Targeting the relaxin-3/RXFP3 system: a patent review for the last two decades.

INTRODUCTION: The neuropeptide relaxin-3/RXFP3 system belongs to the relaxin/insulin superfamily and is involved in many important physiological processes, such as stress responses, appetite control, and motivation for reward. Although relaxin-3 is the endogenous agonist for RXFP3, it can also bind to and activate RXFP1 and RXFP4. Consequently, research has been focused on the development of RXFP3-specific peptides and small-molecule ligands to validate the relaxin-3/RXFP3 system as a novel drug target. AREAS COVERED: This review provides an overview of patents on the relaxin-3/RXFP3 system covering ligand development and pharmacological studies since 2003. Related patents and literature reports were obtained from established sources including SciFinder, Google Patents, and Espacenet for patents and SciFinder, PubMed, and Google Scholar for literature reports. EXPERT OPINION: There has been an increasing amount of patent activities around relaxin-3/RXFP3, highlighting the importance of this novel neuropeptide system for drug discovery. The development of relaxin-3 derived peptides and small-molecule modulators, as well as behavioral studies in rodents, have shown that the relaxin-3/RXFP3 system is a promising drug target for treating various metabolic and neuropsychiatric diseases including obesity, anxiety, and alcohol addiction.

An Outline of the Immunogenic Potential of Progressing SARSCoV- 2 Vaccine Technologies among Children and Adolescents.

BACKGROUND: SARS-CoV-2, a highly dynamic beta-coronavirus, can afflict all age groups. Notably, over 16100 mortalities have been recorded among children as yet. In this regard, many vaccine projects are operational to assess immuno-potency among young cohorts. A bulk of reports have evidenced the efficacy of these immunization technologies in the elderly population, though the impact is yet to be determined among children. OBJECTIVES: This review is envisioned to outline the current efficacy of contributing vaccine technologies and examine the dose-dependent impact of immunization regimens in lowering the risks of SARS-CoV-2 infections among children and adolescents. Furthermore, the current review exclusively estimated the vaccine impact at current doses. METHODS: A total of 52 research papers extracted from PubMed, Pubmed Central, Science Direct, Research Gate, Google Scholar and Semantic Scholar were screened along with an emphasis on patents. Inclusion criteria involved all published reports directly or indirectly linked to the contributing vaccine candidates that are operational among the young cohort. Unrelated research papers were excluded from the study. Key search terminologies included information on vaccine identifiers, such as name, type and clinical trial ID, and successively restricted to children and adolscents age groups. RESULTS: Several vaccine designs, such as mRNA-based vaccinations, viral vector vaccines, DNA vaccines, inactivated vaccines, recombinant vaccines, and protein-based immunizations, are being examined at various stages of clinical trials to gauge the effects on children and adolescents. With reference to the published reports, the mRNA 1273 (1610 GMT; 6-10 yrs, 1401 GMT; 12-15 yrs), BNT162b2 (1407 GMT; 6 months- <2 yrs, 1535 GMT; 2-4 yrs, 4583 GMT; 5-11 yrs, 1239.5 GMT; 12-15 yrs) and Ad5 nCoV (1037.5 GMT; 6-17 yrs) offered relatively high neutralization titers with sharp seroconversion rates compared to MVC-COV1901 (648.5 GMT; 12-17 yrs) and ZyCoV-D (133.49 GMT; 12-17 yrs), which produced modest immune responses. CONCLUSION: Currently, the WHO is analyzing emerging evidence to issue an emergency use list of vaccines for vaccinating children and adolescents.

Exploring Trachyspermum ammi and Foeniculum vulgare in Hydroponic System and Compare its Chemical Constituents with Soil-Based Method: A Prospective in Agriculture.

