and crystallinity. The dissolution profiles of IDBNC stabilized by different stabilizers were notably different, indicating the critical influence of stabilizers on the release rate of IDB. The Soluplus-stabilized IDBNC (IDBNC400 nm/Soluplus) achieved better absorption than HPMC stabilized IDBNC (IDBNC400 nm/HPMC). The pharmacokinetic study demonstrated that Soluplus-stabilized IDBNC had preferable kinetics, with an AUC0-24h of IDBNC400 nm/Soluplus (3.08-fold relative to IDB suspension), compared to IDBNC400 nm/HPMC (1.88-fold).Conclusions: Choice of stabilizer plays an important role in the formulation of IDBNC. We anticipate that the role of stabilizers in the pharmacokinetic disposition of IDBNC has significant implications for a wide range of other drug crystal formulations.

Effects of environmental variation on stable isotope abundances during typical seasonal floodplain dry season litter decomposition.

Unique hydrological characteristics and complex topography can create wide-ranging dry season environmental heterogeneity in response to groundwater level across China's Jiangxi Province Poyang Lake wetland. Soil traits are one of several fluctuating environmental variables. To determine the effects of soil variables on stable isotope (δ13C and δ15N) abundances during decomposition, we performed a field experiment using Carex cinerascens along a groundwater level gradient (GT-L: -25 to -50cm, GT-LM: -15 to -25cm, GT-MH: -5 to -15cm, GT-H: 5 to -5cm) in a shallow lake. Twelve soil properties-including total organic carbon (TOC), nitrogen (N), pH, moisture, bulk density, clay, silt, sand, peroxidase, cellulase, microbial biomass carbon (MBC), and microbial biomass nitrogen-were measured in surface soil samples to assess soil environmental conditions. Analyses were performed to determine the effects of soil traits and lignin degradation on changes in stable isotope abundances. This study revealed that stable isotope abundances were significantly lower at high groundwater levels than at low groundwater levels. Lignin degradation was associated with a decrease in both δ13C and δ15N abundances. These two stable isotopes were positively related with soil N and bulk density, but negatively with pH and microbial quotient (MBC/TOC). Variation partitioning analysis (VPA) showed that soil variables and lignin decay rates explained 80.1% of the δ13C variation and 42.8% of the δ15N variation. Soil chemical and biological variables exhibited significant interactions with lignin decay rates, indicating they may affect stable isotope abundances via complex mechanisms. Our results indicate that the change in stable isotope abundances during decomposition may be affected directly by soil variables or indirectly through lignin degradation. Our results provide useful insight for understanding the roles of litter decomposition and soil traits in changing environmental conditions of seasonal floodplain wetlands.

Combined effects of climate, restoration measures and slope position in change in soil chemical properties and nutrient loss across lands affected by the Wenchuan Earthquake in China.

The MS 8.0Wenchuan Earthquake in 2008 caused huge damage to land cover in the northwest of China's Sichuan province. In order to determine the nutrient loss and short term characteristics of change in soil chemical properties, we established an experiment with three treatments ('undestroyed', 'destroyed and treated', and 'destroyed and untreated'), two climate types (semi-arid hot climate and subtropical monsoon climate), and three slope positions (upslope, mid-slope, and bottom-slope) in 2011. Ten soil properties-including pH, organic carbon, total nitrogen, total phosphorus, total potassium, Ca2+, Mg2+, alkaline hydrolysable nitrogen, available phosphorus, and available potassium-were measured in surface soil samples in December 2014. Analyses were performed to compare the characteristics of 3-year change in soil chemical properties in two climate zones. This study revealed that soil organic carbon, total nitrogen, Ca2+ content, alkaline hydrolysable nitrogen, available phosphorus, and available potassium were significantly higher in subtropical monsoon climate zones than in semi-arid hot climate zones. However, subtropical monsoon climate zones had a higher decrease in soil organic carbon, total nitrogen, total phosphorus, total potassium, and alkaline hydrolysable nitrogen in 'destroyed and untreated' sites than in semi-arid hot climate zones. Most soil chemical properties exhibited significant interactions, indicating that they may degrade or develop concomitantly. 'Destroyed and treated' sites in both climate types had lower C:P and N:P ratios than 'destroyed and untreated' sites. Principal component analysis (PCA) showed that the first, second, and third principal components explained 76.53% of the variation and might be interpreted as structural integrity, nutrient supply availability, and efficiency of soil; the difference of soil parent material; as well as weathering and leaching effects. Our study indicated that the characteristics of short term change in soil properties were affected by climate types and treatments, but not slope positions. Our results provide useful information for the selection of restoration countermeasures in different climate types to facilitate ecological restoration and reconstruction strategies in earthquake-affected areas.

[Carbon source metabolic diversity of soil microbial community under different climate types in the area affected by Wenchuan earthquake].

The MS8.0 Wenchuan earthquake in 2008 led to huge damage to land covers in northwest Sichuan, one of the critical fragile eco-regions in China which can be divided into Semi-arid dry hot climate zone (SDHC) and Subtropical humid monsoon climate zone (SHMC). Using the method of Bilog-ECO-microplate technique, this paper aimed to determine the functional diversity of soil microbial community in the earthquake-affected areas which can be divided into undamaged area (U), recover area (R) and damaged area without recovery (D) under different climate types, in order to provide scientific basis for ecological recovery. The results indicated that the average-well-color-development (AWCD) in undamaged area and recovery area showed SDHC > SHMC, which was contrary to the AWCD in the damaged area without recovery. The AWCD of damaged area without recovery was the lowest in both climate zones. The number of carbon source utilization types of soil microbial in SHMC zone was significantly higher than that in SDHC zone. The carbon source utilization types in both climate zones presented a trend of recover area > undamaged area > damaged area without recovery. The carbon source metabolic diversity characteristic of soil microbial community was significantly different in different climate zones. The diversity index and evenness index both showed a ranking of undamaged area > recover area > damaged area without recovery. In addition, the recovery area had the highest richness index. The soil microbial carbon sources metabolism characteristic was affected by soil nutrient, aboveground vegetation biomass and vegetation coverage to some extent. In conclusion, earthquake and its secondary disasters influenced the carbon source metabolic diversity characteristic of soil microbial community mainly through the change of aboveground vegetation and soil environmental factors.