Recent Advances of Bioactive Marine Natural Products in Drug Discovery

Marine natural products(MNPs)are valuable resources for drug development.To date,17 drugs from marine sources are in clinical use,and 33 pharmaceutical compounds are in clinical trials.Presently the success of drug development from the marine resources is higher than the industry average.It is a feasible strategy to conduct the discovery of druglead compounds based on marine chemical ecology by fully exploiting the pharmacological potential of marine chemical defense matters.In the search for bioactive MNPs,our group has constructed a biological resources library including more than 1500 strains of fungi.Focusing on the strategy of Blue Drug Library,we have discovered a series of novel MNPs with abundant biological functions.Highly efficient and scalable total synthesis of(+)-aniduquinolone A(44)and pesimquinolone I(48)have been completed,which will facilitate access to sufficient quantities of candidates for in vivo pharmacological and toxicological studies.As a nucleoprotein(NP)inhibitor,QLA(75)possesses significant anti-influenza A virus(IAV)activities both in vitro and in vivo.CHNQD-00803(76)is a potent and selective AMP-activated kinase(AMPK)activator that can effectively inhibit metabolic disorders and metabolic dysfunction-associated steatohepatitis(MASH)progression.Moreover,we identified two new candidate molecules with potent anti-hepatocellular carcinoma effects.Particularly,as a natural guanine-nucleotide exchange factors for ADP-ribosylation factor GTPases(Arf-GEFs)inhibitor prodrug,CHNQD-01255(78)is qualified to be developed as a targeted candidate anticancer drug,which may be promising to apply for cancer immunotherapy.Hence,it is evident that MNPs play an important role in drug development.

Effects of Maillard reaction and its product AGEs on aging and age-related diseases

Maillard reaction(MR)is a non-enzymatic browning reaction commonly seen in food processing,which occurs between reducing sugars and compounds with amino groups.Despite certain advantages based on Maillard reaction products(MRPs)found in some food for health and storage application have appeared,however,the MR occurring in human physiological environment can produce advanced glycation end products(AGEs)by non-enzymatic modification of macromolecules such as proteins,lipids and nucleic acid,which could change the structure and functional activity of the molecules themselves.In this review,we take AGEs as our main object,on the one hand,discuss physiologic aging,that is,age-dependent covalent cross-linking and modification of proteins such as collagen that occur in eyes and skin containing connective tissue.On the other hand,pathological aging associated with autoimmune and inflammatory diseases,neurodegenerative diseases,diabetes and diabetic nephropathy,cardiovascular diseases and bone degenerative diseases have been mainly proposed.Based on the series of adverse effects of accelerated aging and disease pathologies caused by MRPs,the possible harm caused by some MR can be slowed down or inhibited by artificial drug intervention,dietary pattern and lifestyle control.It also stimulates people's curiosity to continue to explore the potential link between the MR and human aging and health,which should be paid more attention to for the development of life sciences.

Prioritised identification of structural classes of natural products from higher plants in the expedition of antimalarial drug discovery

The emergence and spread of drug-recalcitrant Plasmodium falciparum parasites threaten to reverse the gains made in the fight against malaria.Urgent measures need to be taken to curb this impending challenge.The higher plant-derived sesquiterpene,quinoline alkaloids,and naphthoquinone natural product classes of compounds have previously served as phenomenal chemical scaffolds from which integral antimalarial drugs were developed.Historical successes serve as an inspiration for the continued investigation of plant-derived natural products compounds in search of novel molecular templates from which new antimalarial drugs could be developed.The aim of this study was to identify potential chemical scaffolds for malaria drug discovery following analysis of historical data on phytochemicals screened in vitro against P.falciparum.To identify these novel scaffolds,we queried an in-house manually curated database of plant-derived natural product compounds and their in vitro biological data.Natural products were assigned to different structural classes using NPClassifier.To identify the most promising chemical scaffolds,we then correlated natural compound class with bioactivity and other data,namely(i)potency,(ii)resistance index,(iii)selectivity index and(iv)physicochemical properties.We used an unbiased scoring system to rank the different natural product classes based on the assessment of their bioactivity data.From this analysis we identified the top-ranked natural product pathway as the alkaloids.The top three ranked super classes identified were(i)pseudoalkaloids,(ii)naphthalenes and(iii)tyrosine alkaloids and the top five ranked classes(i)quassinoids(of super class triterpenoids),(ii)steroidal alkaloids(of super class pseudoalkaloids)(iii)cycloeudesmane sesquiterpenoids(of super class triterpenoids)(iv)isoquinoline alkaloids(of super class tyrosine alkaloids)and(v)naphthoquinones(of super class naphthalenes).Launched chemical space of these identified classes of compounds was,by and large,distinct from that of‘legacy’antimalarial drugs.Our study was able to identify chemical scaffolds with acceptable biological properties that are structurally different from current and previously used antimalarial drugs.These molecules have the potential to be developed into new antimalarial drugs.

