What, Where, When and How of COVID-19 Patents Landscape: A Bibliometrics Review.

Two years after COVID-19 came into being, many technologies have been developed to bring highly promising bedside methods to help fight this epidemic disease. However, owing to viral mutation, how far the promise can be realized remains unclear. Patents might act as an additional source of information for informing research and policy and anticipating important future technology developments. A comprehensive study of 3741 COVID-19-related patents (3,543 patent families) worldwide was conducted using the Derwent Innovation database. Descriptive statistics and social network analysis were used in the patent landscape. The number of COVID-19 applications, especially those related to treatment and prevention, continued to rise, accompanied by increases in governmental and academic patent assignees. Although China dominated COVID-19 technologies, this position is worth discussing, especially in terms of the outstanding role of India and the US in the assignee collaboration network as well as the outstanding invention portfolio in Italy. Intellectual property barriers and racist treatment were reduced, as reflected by individual partnerships, transparent commercial licensing and diversified portfolios. Critical technological issues are personalized immunity, traditional Chinese medicine, epidemic prediction, artificial intelligence tools, and nucleic acid detection. Notable challenges include balancing commercial competition and humanitarian interests. The results provide a significant reference for decision-making by researchers, clinicians, policymakers, and investors with an interest in COVID-19 control.

Quality Status Analysis and Intrinsic Connection Research of Growing place, Morphological Characteristics, and Quality of Chinese Medicine: Cyperi Rhizoma (Xiangfu) as a Case Study.

Materials and Methods: The macroscopic characteristics of CR as well as its moisture, ethanol extract, essential oil, total ash, and acid-insoluble ash contents were examined and calculated. In addition, qualitative identification and quantitative determination of α-cyperone, cyperotundone, and nootkatone were simultaneously performed, and a high-performance liquid chromatography (HPLC) fingerprint chromatogram was established. Inductively coupled plasma mass spectrometry and gas chromatography methods recorded in ChP were used to measure the contents of residues of heavy metal and deleterious elements as well as residues of organochlorine pesticide, respectively. Hierarchical cluster analysis and typical canonical correlation analysis were performed using Origin 9.1 and SPSS 23.0 to explore the correlation between CR's growth area, morphological characteristics, and quality. Results: Of the 47 batches of CR analyzed, only 4 collected from the province of Shandong had a flat appearance, which did not accord with the macroscopic characteristics of CR. Overall, only 4 batches met ChP standards for CR. In addition, 30 and 38 batches did not meet the requirements for moisture content and essential oil content, respectively. The similarity values of HPLC fingerprints ranged from 0.568 to 0.986. Results of hierarchical cluster analysis for ethanol extracts, essential oil, α-cyperone, cyperotundone, and nootkatone and the HPLC fingerprints (total peak time and peak area) suggested that the samples could be classified into four clusters, with no significant difference in growth geographic areas among them. Results of canonical correlation analysis indicated that the first canonical pair could represent the correlation between macroscopic characteristics (vector 1) and chemical quality (vector 2), with shorter diameter and length denoting lower ethanol extract content and higher nootkatone content in a single grain of CR. Conclusions: Crude medicinal materials were collected and examined in this study to reflect the overall quality status of CR in China. The methods chosen to detect, calculate, and analyze the quality of CR were suitable to the investigation, and the results are crucial not only for estimating the current quality status of CR, but also for conducting further research into its cultivation, quality assurance, and commodity specification. Besides, this mode of investigation could be used to evaluate other medicines.

Key quality factors for Chinese herbal medicines entering the EU market.

Chinese herbal medicines (CHMs) have unique advantages in the prevention and treatment of diseases, which are widely recognized in the world. More and more CHMs are becoming increasingly popular in the international markets. However, the quality control of CHMs is a significant issue for their acceptance and recognition in the international market. This review mainly focuses on the quality requirements for CHMs to enter the European Union (EU) market. Both Chinese and European regulations and quality controls are compared. Firstly, the EU medicinal regulatory system and relevant regulations were reviewed. Secondly, the key factors of the quality control of CHMs, including Chinese herbal drugs, extracts and products were compared with those of European herbal medicines in the EU market. Subsequently, three main registration routes for herbal medicinal products including Chinese herbal medicinal products entering the EU were introduced. Furthermore, the legal status of traditional Chinese medicine granules in the EU was also discussed. Through the comparison of the key quality factors for CHMs in China and the EU, the similarities and differences in terms of quality requirements and regulations are addressed, which provides a reference for the development of CHMs into the EU market.

