Treatment Of Human Diseases Research Articles

Sigma Receptor Ligands Are Potent Antiprion Compounds that Act Independently of Sigma Receptor Binding.

Prion diseases are invariably fatal neurodegenerative diseases of humans and other animals for which there are no effective treatment options. Previous work from our laboratory identified phenethylpiperidines as a novel class of anti-prion compounds. While working to identify the molecular target(s) of these molecules, we unexpectedly discovered ten novel antiprion compounds based on their known ability to bind to the sigma receptors, σ1R and σ2R, which are currently being tested as therapeutic or diagnostic targets for cancer and neuropsychiatric disorders. Surprisingly, however, knockout of the respective genes encoding σ1R and σ2R (Sigmar1 and Tmem97) in prion-infected N2a cells did not alter the antiprion activity of these compounds, demonstrating that these receptors are not the direct targets responsible for the antiprion effects of their ligands. Further investigation of the most potent molecules established that they are efficacious against multiple prion strains and protect against downstream prion-mediated synaptotoxicity. While the precise details of the mechanism of action of these molecules remain to be determined, the present work forms the basis for further investigation of these compounds in preclinical studies. Given the therapeutic utility of several of the tested compounds, including rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and the ongoing clinical trials of SA 4503 and ANAVEX2-73 for ischemic stroke and Alzheimer's disease, respectively, this work has immediate implications for the treatment of human prion disease.

Moss-produced human complement factor H with modified glycans has an extended half-life and improved biological activity

Most drugs that target the complement system are designed to inhibit the complement pathway at either the proximal or terminal levels. The use of a natural complement regulator such as factor H (FH) could provide a superior treatment option by restoring the balance of an overactive complement system while preserving its normal physiological functions. Until now, the systemic treatment of complement-associated disorders with FH has been deemed unfeasible, primarily due to high production costs, risks related to FH purified from donors’ blood, and the challenging expression of recombinant FH in different host systems. We recently demonstrated that a moss-based expression system can produce high yields of properly folded, fully functional, recombinant FH. However, the half-life of the initial variant (CPV-101) was relatively short. Here we show that the same polypeptide with modified glycosylation (CPV-104) achieves a pharmacokinetic profile comparable to that of native FH derived from human serum. The treatment of FH-deficient mice with CPV-104 significantly improved important efficacy parameters such as the normalization of serum C3 levels and the rapid degradation of C3 deposits in the kidney compared to treatment with CPV-101. Furthermore, CPV-104 showed comparable functionality to serum-derived FH in vitro, as well as similar performance in ex vivo assays involving samples from patients with atypical hemolytic uremic syndrome, C3 glomerulopathy and paroxysomal nocturnal hematuria. CPV-104 – the human FH analog expressed in moss – will therefore allow the treatment of complement-associated human diseases by rebalancing instead of inhibiting the complement cascade.

Animal models for the treatment of human diseases

Abstract Currently, studies conducted on animal models provide new insight into the aetiology and course of various pathological conditions in humans. Due to the cause of disease, animal models can be divided into two categories: natural models, such as nude mice, and induced models, such as transgenic pigs. This article discusses several examples of animal models and their contributions to the development of effective therapies for human diseases such as muscular dystrophy, cystic fibrosis, and atherosclerosis. In addition, we presented the latest news on gene therapy, xenotransplantation, and drug trials in humans and animals.

GCMS-based Phytochemical Profiling of L. camara Induces Apoptosis and Cell Cycle Arrest in Lung Cancer

In this paper, the focus is on the phytochemical study of Lantana camara L. leaf extract, specifically its antioxidant and anti-cancer effects. The study shows that all solvent extracts have significant antioxidant and anticancer activity. However, the methanol liquid extract of L. camara leaf contains higher levels of metabolites than other solvents. The methanolic extracts of the leaves of four distinct species of Lantana camara also have high levels of terpenoid chemicals, which demonstrate strong antioxidant and free radical elimination properties. With further research, it is possible that useful medications can be developed for the treatment of various human diseases, especially lung cancer.