Efficacy of Bee Products(Anzer Honey,Pollen and Propolis)in Detection and Healing of Damage Induced by Antidiabetic Drug Vildagliptin/Metformin Hydrochloride in Healthy Human Pancreatic Cells:Cytotoxic,Genotoxic and Biochemical Studies

Background and Objective Although drugs are powerful therapeutic agents,they have a range of side effects.These side effects are sometimes cellular and not clinically noticeable.Vildagliptin/metformin hydrochloride is one of the most widely used oral antidiabetic drugs with two active ingredients.In this study,we investigated its harmful effects on the metabolic activation system in healthy human pancreatic cells“hTERT-HPNE”,and we aimed to improve these harmful effects by natural products.To benefit from the healing effect,we used the unique natural products produced by the bees of the Anzer Plateau in the Eastern Black Sea Region of Turkey.Methods Cytotoxic and genotoxic effects of the drug were investigated by different tests,such as MTT,flow cytometry-apoptosis and comet assays.Anzer honey,pollen and propolis were analyzed by gas chromatography/mass spectrometry(G/C-MS).A total of 19 compounds were detected,constituting 99.9%of the samples.Results The decrease in cell viability at all drug concentrations was statistically significant compared to the negative control(P<0.05).A statistically significant decrease was detected in the apoptosis caused by vildagliptin/metformin hydrochloride with the supplementation of Anzer honey,pollen and propolis in hTERT-HPNE cells(P<0.05).Conclusion This study can contribute to other studies testing the healing properties of natural products against the side effects of oral antidiabetics in human cells.In particular,Anzer honey,pollen and propolis can be used as additional foods to maintain cell viability and improve heal damage and can be evaluated against side effects in other drug studies.

Research progress on natural products against hepatocellular carcinoma

Hepatocellular carcinoma(HCC)remains a prevalent and challenging malignancy globally,characterized by its numerous causal factors and generally unfavorable prognosis.In the relentless pursuit of effective treatment modalities,natural products have emerged as a promising and relatively non-toxic alternative,garnering significant interest.The integration of natural products with contemporary medical research has yielded encouraging therapeutic outcomes in the management of HCC.This review offers a comprehensive overview of the causal factors underlying HCC,and the diverse treatment options available,and highlights the advancements made by natural products in anti-HCC research.Particularly,we provide an outline of the various types of natural products,their corresponding nomenclature,target molecules,and mechanisms of action that exhibit anti-HCC activities.Natural products are anticipated to play a pivotal role in future comprehensive treatment plans for liver cancer,potentially offering patients improved survival rates and an enhanced quality of life.

Effect of Homoeopathic Drugs to Control Growth and Production of <i>A. flavus</i>

Five common homoeopathic drugs viz., Belladonna, Bryonia, Colchicum, Colocynth and Lathyrus sat were selected and tested against growth and aflatoxin production of Aspergillus flavus. The result indicates that all five drugs suppressed the growth of A. flavus. The lower concentration of all the tested drugs induced maximum growth of fungi and maximum production of aflatoxin. However, the growth as well as aflatoxin production potentiality was considerably decreased when the concentration of the drug was increased. Out of all the five drugs, Bryonia was comparatively less effective with respect to inhibition in aflatoxin production. But Belladonna was found to be most effective drug on growth and aflatoxin production.

