Molecular recognition and interaction between human plasminogen Kringle 5 and A2M domain in human complement C5 by biospecific methods coupled with molecular dynamics simulation.

The potent angiogenesis inhibitor known as human plasminogen Kringle 5 has shown promise in the treatment of vascular disorders and malignancies. The study aimed to investigate the recognition and interaction between Kringle 5 and the A2M domain of human complement component C5 using bio-specific methodologies and molecular dynamics (MD) simulation. Initially, the specific interaction between Kringle 5 and A2M was confirmed and characterized through Ligand Blot and ELISA, yielding the dissociation constant (Kd) of 1.70 × 10-7 mol/L. Then, Kringle 5 showcased a dose-dependent inhibition of the production of C5a in lung cancer A549 cells, consequently impeding their proliferation and migration. Following the utilization of frontal affinity chromatography (FAC), it was revealed that there exists a singular binding site with the binding constant (Ka) of 3.79 × 105 L/mol. Following the implementation of homology modeling and MD optimization, the detailed results indicate that only a specific segment of the N-terminal structure of the A2M molecule engages in interaction with Kringle 5 throughout the binding process and the principal driving forces encompass electrostatic force, hydrogen bonding, and van der Waals force. In conclusion, the A2M domain of human complement C5 emerges as a plausible binding target for Kringle 5 in vivo.

Molecular recognition and binding between human plasminogen Kringle 5 and α-chain of human complement component C3b by frontal chromatography and dynamics simulation.

The binding and molecular recognition between α-chain of human complement C3b (α-chain of C3b) and human plasminogen Kringle 5 (Kringle 5) were studied and explored by frontal chromatography and dynamics simulation in the combination of bio-specific technologies. The specific interaction between the α-chain of C3b and Kringle 5 was initially confirmed by ligand blot and ELISA (Kd = 4.243×10-6 L/mol). Furthermore, the binding determination conducted via frontal chromatography showed that the presence of a single binding site between them, with the binding constant of 2.98 × 105 L/mol. Then the molecular recognition by dynamics simulation and molecular docking showed that there were 9 and 13 amino acid residues respective in the Kringle 5 and α-chain of C3b directly implicated in the binding and the main stabilizing forces were electrostatic force (-55.99 ± 11.82 kcal/mol) and Van der Waals forces (-42.70 ± 3.45 kcal/mol). Additionally, a loop structure (65-71) in Kringle 5 underwent a conformational change from a random structure to an α-helix and a loop structure (417-425) in α-chain of C3b was closer to the molecular center, both of them were more conducive to the binding between them. Meanwhile, the involvement of the lysine binding site of Kringle 5 played an important role in the binding process. In addition, the erythrocyte-antibody complement rosette assay substantiated that the presence of Kringle 5 hindered the transportation of α-chain of C3b to antigen-antibody complex in a dose-dependent manner. These findings collectively indicated that the α-chain of C3b is very likely a receptor protein for Kringle 5, which provides a methodology for other similar investigations and valuable insights into expansion of the pharmacological effects and potential application of Kringle 5 in immune-related diseases.

Extraction, purification, structural characteristics and biological properties of the polysaccharides from Armillaria mellea (Vahl) P. Kumm.: A review.

Armillaria mellea (Vahl) P. Kumm. is a well-known homoeopathic plant with medicinal and culinary uses. Modern phytochemical researchers have successfully extracted and purified over 40 types of A. mellea polysaccharides (AMPs) from the fruiting bodies, hyphae and fermentation broth of A. mellea, and some of them have been analyzed and identified by their chemical structures. The impressive biological activity of these polysaccharides has been recognized by scientists worldwide. Many studies show that AMPs have remarkable antioxidant, anti-diabetic, anti-tumor, anti-inflammatory, immunoregulatory, hypolipidemic, thrombectomy, anti-aging, pulmonary protective, hepatic protective, anti-Alzheimer's properties, etc. However, the current understanding of the relationships between their chemical structure and biological activity, toxicological effects and pharmacokinetics remains limited. This article provides a systematic review of the research conducted over the past decades on the extraction and purification methods, structural characteristics, biological activity and mechanism of action of AMPs. The aim is to provide a research base that will benefit the future application of AMPs as therapeutic drugs and functional foods, and also provide insights for the further development of AMPs.