BACKGROUND: The forthcoming problems will be of food, and soil due to environmental alteration, growing populations, pollution, and exhaustion of natural resources among other factors. Hydroponic farming has the capacity to alleviate the intimidation of these con-cerned issues in the agricultural system. Hydroponics is recommended as an alternative way to enhance product yield compared to conventional agriculture. OBJECTIVE: The present study aimed to determine the different growth parameters and constituents of soil-grown and hydroponically grown Trachyspermum ammi and Foeniculum vulgare for the first time, which could be a patentable in future. METHODS: In this study, extraction was carried out by maceration method using methanol as a solvent whereas, growth parameters were performed by the leaves number, plant height, and leaf area. Chlorophyll content was also performed in both sources. Further, a comparison of chemical constituents from different sources was analyzed by GC-MS. RESULTS: The bioactive components in hydroponically grown T. ammi were found more as compared to soil-grown T. ammi. The GC-MS analysis revealed the presence of various compounds in the methanolic extract of plant materials. CONCLUSION: Hence, hydroponics could be an alternative in agriculture and this system is now accepted globally. This method provides diverse perspectives for farmers to harvest high-yield, better quality, and enhanced bioactive compounds.

Recent developments of HSP90 inhibitors: an updated patent review (2020-present).

INTRODUCTION: The 90-kDa heat shock protein (HSP90) functions as a molecular chaperone, it assumes a significant role in diseases such as cancer, inflammation, neurodegeneration, and infection. Therefore, the research and development of HSP90 inhibitors have garnered considerable attention. AREAS COVERED: The primary references source for this review is patents obtained from SciFinder, encompassing patents on HSP90 inhibitors from the period of 2020 to 2023.This review includes a thorough analysis of their structural attributes, pharmacological properties, and potential clinical utilities. EXPERT OPINION: In the past few years, HSP90 inhibitors targeting ATP binding pocket are still predominate and one of them has been launched, besides, novel drug design strategies like C-terminal targeting, isoform selective inhibiting and bifunctional molecules are booming, aiming to improve the efficacy and safety. With expanded drug types and applications, HSP90 inhibitors may gradually becoming a sagacious option for treating various diseases.

Therapeutic cysteine protease inhibitors: a patent review (2018-present).

INTRODUCTION: Cysteine proteases are involved in a broad range of biological functions, ranging from extracellular matrix turnover to immunity. Playing an important role in the onset and progression of several diseases, including cancer, immune-related and neurodegenerative disease, viral and parasitic infections, cysteine proteases represent an attractive drug target for the development of therapeutic tools. AREAS COVERED: Recent scientific and patent literature focusing on the design and study of cysteine protease inhibitors with potential therapeutic application has been reviewed. EXPERT OPINION: The discovery of a number of effective structurally diverse cysteine protease inhibitors opened up new challenges and opportunities for the development of therapeutic tools. Mechanistic studies and the availability of X-ray crystal structures of some proteases, alone and in complex with inhibitors, provide crucial information for the rational design and development of efficient and selective cysteine protease inhibitors as preclinical candidates for the treatment of different diseases.

Targeting the EGFR/RAS/RAF signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023).

INTRODUCTION: Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer insights for drug discovery. This review discusses the drug design and development efforts ofinhibitors targeting these proteins over the past 3 years, detailingtheir structures, selectivity, efficacy, and combination therapy.Strategies to combat drug resistance and minimize toxicities areexplored, along with future research directions. AREA COVERED: This review encompasses clinical trials and patents on EGFR, KRAS,and BRAF inhibitors from 2020 to 2023, including advancements indesign and synthesis of proteolysis targeting chimeras (PROTACs) forprotein degradation. EXPERT OPINION: To tackle drug resistance, designing allosteric fourth-generationEGFR inhibitors is vital. Covalent, allosteric, or combinationaltherapies, along with PROTAC degraders, are key methods to addressresistance and toxicity in KRAS and BRAF inhibitors.

Peroxisome Proliferator-Activated Receptor agonists and antagonists: an updated patent review (2020-2023).