Antimicrobial drug resistance of Staphylococcus aureus in dairy products

Objective:To evaluate the prevalence of multidrug resistant Staphylococcus aureus(S.aureus) in dairy products.Methods:Isolation and identification of S.aureus were performed in 3 dairybased food products.The isolates were tested for their susceptibility to 5 different common antimicrobial drugs.Results:Of 50 samples examined,5(10%) were contaminated with 5. aureus.Subsequently,the 5 isolates were subjected to antimicrobial resistance pattern using five antibiotic discs(methicillin,vancomycin,kanamycin,chloramphenicol and tetracycline).Sample 29 showed resistance to methicillin and vancomycin.Sample 18 showed intermediate response to tetracycline.The other samples were susceptible to all the antibiotics tested.Conclusions:The results provide preliminary data on sources of food contamination which may act as vehicles for the transmission of antimicrobial-resistant Staphylococcus.Therefore,it enables us to develop preventive strategies to avoid the emergence of new strains of resistant S.aureus.

The Success of Natural Products in Drug Discovery

Drug discovery leading to robust and viable lead candidates’ remains a challenging scientific task, which is the transition from a screening hit to a drug candidate, requires expertise and experience. Natural products and their derivatives have been recognized for many years as a source of therapeutic agents and of structural diversity. However, in addition to their chemical structure diversity and their biodiversity, the development of new technologies has revolutionized the screening of natural products in discovering new drugs. Applying these technologies compensates for the inherent limitations of natural products and offers a unique opportunity to re-establish natural products as a major source for drug discovery. The present article attempts to describe the utilization of compounds derived from natural resources as drug candidates, with a focus on the success of these resources in the process of finding and discovering new and effective drug compounds, an approach commonly referred to as “natural product drug discovery”.

Natural products as a crucial source of anti-inflammatory drugs: recent trends and advancements

Natural active molecules are key sources of modern innovative drugs. Particularly, a great amount of natural active molecules have been reported to possess promising therapeutic effects on inflammatory diseases, including asthma, rheumatoid arthritis, hepatitis, enteritis, metabolic disorders and neurodegenerative diseases. However, these natural active molecules with various molecular structures usually exert anti-inflammatory effects through diversiform pharmacological mechanisms, which is necessary to be summarized systematically. In this review, we introduced the current major anti-inflammatory natural active molecules based on their chemical structures, and discussed their pharmacological mechanisms including anti-inflammatory molecular signaling pathways and potential target proteins, which providing a referential significance on the development of novel anti-inflammatory drugs, and also revealing new therapeutic strategies for inflammatory diseases.

Anticancer drug screening of natural products:In vitro cytotoxicity assays,techniques,and challenges

Natural products include several diverse compounds that have been found to be effective against cancer.Discovering anticancer compounds in nature is a multistep and complex process that requires pre-clinical and clinical studies.Only a few of the available natural products are used to treat cancer since most of them have very high complexity and low bioavailability.Therefore,the process of anticancer drug discovery requires a straightforward and effective method to assess anticancer activity using in vitro assays.This review summarizes various cell-based assays and techniques used to measure cell viability,migration,and apoptosis,focusing in particular on the principles,mechanisms,advantages,and disadvantages of each assay to provide a preliminary platform for cancer drug discovery.

Exploring of drug leads from diversity-oriented Michael-acceptor library derived from natural products

A potential strategy for drug lead identification and in-active natural products re-discovery is elaborated.Starting from fifteen structurally diverse natural products,a focused library featured by Michael acceptors is constructed with IBX mediated oxidation.Biological assay on five tumor cell lines indicates that four Michael acceptors,8a,11a,12a,14a,are with improved cytotoxicity(3-10 folds more potent than the parent compounds),which merit further investigations.Further thiol-sensitive assay of the active hit 8a revealed that it was an irreversible Michael acceptor.The results suggest that the strategy is not only effective and relatively high discovery rate(28%),but also resource saving.

Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway

Immunogenic Cell Death(ICD)represents a mechanism of enhancing T cell-driven response against tumor cells.The process is enabled by release of damage-associated molecular patterns(DAMPs)and cytokines by dying cells.Based on molecular studies and clinical marker assessment,ICD can be a new target for cancer chemotherapy hitherto restricted to a few conventional anticancer drugs.In view of the development of small molecules in targeted cancer therapy,we reported the preliminary evidence on the role of the natural product lepadin A(1)as a novel ICD inducer.Here we describe the ICD mechanism of lepadin A(1)by proving the translocation of the protein calreticulin(CRT)to the plasma membrane of human A2058 melanoma cells.CRT exposure is an ICD marker in clinical studies and was associated with the activation of the intrinsic apoptotic pathway in A2058 cells with lepadin A(1).After the treatment,the tumour cells acquired the ability to activate dendritic cells(DCs)with cytokine release and costimulatory molecule expression that is consistent with a phenotypic profile committed to priming T lymphocytes via a CD91-dependent mechanism.The effect of lepadin A(1)was dose-dependent and comparable to the response of the chemotherapy drug doxorubicin(2),a well-established ICD inducer.