A comprehensive quality analysis of randomized controlled clinical trials of Asian ginseng and American ginseng based on the CONSORT guideline.

Ginseng is an international herb that has been used for thousands of years. Two species most commonly applied and investigated in the ginseng family are Asian ginseng and American ginseng. The number of randomized controlled clinical trials (RCTs) has conspicuously increased, driven by the rapid development of ginseng. However, the reporting of RCT items of ginseng is deficient because of different trial designs and reporting formats, which is a challenge for researchers who are looking for the data with high quality and reliability. Thus, this study focused on providing an extensive analysis of these two species and examined the quality of the RCTs, based on the Consolidated Standards of Reporting Trials (CONSORT) guideline. Ninety-one RCTs conducted from 1980 to 2019 that were related to Asian ginseng and American ginseng used singly met our inclusion criteria. We found that the reporting quality of the two species has improved during the past 40 years. Publication date and sample size were significantly associated with the reporting quality. Rigorous RCTs designed for the species of ginseng are warranted, which can shed light on product research and development of ginseng in the future.

Litchi (Litchi chinensis Sonn.): a comprehensive review of phytochemistry, medicinal properties, and product development.

Since ancient times, litchi has been well recognized as a functional food for the management of various ailments. Many bioactives, including flavanoids, anthocyanins, phenolics, sesquiterpenes, triterpenes, and lignans, have been identified from litchi with a myriad of biological properties both in vitro and in vivo. In spite of the extensive research progress, systemic reviews regarding the bioactives of litchi are rather scarce. Therefore, it is crucial to comprehensively analyze the pharmacological activities and the structure-activity relationships of the abundant bioactives of litchi. Besides, more and more studies have focused on litchi preservation and development of its by-products, which is significant for enhancing the economic value of litchi. Based on the analysis of published articles and patents, this review aims to reveal the development trends of litchi in the healthcare field by providing a systematic summary of the pharmacological activities of its extracts, its phytochemical composition, and the nutritional and potential health benefits of litchi seed, pulp and pericarp with structure-activity relationship analysis. In addition, its by-products also exhibited promising development potential in the field of material science and environmental protection. Furthermore, this study also provides an overview of the strategies of the postharvest storage and processing of litchi.

9-Bromo-2,3-diethylbenzo[de]chromene-7,8-dione (MSN54): A novel non-intercalative topoisomerase II catalytic inhibitor.

Novel mansonone F derivative MSN54 (9-bromo-2,3-diethylbenzo[de]chromene-7,8-dione) exhibited significant cytotoxicity against twelve human tumor cell lines in vitro, with particularly strong potency against HL-60/MX2 cell line resistant to Topo II poisons. MSN54 was found to have IC50 of 0.69 and 1.43 µM against HL-60 and HL-60/MX2 cells, respectively. The resistance index is 10 times lower than that of the positive control VP-16 (etoposide). Various biological assays confirmed that MSN54 acted as a Topo IIα specific non-intercalative catalytic inhibitor. Furthermore, MSN54 exhibited good antitumor efficacy and low toxicity at a dose of 5 mg/kg in A549 tumor xenograft models. Thus, compound MSN54 is a promising candidate for the development of novel antitumor agents.

Specific NLRP3 inflammasome inhibitors: promising therapeutic agents for inflammatory diseases.

Innate immunity serves as a first line of defence against danger signals, invading pathogens and microbes. The inflammasomes, as pattern recognition receptors, sense these danger signals to initiate pro-inflammatory cascades. The nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome is the most well characterised inflammasome, and its aberrant activation is implicated in many inflammatory diseases. In the past decade, targeting the NLRP3 inflammasome has become an emerging strategy for inflammatory diseases. To avoid off-target immunosuppressive effects, specific NLRP3 inhibitors have been developed and show promising therapeutic effects. This review discusses the therapeutic effects and clinical perspectives of specific NLRP3 inhibitors, as well as recent progress in the development of these inhibitors for the treatment of inflammatory diseases.

Ginseng: A bibliometric analysis of 40-year journey of global clinical trials.