INTRODUCTION: The search for novel compounds targeting Peroxisome Proliferator-Activated Receptors (PPARs) is currently ongoing, starting from the previous successfully identification of selective, dual or pan agonists. In last years, researchers' efforts are mainly paid to the discovery of PPARγ and δ modulators, both agonists and antagonists, selective or with a dual-multitarget profile. Some of these compounds are currently under clinical trials for the treatment of primary biliary cirrhosis, nonalcoholic fatty liver disease, hepatic, and renal diseases. AREAS COVERED: A critical analysis of patents deposited in the range 2020-2023 was carried out. The novel compounds discovered were classified as selective PPAR modulators, dual and multitarget PPAR agonists. The use of PPAR ligands in combination with other drugs was also discussed, together with novel therapeutic indications proposed for them. EXPERT OPINION: From the analysis of the patent literature, the current emerging landscape sees the necessity to obtain PPAR multitarget compounds, with a balanced potency on three subtypes and the ability to modulate different targets. This multitarget action holds great promise as a novel approach to complex disorders, as metabolic, inflammatory diseases, and cancer. The utility of PPAR ligands in the immunotherapy field also opens an innovative scenario, that could deserve further applications.

Patents on Risk Evaluation and Mitigation Strategies for Prescription Drugs and Generic Competition.

This cross-sectional study identifies the prevalence of patents on risk evaluation and mitigation strategies and their association with delaying generic competition.

Delivery Device Patents on GLP-1 Receptor Agonists.

This study analyzed the US Food and Drug Administration­listed patents on glucagon-like peptide 1 (GLP-1) receptor agonists to determine their claim characteristics and the potential barriers they pose to generic entry.

Premarket Notifications and Patents for Breast Pumps Before and After the ACA.

This study investigates whether ACA policies to increase access to breast pumps and lactation care were associated with innovation in the market for breast pumps.

The Role of Light on the Microalgae Biotechnology: Fundamentals, Technological Approaches, and Sustainability Issues.

Light energy directly affects microalgae growth and productivity. Microalgae in natural environments receive light through solar fluxes, and their duration and distribution are highly variable over time. Consequently, microalgae must adjust their photosynthetic processes to avoid photo limitation and photoinhibition and maximize yield. Considering these circumstances, adjusting light capture through artificial lighting in the main culture systems benefits microalgae growth and induces the production of commercially important compounds. In this sense, this review provides a comprehensive study of the role of light in microalgae biotechnology. For this, we present the main fundamentals and reactions of metabolism and metabolic alternatives to regulate photosynthetic conversion in microalgae cells. Light conversions based on natural and artificial systems are compared, mainly demonstrating the impact of solar radiation on natural systems and lighting devices, spectral compositions, periodic modulations, and light fluxes when using artificial lighting systems. The most commonly used photobioreactor design and performance are shown herein, in addition to a more detailed discussion of light-dependent approaches in these photobioreactors. In addition, we present the principal advances in photobioreactor projects, focusing on lighting, through a patent-based analysis to map technological trends. Lastly, sustainability and economic issues in commercializing microalgae products were presented.

Comparison of Five Escherichia coli Strains to Achieve the Maximum Yield of a Recombinant Immunotoxin Consisting of an Antibody against VEGF Conjugated with MAP30 Toxin in a Benchtop Bioreactor.

BACKGROUND: Cancer is among the leading causes of death worldwide, imposing high costs on the health systems of all societies. Extensive biological studies are required to discover appropriate therapies. Escherichia coli has long been regarded as one of the main biotechnological bio-factories to produce recombinant protein-based therapeutics. In the present study, five strains of E. coli were compared to achieve the maximum production of a previously designed recombinant immunotoxin-carrying MAP30 toxin against VEGF-overexpressed cancer cells in a benchtop bioreactor. METHODS: The recombinant immunotoxin coding gene sequence was extracted from the NCBI database. The host used to produce the recombinant immunotoxin were five E. coli strains of BL21 (DE3), DH5α, SHuffle®T7, XL1-Blue, and Rosetta-gamiTM (DE3). CaCl2 method was used for bacterial transformation. Bacterial growth measurements were performed using optical density measurements at 600 nm. The immunotoxin production was measured using SDS-PAGE analysis. The best-producing strain was cultivated in a 10-L benchtop stirred tank bioreactor. Recent patents on this field were also studied. RESULTS: The results demonstrated that the BL21 (DE3) strain had the highest expression of recombinant protein in comparison to other strains. Moreover, the cell growth of E. coli BL21 (DE3) and SHuffle®T7 strains before transformation in the LB medium, were significantly higher in comparison to other strains. Additionally, the transformation of Rosettagami was associated with decreased cell proliferation. The transformation of the XL1-Blue strain did not effect cell growth. Analysis of the growth kinetics demonstrated appropriate proliferation of the transformed BL21 (DE3) cells in the laboratory benchtop bioreactor. CONCLUSIONS: Based on the results of this study, the BL21 (DE3) strain could be used as a suitable host for the production of the recombinant immunotoxin against VEGF in stirred tank bioreactor, which can be employed for the treatment of tumors. Yet, its precise mechanism must be explored in extensive studies.