Successful generic drug product development:From research to marketing approval

Recently,generic drug products have played an increasingly important role in the health care system globally,especially in the developing world,as they provide for an effective and more affordable alternative for healthcare professionals.Generic drug products are proven therapeutically equivalent to the corresponding innovator’s product,and hence can be substituted in clinical practice.The objective of generic drug development is to develop a stable and bioequivalent generic drug product with desirable properties in a timely manner.This presentation is intended to summarize three important sequential stages essential for successful generic drug development based on a regulatory experience in reviewing and evaluating the Pharmaceutical Development Section(P2)of the ASEAN Common Technical Dossier(ACTD)of generic drug product applications submitted to the Food and Drug Administration,Thailand[1,2].

The 4th Euro-Mediterranean Conference of Natural Products and Drug Discovery: Back to Mother Nature (BioNat-IV), Cairo/Sharm El-Sheikh, Egypt, March 3–7, 2015

The 4 th Euro-Mediterranean Conference of Natural Products and Drug Discovery: Back to Mother Nature (Bio Nat-IV) was recently (from March 3 rd through 7 th, 2015) convened in Cairo and Sharm El-Sheikh along the Red Sea coast of Egypt. Overall, the meeting provided a platform for scientists from different nations to discuss emerging ideas that focused on cell signaling in cancer;the pathogenesis of autoimmune diseases;the identification and use of natural products as well as novel drug delivery approaches for the treatment of cancer,arthritis, diabetes, tuberculosis, fungal infection, etc.;and untapped or unconventional sources for natural products. This fourth in a row conference tried to bridge the gap not only between basic research and clinical applications, but also between developed nations and developing countries. With the continuing success of these past meetings, the fifth EuroMediterranean Conference of Natural Products and Drug Discovery(BioNat-V) is slated to be in February 2017.

The Role of Medical Literature, Clinical Trials and Experimental Research in Drug Product-Injury Litigation: A Primer with Two Examples

When any type of product has been ordered to be removed from the marketplace by a governmental regulatory body, that action is a powerful indicator that the product has been determined to be unsafe for further use, thereby branding the product as defective and opening up the possibility of product liability litigation. When the product is a drug or medical device, it is especially serious since the possibility of personal injury (acute and/or chronic) or death may occur. Needless to say, in these situations, product injury litigation will almost surely follow. We review the definition and requisite claims needed to establish drug product liability, and the role that the medical literature, clinical trial data, and even experimental research data can play in product (drug)-injury litigation. We show how each of these resources played a significant role in two well-known cases: Fen-Phen and thimerosal. The ultimate goal of such knowledge is to make better informed decisions about drug safety.

Natural Products as Potential Lead Compounds for Drug Discovery Against SARS-CoV-2

For the past 2 years,the coronavirus responsible for the COVID-19 infection has become a world pandemic,ruining the lives and economies of several nations in the world.This has scaled up research on the virus and the resulting infection with the goal of developing new vaccines and therapies.Natural products are known to be a rich source of lead compounds for drug discovery,including against infectious diseases caused by microbes(viruses,bacteria and fungi).In this review article,we conducted a literature survey aimed at identifying natural products with inhibitory concentrations against the coronaviruses or their target proteins,which lie below 10μM.This led to the identification of 42 compounds belonging to the alkaloid,flavonoid,terpenoid,phenolic,xanthone and saponin classes.The cut off concentration of 10μM was to limit the study to the most potent chemical entities,which could be developed into therapies against the viral infection to make a contribution towards limiting the spread of the disease.