BACKGROUND: Ginseng has a long history of widespread use and remarkable effects as traditional medicine, adjuvant and dietary supplement. The therapeutic value, diverse functionalities and rapid development of ginseng have driven a significant increase in the number of ginseng clinical trials, ranging from its use in various ailments, formulation to safety concerns. Despite the persistent interest in ginseng clinical research, the medical effectiveness of ginseng is inconclusive and there is a lack of bibliometric analysis of the hundreds of ginseng clinical trials. AIM OF REVIEW: This review aims to provide an extensive overview of ginseng clinical trials over the past 40 years (1979-2018) in combination with a qualitative and quantitative analysis. The annual clinical trial analysis of time distribution, country and institution network analysis for space cooperation, statistical analysis for various functions, as well as efficiency and effect size were performed for global ginseng clinical trials. Besides, preparation categories, administration routes, and the safety of ginseng clinical trials were also investigated. KEY SCIENTIFIC CONCEPTS OF REVIEW: The 40-year journey of ginseng clinical trials has experienced emerging, boom, and stable or transitional stages. The global network of ginseng clinical trials has relevant regional distribution in Asia, North America and Europe. South Korea makes a great contribution to building up large research clusters and strong cooperation links. Universities are the key contributors to ginseng clinical trials. The development of ginseng products could be focused on the clinical trial in diseases with higher effectiveness or effect size, such as sexual function and cognitive & behavior and require rigorous investigations and evidence to evaluate safety. More attention should be paid to different effects from different preparations. We believe this review will provide new insights into the understanding of global ginseng clinical trials and identifies potential future perspectives for research and development of ginseng.

An integrated microbiome and metabolomic analysis identifies immunoenhancing features of Ganoderma lucidum spores oil in mice.

Ganoderma lucidum (Leyss. ex Fr.) Karst. is a valuable dietary supplement used worldwide for promoting health as well as a medicinal fungus for handling fatigue, immunological disorders, and cancer. Previous studies have revealed the immunoenhancing effect of G. lucidum and the polysaccharide extract, with potential involvement of gut microbiome. The oil of G. lucidum spores (GLSO)is one of the well-known G. lucidum-related products. However, there is little evidence supporting the immune promotion activity and the underlying mechanisms. The present study aims to investigate the immunoenhancing effect of GLSO in mice. GLSO enhanced macrophage phagocytosis and NK cell cytotoxicity of mice. Further microbiome and metabolomics studies showed that GLSO induced structural rearrangement of gut microbiota, mediating alterations in a wide range of metabolites. By clustering, multivariate and correlation analysis, the immunoenhancing effect of GLSO was found to be highly correlated with elevated abundance of several bacterial genera (Lactobacillus, Turicibacter and Romboutsia) and species (Lactobacillus_intestinalis and Lactobacillus_reuteri), and decreased level of Staphylococcus and Helicobacter, which resulted in the regulation of a range of key metabolites such as dopamine, prolyl-glutamine, pentahomomethionine, leucyl-glutamine, l-threonine, stearoylcarnitine, dolichyl ß-d-glucosyl phosphate, etc. These results provide new insights into the understanding of the modulatory effect of GLSO on immune system.

Astragali Radix (Huangqi): A promising edible immunomodulatory herbal medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix (AR, Huangqi in Chinese), the dried root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or A. membranaceus (Fisch.) Bge., possesses diverse therapeutic effects against fatigue, dyspepsia, diarrhea, heart diseases, hepatitis, and anemia. In recent years, increasing evidence has indicated the multiple immunomodulatory activities of AR in preclinical and clinical studies. AIM OF THE REVIEW: This review attempts to elaborate the immunomodulatory effects of AR and its potential application in the treatment of immune related diseases. MATERIALS AND METHODS: A comprehensive literature search AR was carried out using multiple internationally recognized databases (including Web of Science, Google Scholar, PubMed, ScienceDirect, Wiley, ACS, Springer, Taylor & Francis, and CNKI). RESULTS: The immunomodulatory effects of AR are closely attributed to its active constituents such as polysaccharides, saponins, and flavonoids. We also demonstrate that AR can be used as a potential therapeutic intervention for immune related diseases through regulating immune organs, mucosal immune, and immune system (innate immunity and acquired immunity). CONCLUSION: AR promotes the development of immune organs, enhances mucosal immune function, increases the quantity and phagocytic capacity of innate immunity, promotes the maturation and differentiation of acquired immunity cells, and improves the expression of antibodies in acquired immunity. We believe that AR has a broad research space in the adjuvant treatment of immune related diseases, which could be a breakthrough point to improve the application value of AR.

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine.

Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including anti-proliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, ß-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints.