Gonadotropic Activity of Pituitary Extract of African Catfish, Clarias gariepinus, in Mammals using Immature Wistar Rats as Models.

BACKGROUND: The pituitary glands normally produce and stores gonadotropic hormones (GnH) that are responsible for ovulation and spermiation in animals. However, whether fish pituitary extracts can elicit same effects in treated animals need elucidation as a prelude to their practical usage in animals. OBJECTIVES: The aim of this study was to investigate the oestrus-inducing potential of the pituitary gland extract of the Africa Catfish (Clarias gariepinus) in immature Wistar rats. METHODS: The experiment involved the use of 18 immature female Wistar rats and 10 male catfish brood stocks with the use of six Wistar rats per groups as follows: Group A had human chorionic gonadotropin (hCG) treatment. Group B had only normal saline treatment as the control whereas Group C had the C. gariepinus pituitary extract administration to induce oestrus with treatments occurring twice six hours apart in each group. RESULTS: There was an obvious expression of visible signs of heat and the presence of uterine horn oedema with significant (p < 0.05) increase in reproductive tract weight and uterine width and length. However, only progesterone levels increased significantly (p < 0.05) in the hCG and the C. gariepinus pituitary extract treated groups compared to other assayed hormones. CONCLUSION: These results showed that C. gariepinus pituitary extract has the capacity to induce oestrus in Wistar rats because of its gonadotropic effects, which needs further investigations at higher doses and for longer exposure periods for possible oestrus induction and synchronization in higher mammals. Further favourable results could herald the possible patent of the catfish pituitary extract for either experimental or commercial use in mammals.

Nano Lipid Carriers as a Promising Drug Delivery Carrier for Neurodegenerative Disorders - An Overview of Recent Advances.

The last few decades have seen a rise in the number of deaths caused by neurological disorders. The blood-brain barrier (BBB), which is very complex and has multiple mechanisms, makes drug delivery to the brain challenging for many scientists. Lipid nanoparticles (LNPs) such as nanoemulsions, solid-lipid nanoparticles, liposomes, and nano lipid carriers (NLCs) exhibit enhanced bioavailability and flexibility among these nanocarriers. NLCs are found to be very effective. In the last few decades, they have been a center of attraction for controlled drug delivery. According to the current global status of specific neurological disorders, out of all LNPs, NLC significantly reduces the cross-permeability of drugs through the BBB due to their peculiar properties. They offer a host of advantages over other carriers because of their biocompatibility, safety, non-toxicity, non-irritating behavior, stability, high encapsulation efficiency, high drug loading, high drug targeting, control of drug release, and ease in manufacturing. The biocompatible lipid matrix is ideally suited as a drug carrier system due to the nano-size range. For certain neurological conditions such as Parkinsonism, Alzheimer's, Epilepsy, Multiple sclerosis, and Brain cancer, we examined recent advances in NLCs to improve brain targeting of bioactive with special attention to formulation aspects and pharmacokinetic characteristics. This article also provides a brief overview of a critical approach for brain targeting, i.e., direct nose-to-brain drug delivery and some recent patents published on NLC".

Human Chorionic Gonadotropin Regulates the Smad Signaling Pathway by Antagonizing TGF-ß in Giant Cell Tumor of Bone.