Development of Generic Drug Products by Pharmaceutical Industries Considering Regulatory Aspects: A Review

Development of generic drug product by pharmaceutical industry is a scientific and technical approach which is totally different from developing a reference or innovator product. Most of the developing countries focus on developing the generic drug products because huge amount of investment is required for innovation and to develop reference product. The generic medicine has to be bioequivalent to the innovator drug and ensure the same biological effect with proper safety and efficacy. Nowadays, the pharmaceutical industries focus on the development of generic product as this does not require that much time and cost compared to the innovator company. But development of generic product is also difficult as it contains the same therapeutic efficacy as innovator. The development approach is based on the target market, i.e. US market, EU market. If a manufacturer targets the US market, then all excipients should be USP grade, analysis should be conducted by USP method or in-house method and stability studies as well. Prior and during the development of generic drug product API selection, dosage form selection, reference product selection and characterization, formulation development, analytical method development, tech transfer or submission batch are prime concern. Then again, bioequivalence study, drug registration procedure and commercialization of the generic product considering regulatory guidance of respective regulatory agencies and the approaches taken by the regulatory agencies for the development of registration of generic medicines are also crucial as well for the development of generic drug product. The aim of this study was to review the entire stage of a generic drug development by a generic pharmaceutical company.

Antimicrobial Resistance Patterns of Selected <i>Enterobacteriaceae</i>Isolated from Commercial Poultry Production Systems in Kiambu County, Kenya

Introduction: In the last two decades, the treatment of enteric infections has been complicated by the emergence of antimicrobial resistant strains. Occurrence of multidrug resistant Extended Spectrum Beta Lactamase (ESBL) producing Enterobactaeraceae poses the greatest risk to public health by raising morbidity and mortality by six folds in developing countries. The present study aims to determine the antibiotics resistance patterns of selected Enterobacteriaceae isolated from commercial poultry production systems in Kiambu County. Methods: A laboratory based cross-sectional study was conducted in six purposively selected Sub-Counties of Kiambu County from October 2020, to February 2021. A total of 437 fecal samples were collected from each household. The antibiotic susceptibility testing using disk diffusion method was used against E. coli; Salmonella spps.; Shigella spps.; and Klebsiella spps. which were isolated and identified through standard biochemical. Results: Out of 437 fecal and stool samples collected, 591 isolates were recovered with E. coli (48.9%) being the most frequently identified, followed by Shigella spps. (18.8%), Salmonella spps. (18.3%), and Klebsiella spps. (14.0%). The study shows there was high prevalence of multiple resistance among isolates especially to Sulfamethoxazole (79%), Trimethoprim (71%), and Tetracyclines (59%), correspondingly. Additionally, the isolates showed the highest rate of susceptibility against Cefuroxime (94%), Gentamicin (93%), Ceftriaxone (91%), Cefepime (89%), Cefotaxime (85%), Ceftazidime (84%), and Chloramphenicol (77%), respectively. Discussion: Our study indicates that both fecal and stool materials from commercial poultry and humans can be reservoir of multi-drug resistance enteric’s which can be a potential route of transmission of resistance genes, which pose a great risk to public health of Kiambu Residence.

阴道环体外理化评价方法研究进展

目的:研究分析阴道环体外理化评价方法的研究进展和应用情况,并对存在的问题进行探讨,为我国该类产品的质量控制和科学监管提供参考。方法:梳理国内外阴道环研发和上市产品现状,对体外理化评价方法如药物释放测试、机械性能测试等进行总结和分析。结果:阴道环作为一种新型药械组合产品,目前国内外缺乏该类产品体外理化评价的标准方法。结论:阴道环在艾滋病预防及妇科疾病的治疗方面展现出巨大的应用前景,由于其具备药品和器械双重特点,决定了其质量控制和评价手段不能单纯地按照药品的相关要求来进行,亟需开展阴道环体外评价试验方法标准化的相关研究。

新型定量分装装置的研发及其在国家药品标准物质制备中的应用

目的:优化标国家药品准物质的分装方式,研发一种新型可调的节定量分装设备,用于提高分装效率和生产质量。方法:采用不锈钢材质,制作可调节容积槽和配套刮板,固定体积进行粉末样品的分装。结果:使用分装装置选用化学药品、药用辅料等31种均匀粉末样品进行分装。其测试波动范围较小、准确性高,不同样本之间使用效果一致,分装效率与统天平单支称重的分装方式进行比较提高147%。结论:该装置能显著缩短分装时间,提高生产效率,满足药品标准物质分装规格要求。为药品标准物质的生产制备带来更为显著的便利和价值。