Design, synthesis and biological evaluation of novel perimidine o-quinone derivatives as non-intercalative topoisomerase II catalytic inhibitors.

For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o-quinone derivatives containing the o-quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC50 ≤ 1 µM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 µM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC50 = 7.54 µM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner.

Network pharmacology-based identification for therapeutic mechanism of Ling-Gui-Zhu-Gan decoction in the metabolic syndrome induced by antipsychotic drugs.

BACKGROUND: The metabolic syndrome (MetS) is a common side effect of second-generation antipsychotic drugs (SGAs), leading to poor prognosis in patients with mental illness. The traditional Chinese herbal formula Ling-Gui-Zhu-Gan decoction (LGZGD) is a clinically validated remedy for SGAs-induced MetS, but its underlying mechanism remains unclear. METHODS: A network pharmacology-based analysis was performed to explore predicted plasma-absorbed components, putative therapeutic targets, and main pathways involved in LGZGD bioactivity. We constructed a target interaction network between the predicted targets of LGZGD and the known targets of MetS, after which we extracted major hubs using topological analysis. Thereafter, the maximum value of "edge betweenness" of all interactions was defined as a bottleneck, which suggested its importance in connecting all targets in the network. Finally, a pathway enrichment analysis of major hubs was used to reveal the biological functions of LGZGD. RESULTS: This approach identified 120 compounds and 361 candidate targets of LGZGD. According to the data generated in this study, the interaction between JUN and APOA1 plays a vital role in the treatment of SGAs-induced MetS using LGZGD. Interestingly, JUN was a putative target of LGZGD and APOA1 is one of the known targets of both MetS and SGAs (olanzapine and clozapine). LGZGD was significantly associated with several pathways including PI3K-Akt signaling, insulin resistance, and MAPK signaling pathway. CONCLUSIONS: LGZGD might inhibit JUN and thereby increases the expression of APOA1 to maintain metabolic homeostasis via some vital pathways.

Metabolic adverse effects of olanzapine on cognitive dysfunction: A possible relationship between BDNF and TNF-alpha.

OBJECTIVE: There is accumulating evidence indicating that long-term treatment with second-generation antipsychotics (SGAs) results in metabolic syndrome (MetS) and cognitive impairment. This evidence suggests an intrinsic link between antipsychotic-induced MetS and cognitive dysfunction in schizophrenia patients. Olanzapine is a commonly prescribed SGA with a significantly higher MetS risk than that of most antipsychotics. In this study, we hypothesized that olanzapine-induced MetS may exacerbate cognitive dysfunction in patients with schizophrenia. METHODS: A sample of 216 schizophrenia patients receiving long-term olanzapine monotherapy were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program's Adult Treatment Panel III. We also recruited 72 healthy individuals for a control group. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Plasma brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-alpha) were measured by an enzyme-linked immunosorbent assay for 108 patients and 47 controls. RESULTS: Among the 216 schizophrenia patients receiving olanzapine monotherapy, MetS was found in 95/216 (44%). Patients with MetS had more negative symptoms, higher total scores in PANSS (Ps<0.05) and lower immediate memory, attention, delayed memory and total scores in RBANS (Ps<0.01). Stepwise multivariate linear regression analysis revealed that increased glucose was the independent risk factor for cognitive dysfunction (t=-2.57, P=0.01). Patients with MetS had significantly lower BDNF (F=6.49, P=0.012) and higher TNF-alpha (F=5.08, P=0.026) levels than those without MetS. There was a negative correlation between the BDNF and TNF-alpha levels in the patients (r=-0.196, P=0.042). CONCLUSION: Our findings provide evidence suggesting that the metabolic adverse effects of olanzapine may aggravate cognitive dysfunction in patients with schizophrenia through an interaction between BDNF and TNF-alpha.

Design, Synthesis, and Evaluation of Isaindigotone Derivatives To Downregulate c-myc Transcription via Disrupting the Interaction of NM23-H2 with G-Quadruplex.