BACKGROUND: Giant cell tumor of bone (GCTB) is a locally aggressive bone tumour aggravated by stromal cell proliferation and metastasis. OBJECTIVE: We investigated the mechanism of action of human chorionic gonadotropin (HCG) in mediating GCTB proliferation and invasion. METHODS: The expression of HCG was quantified using quantitative real-time PCR. After the primary stromal cells were isolated and identified, the function of HCG in GCTB was estimated using the cell counting kit-8, flow cytometry, scratch experiment, transwell assay, Western blot, and immunofluorescence. Moreover, the mechanism of HCG was assessed through western blotting. RESULTS: HCG expression was decreased in clinical tissue samples from patients with GCTB. We validated that HCG repressed stromal cell proliferation, migration, invasion, autophagy, and epithelial- mesenchymal transition (EMT) and promoted cell apoptosis in GCTB. We also verified that HCG repressed the autophagy and EMT of stromal cells through the Smad signaling axis in GCTB. HCG inhibited the transduction of the Smad signaling pathway by restraining the binding of the TGF-ß II receptor to ligand Activin A. CONCLUSION: HCG restrained the Smad signaling pathway by antagonizing TGF-ß signaling in GCTB. HCG may serve as a useful patent to treat GCTB.

Development and Evaluation of a Novel Hyaluronic Acid and Chitosan-modified Phytosome for Co-delivery of Oxymatrine and Glycyrrhizin for Combination Therapy.

BACKGROUND: Multidrug resistance (MDR) of cancer cells is a major obstacle to efficient cancer chemotherapy. Combination therapy is expected to enhance the anticancer effect and reverse MDR. Numerous patents involve different kinds of nanoparticles for the co-delivery of multiple chemotherapeutics, but the FDA has approved none. OBJECTIVE: In this study, oxymatrine (OMT) and glycyrrhizin (GL) were co-loaded into phytosomes as the core of nanocarriers, and the shell was cross-linked with chitosan (CS) and hyaluronic acid (HA) with the capability for the controlled, sequential release and the targeted drug uptake. METHODS: Phospholipid complexes of OMT and GL (OGPs) were prepared by a solvent evaporation technique and could self-assemble in an aqueous solution to form phytosomes. CS and HA were sequentially coated on the surface of OGPs via electrostatic interactions to obtain CS coated OGPs (CS-OGPs) and HA modified CS-OGPs (HA-CS-OGPs), respectively. The particle size and zeta potential were measured to optimize the formulations. In vitro cytotoxicity and cellular uptake experiments on HepG2 cells were performed to evaluate the anticancer activity. RESULTS: OGPs were obtained with nano-size around 100 nm, and CS and HA coating on phytosomes could change the particle size and surface potential. The drug loading of OMT and GL showed that the nanocarriers could maintain a fixed ratio of 1:1. The in vitro release experiments indicated the release of OMT and GL was pH-dependent and sequential: the release of OMT from CS-OGPs and HA-CS-OGPs was significantly increased at pH 5.0 compared to the release at pH 7.4, while GL exhibited sustained released from CS-OGPs and HA-CS-OGPs at pH 5.0. Furthermore, in vitro cytotoxicity and cellular uptake experiments on HepG2 cells demonstrated that the co-delivery system based on phytosomes had significant synergistic anti-tumor activities, and the effects were enhanced by CS and HA modification. CONCLUSION: The delivery of OMT and GL via HA-CS-OGPs might be a promising treatment to reverse MDR in cancer therapy.

Circ_0070203 Promotes Epithelial-mesenchymal Transition in Ovarian Serous Cystadenocarcinoma through miR-370-3p/TGFßR2 Axis.