The fluorescence regulation of a tri-functional oligonucleotide probe HEX-OND in detecting Pb(II), cysteine, and K(I) based on two G-quadruplex forms.

A novel tri-functional probe HEX-OND was developed for detecting Pb(II), cysteine (Cys), and K(I) by fluorescence quenching, recovery, and amplification strategies respectively, based on Pb(II)-induced chair-type G-quadruplex (CGQ) and K(I)-induced parallel G-quadruplex (PGQ). The thermodynamic mechanism was illustrated as that HEX-OND transformed into CGQ by associating equimolar Pb(II) (K1 = 1.10 ± 0.25 × 106 L/mol), forcing (G)2 spontaneously approaching and static-quenching HEX (5'-hexachlorofluorescein phosphoramidite) in the photo-induced electron transfer (PET) way by the van der Waals force and hydrogen bond (K2 = 5.14 ± 1.65 × 107 L/mol); the additional Cys recovered fluorescence in the molecular ratio of 2:1 via Pb(II)-precipitation induced CGQ destruction (K3 = 3.03 ± 0.77 × 109 L/mol); the equimolar K(I) induced HEX-OND transforming into PGQ (K4 = 3.53 ± 0.30 × 104 L/mol) and specifically associating with the equimolar N-methyl mesoporphyrin IX (NMM) by hydrophobic force (K5 = 3.48 ± 1.08 × 105 L/mol), leading to the fluorescence enhancement. Moreover, the practicability results showed that the detection limits reached a nanomolar level for Pb(II) and Cys and micromolar for K(I), with mere disturbances for 6, 10, and 5 kinds of other substances, respectively; no significant deviations of the real sample detection results were found between the well-understood methods with ours in detecting Pb(II) and Cys, and K(I) could be recognized and quantified even in the presence of Na(I) with 5000 and 600 fold respectively. The results demonstrated the triple-function, sensitivity, selectivity, and tremendous application feasibility of the current probe in sensing Pb(II), Cys, and K(I).

Solanum nigrum Linn.: An Insight into Current Research on Traditional Uses, Phytochemistry, and Pharmacology.

Solanum nigrum Linn., is a common edible medicinal herb of the Solanaceae family which is native to Southeast Asia and is now widely distributed in temperate to tropical regions of Europe, Asia, and America. Traditionally, it has been used to treat various cancers, acute nephritis, urethritis, leucorrhea, sore throat, toothache, dermatitis, eczema, carbuncles, and furuncles. Up to now, 188 chemical constituents have been identified from S. nigrum. Among them, steroidal saponins, alkaloids, phenols, and polysaccharides are the major bioactive constituents. Investigations of pharmacological activities of S. nigrum revealed that this edible medicinal herb exhibits a wide range of therapeutic potential, including antitumor, anti-inflammatory, antioxidant, antibacterial, and neuroprotective activities both in vivo and in vitro. This article presents a comprehensive and systematic overview of the botanical, traditional uses, phytochemical compositions, pharmacological properties, clinical trials, and toxicity of S. nigrum to provide the latest information for further exploitation and applications of S. nigrum in functional foods and medicines.

Isodon rubescens (Hemls.) Hara.: A Comprehensive Review on Traditional Uses, Phytochemistry, and Pharmacological Activities.

Isodon rubescens is a medicinal and food plant, often eaten as a wild vegetable in ancient China, and has been widely used for decades to treat sore throats, tonsillitis, colds and headaches, bronchitis, chronic hepatitis, joint rheumatism, snake and insect bites, and various cancers. This comprehensive and systematic review of the ethnomedicinal uses, phytochemical composition, pharmacological activity, quality control and toxicology of I. rubescens provides updated information for the further development and application in the fields of functional foods and new drugs research. To date, a total of 324 substances have been isolated and identified from the plant, including terpenoids, flavonoids, polyphenols, alkaloids, amino acids, and volatile oils. Among these substances, diterpenoids are the most important and abundant bioactive components. In the past decades pharmacological studies have shown that I. rubescens has significant biological activities, especially in the modulation of antitumor and multidrug resistance. However, most of these studies have been conducted in vitro. In-depth in vivo studies on the quality control of its crude extracts and active ingredients, as well as on metabolite identification are still very limited. Therefore, more well-designed preclinical and clinical studies are needed to confirm the reported therapeutic potential of I. rubescens.