Transcriptional control of c-myc oncogene is an important strategy for antitumor drug design. G-quadruplexes in the promoter region have been proven to be the transcriptional down-regulator of this gene. The transcriptional factor NM23-H2 can reactivate c-myc transcription by unwinding the G-quadruplex structure. Thus, down-regulation of c-myc transcription via disrupting G-quadruplex-NM23-H2 interaction might be a potential approach for cancer therapy. Here, a series of new isaindigotone derivatives were designed and synthesized based on our previous study. The abilities of these derivatives on interacting with G-quadruplexes or NM23-H2, and disrupting G-quadruplex-NM23-H2 interaction were evaluated. Among these derivatives, 19d and 22d showed remarkable abilities on disrupting G-quadruplex-NM23-H2 interaction. They exhibited significant effects on c-myc-relating processes in SiHa cells, including inhibiting the transcription and translation, inhibiting cellular proliferation, inducing apoptosis, and regulating cell cycle. Our findings provided the basis for the anticancer strategy based on c-myc transcriptional regulation via small molecules disrupting G-quadruplex-protein interaction.

A colorimetric and fluorescent dual probe for palladium in aqueous medium and live cell imaging.

A colorimetric and fluorescent dual probe for palladium species was rationally developed by combining the resorufin fluorophore with allyl chloroformate. The probe enables the visual detection of palladium based on its vivid color change from pale yellow to pink and its fluorescence off-on response to palladium in PBS solution. The detection limit was calculated to be as low as 2.1 nM. The live cell imaging results showed that this probe could be used as an effective fluorescent probe for detecting intracellular palladium species. All these results featured its promising application prospects in the palladium analytical field.

Synthesis and Mechanism Studies of 1,3-Benzoazolyl Substituted Pyrrolo[2,3-b]pyrazine Derivatives as Nonintercalative Topoisomerase II Catalytic Inhibitors.

Novel topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of anticancer agents. In this study, a series of 1,3-benzoazolyl-substituted pyrrolo[2,3-b]pyrazine derivatives were designed, synthesized, and evaluated as potential Topo II catalytic inhibitors. It was found that some of derivatives had good antiproliferative activity on seven cancer cell lines, especially on HL-60/MX2, a cancer cell line derivative from HL-60 that is resistant to Topo II poison. Topo II mediated DNA relaxation assay results showed that derivatives could significantly inhibit the activity of Topo II, and the structure-activity relationship studies indicated the importance of the alkylamino side chain and the benzoazolyl group. Further mechanism studies revealed that derivatives function as Topo II nonintercalative catalytic inhibitors and may block the ATP binding site of Topo II. Moreover, flow cytometric analysis showed that this class of compounds could induce apoptosis of HL-60 cells.

Blocking the binding of WT1 to bcl-2 promoter by G-quadruplex ligand SYUIQ-FM05.

At present, wt1, a Wilms' tumor suppressor gene, is recognized as a critical regulator of tumorigenesis and a potential therapeutic target. WT1 shows the ability to regulate the transcription of bcl-2 by binding to a GC-rich region in the promoter, which can then fold into a special DNA secondary structure called the G-quadruplex. This function merits the exploration of the effect of a G-quadruplex ligand on the binding and subsequent regulation of WT1 on the bcl-2 promoter. In the present study, WT1 was found to bind to the double strand containing the G-quadruplex-forming sequence of the bcl-2 promoter. However, the G-quadruplex ligand SYUIQ-FM05 effectively blocked this binding by interacting with the GC-rich sequence. Our new findings are significant in the exploration of new strategies to block WT1's transcriptional regulation for cancer-cell treatment.

Discovery of Small Molecules for Up-Regulating the Translation of Antiamyloidogenic Secretase, a Disintegrin and Metalloproteinase 10 (ADAM10), by Binding to the G-Quadruplex-Forming Sequence in the 5' Untranslated Region (UTR) of Its mRNA.

Up-regulation of a disintegrin and metalloproteinase 10 (ADAM10) to prevent the formation of ß-amyloid (Aß) peptides might be a promising strategy to treat Alzheimer's disease (AD). RNA G-quadruplex motif within the 5'-UTR of the ADAM10 mRNA is an inhibitory element for ADAM10 translation. Thus, mitigation of the suppressive effect of this motif using an RNA G-quadruplex-forming G-rich sequence (QGRS) binder might be a new approach for AD therapy. Herein, a series of new methylquinolinium derivatives were synthesized and screened by surface plasmon resonance (SPR) and the dual-luciferase reporter assay. Among them, compound 24 showed selective affinity for the QGRS of ADAM10 and could strongly up-regulate the translation of it. Moreover, treatment with 24 led to a significant increase of the secretion of sAPPα, consequently decreasing the Aß40 in cellular. These results illustrate that the interaction between the RNA QGRS and a small molecule may be a new molecular strategy to modulate the translation of ADAM10.