INTRODUCTION: Circular RNAs (circRNAs) are important biological molecules associated with the pathogenesis of multiple cancers. OBJECTIVE: This work aimed to investigate the function and molecular mechanism of circ_0070203 in high-grade serous ovarian cystadenocarcinoma (HGSOC). METHODS: circRNA microarray was conducted to detect the circ_0070203 expression in HGSOC tissues. Bioinformatics analysis was used to find the binding sites between circ_0070203, miR- 370-3p and TGFßR2. Real-time quantitative reverse transcription PCR (RT-qPCR) was executed to detect the expressions of circ_0070203, miR-370-3p and TGFßR2 in HGSOC tissues and SKOV3 cells. Dual-luciferase reporter gene assay was used to validate the relationships between miR-370-3p and circ_0070203 or TGFßR2. Besides, transwell assays were conducted to assess the migrative, invasive abilities of ovarian cancer (OC) cells. Western blotting was adopted to detect the expression of epithelial-mesenchymal transition (EMT)-related proteins. The related patents were also studied during the research. RESULTS: Circ_0070203 and TGFßR2 were upregulated, while miR-370-3p was downregulated in FIGO stage III-IV HGSOC tissues and SKOV-3 cell lines. circ_0070203 overexpression changed the expression of other EMT-related proteins and enhanced the migrative, invasive abilities of OC cells, while silencing circ_0070203 worked oppositely. Mechanistically, circ_0070203 could upregulate TGFßR2 expression in OC cells via sponging miR-370-3p. CONCLUSION: Circ_0070203 could promote the epithelial-mesenchymal transition, invasion, and metastasis of HGSOC via regulating the miR-370-3p/TGFßR2 axis. Our findings provided a potential biomarker for HGSOC therapy.

A Synergistic Combination of Oleanolic Acid and Apatinib to Enhance Antitumor Effect on Liver Cancer Cells and Protect against Hepatic Injury.

BACKGROUND: As a pentacyclic triterpenoid, OA (oleanolic acid) has exhibited antiinflammatory, immunomodulatory and antitumor effects. VEGFR-2 (vascular endothelial cells receptor-2) tyrosine kinase activity could be inhibited by apatinib, a small-molecule antiangiogenic agent. OBJECTIVE: Thus, this study sought to investigate the mechanism underlying the synergistic antitumor activity of combined OA and apatinib patent. METHODS: Through CCK8 (Cell counting kit 8 assay), flow cytometric and western blotting techniques, we conducted in vitro studies on apatinib and OA effects on cell proliferation and apoptosis in H22 cell line. H22 tumor-burdened mice model was established in vivo, while the related signaling pathways were studied via pathological examination, western blotting and qPCR (quantitative polymerase chain reaction). RESULTS: Growth of H22 cells in vitro and in vivo could be inhibited effectively by apatinib and OA. Thus, OA repaired liver function and inhibited oxidative stress induced by apatinib. CONCLUSION: OA can treat apatinib induced liver injury in H22 Tumor-burdened mice by enhancing the suppresssive effect of apatinib on the growth of tumor.

Nanostructured Lipid Carriers (NLCs) as Effective Drug Delivery Systems: Methods of Preparation and their Therapeutic Applications.

One of the drug delivery technologies is nanostructured lipid carriers (NLCs), which improve drug permeability and thus bioavailability. NLCs are nanoparticles made from a lipid matrix made up of a mixture of solid and liquid lipids. The inclusion of liquid lipids is useful in lowering the ordered structure of solid lipids, increasing nanoparticle loading capacity, and drug entrapment efficiency within NLCs. Hot homogenization, cold homogenization, micro-emulsion, emulsification-solvent diffusion, high shear homogenization, and/or ultrasonication techniques, double emulsion technique, melting dispersion method, membrane contractor technique, and evaporation solvent injection are some of the methods that can be used to make NLCs. Both hydrophilic and lipophilic medicines can be carried out by NLCs. They can deliver medications in a variety of ways, including oral, topical, transdermal, parenteral, and ophthalmic. During the process of preparing this review article, several distinct studies and patent reports about various methods of NLCs formulations, their various therapeutic applications, and various routes of administration were investigated and discussed. The study conducts an in-depth evaluation of the most recent research publications and patents. NLCs have been utilized to treat a variety of disorders, including cancer, fungal infections, bacterial infections, inflammation, liver diseases, and ocular infections, due to their benefits. They can deliver medications to specific locations throughout the body, allowing for drug targeting and a reduction in unwanted side effects. They can also be used to improve bioavailability, reduce the medication's supplied dose, and improve the drug's pharmacological activity.