Curcumin suppresses colorectal tumorigenesis via the Wnt/ß-catenin signaling pathway by downregulating Axin2.

Colorectal cancer (CRC) is the third most common cancer worldwide, with high incidence and mortality rates. Conventional therapies, including surgery, chemotherapy and radiation, are extensively used for the treatment of CRC. However, patients present with adverse effects, such as toxicity, hepatic injury and drug resistance. Thus, there is an urgent requirement to identify effective and safe therapy for CRC. Curcumin (CUR), a polyphenol substrate extracted from the rhizome of Curcuma longa, has been extensively studied for the treatment of CRC due to its high efficacy and fewer side effects. Previous studies have reported that several signaling pathways, such as NF-κB, Wnt/ß-catenin, are involved in the antitumor effects of CUR in vitro. However, the effect and mechanisms in vivo are not yet fully understood. The present study aimed to determine the molecular mechanism of colorectal cancer in vivo. Reverse transcription-quantitative PCR, western blot and immunohistochemistry analyses were performed to determine the underlying molecular mechanism of curcumin's anti-cancer effect in azoxymethane-dextran sodium sulfate induced colorectal cancer. The results of the present study demonstrated that CUR suppressed tumorigenesis in AOM-DSS induced CRC in mice, and anticancer effects were exerted by suppressing the expression of pro-inflammatory cytokines, and downregulating Axin2 in the Wnt/ß-catenin signaling pathway. Taken together, these results exhibit the potential in vivo mechanisms of the anticancer effects of CUR, and highlight Axin2 as a potential therapeutic target for CRC.

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect.

The pyrazolone structural motif is a critical element of drugs aimed at different biological end-points. Medicinal chemistry researches have synthesized drug-like pyrazolone candidates with several medicinal features including antimicrobial, antitumor, CNS (central nervous system) effect, anti-inflammatory activities and so on. Meanwhile, SAR (Structure-Activity Relationship) investigations have drawn attentions among medicinal chemists, along with a plenty of analogues have been derived for multiple targets. In this review, we comprehensively summarize the biological activity and SAR for pyrazolone analogues, wishing to give an overall retrospect and prospect on the pyrazolone derivatives.

Pharmacokinetics of 13 active components in a rat model of middle cerebral artery occlusion after intravenous injection of Radix Salviae miltiorrhizae-Lignum dalbergiae odoriferae prescription.

As a representative formulation of Radix Salviae miltiorrhizae (Danshen)-Lignum Dalbergiae odoriferae (Jiangxiang), Xiangdan injection is widely prescribed for cardio- and cerebrovascular diseases in practice. This necessitates a pharmacokinetic investigation of this formulation to make it safer and more broadly applicable. We developed and validated a sensitive, selective, and reliable high-performance liquid chromatography with tandem mass spectrometry method for the simultaneous determination of 11 phenolic compounds including danshensu plus two diterpenoid quinones like cryptotanshinone and tanshinone IIA in rat. We applied this method for the pharmacokinetic studies of the 13 compounds in a rat model of middle cerebral artery occlusion after intravenous injection of Xiangdan injection or Danshen injection. In sham-operated rats, the animals taking Xiangdan injection exhibited significant growth of the area under the curve for danshensu, protocatechuic aldehyde, and tanshinone IIA compared with the changes seen in the data of those administrated with Danshen injection. Such a pattern was also observed in middle cerebral artery occlusion rats, whereas increased the area under the curve values were observed for danshensu, protocatechuic aldehyde, caffeic acid, rosmarinic acid, and tanshinone IIA. These results demonstrated that synergistic interactions occurred between the components of Danshen and the active compounds of Jiangxiang both in sham-operated and middle cerebral artery occlusion rats, increasing the bioavailability of Danshen. The results presented herein can be used to determine a reference dose for the clinical application of Xiangdan injection, and to elucidate the synergistic mechanism of Danshen and Jiangxiang.