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma.

The term "zoonosis" denotes diseases transmissible among vertebrate animals and humans. These diseases constitute a significant public health challenge, comprising 61% of human pathogens and causing an estimated 2.7 million deaths annually. Zoonoses not only affect human health but also impact animal welfare and economic stability, particularly in low- and middle-income nations. Leishmaniasis and schistosomiasis are two important neglected tropical diseases with a high prevalence in tropical and subtropical areas, imposing significant burdens on affected regions. Schistosomiasis, particularly rampant in sub-Saharan Africa, lacks alternative treatments to praziquantel, prompting concerns regarding parasite resistance. Similarly, leishmaniasis poses challenges with unsatisfactory treatments, urging the development of novel therapeutic strategies. Effective prevention demands a One Health approach, integrating diverse disciplines to enhance diagnostics and develop safer drugs. Metalloenzymes, involved in parasite biology and critical in different biological pathways, emerged in the last few years as useful drug targets for the treatment of human diseases. Herein we have reviewed recent reports on the discovery of inhibitors of metalloenzymes associated with zoonotic diseases like histone deacetylases (HDACs), carbonic anhydrase (CA), arginase, and heme-dependent enzymes.

Phytochemical profiling and GC-MS analysis of methanolic leaf extract of Persicaria hydropiper (L.) H. Gross: An important ethnomedicinal plant

Medicinal plants are the best source of alternative medicine and are acquiring recognition in the area of pharmacological research for the production of plant-based medicines with improved efficacy. Persicaria hydropiper (L.) H-Gross is known worldwide for its use in traditional medicine systems. It possesses numerous therapeutic properties. The present endeavor was taken up to analyze the phytochemical profile and antioxidant activity by DPPH assay of various extracts of Persicaria hydropiper leaves. The preliminary phytochemical screening of acetone, methanol, and aqueous extract of P. hydropiper leaves showed the presence of important phytochemicals such as phenols, tannins, flavonoids, glycosides, terpenoids, and alkaloids. The quantitative estimation revealed elevated amounts of total phenols, flavonoids, tannins, and total alkaloid content. The antioxidant activity also revealed higher radical scavenging activity by the extracts. The Gas Chromatography-Mass Spectrophotometry assay of methanol extract of P. hydropiper leaves detected and identified altogether 54 phytocompounds including 7 major compounds displaying higher peaks such as Andrographolide, 1H-cyclopropa[a] naphthalene, 1a,2,3,5.6,7a7b-octahydro-1,1,7,7a-tetramethyl-[1aR-(1a?,7?,7a?,7b?)-, Cis-Z alpha bisabolene epoxide, 1,8-cyclopentadecadiyne, Aromadendrene oxide (2), Bicyclo[4.1.0]heptane-3-cyclopropyl 7-hydroxymethyl, (cis) and Alpha-guanine. The concentration of phenols, flavonoids, and tannins revealed in the phytochemical profiling of three extracts might be responsible for the strong antioxidant activity of the extracts and the bioactive compounds identified in the GC-MS investigation exhibit important therapeutic properties required for the treatment of various human diseases. Thus, the medicinal use and properties of Persicaria hydropiper may be attributed to the presence of these phytochemical constituents. Further study of the compounds may provide scope for the production of novel drugs with increased efficacy and potency with the ability to cure harmful human diseases.

A combination of polypeptide and magnetic molecular imprinted electrochemical sensor based on BSA-AuNPs/Fe3O4@ZIF-8 for the detection of norfloxacin

Norfloxacin (NOR) is now extensively used for the treatment of human and animal diseases. Unfortunately, large accumulations of NOR will pose a significant threat to the human body. Thus, it is urgent to develop a rapid and sensitive detection technique for the trace determination of NOR. In this study, an electrochemical molecular imprinting sensor with great properties was fabricated for the determination of NOR in milk and environmental water. The incorporation of bovine serum proteins produced a hybrid recognition interface consisting of molecularly imprinted polymers and peptides that provided good recognition properties for norfloxacin. The Fe3O4@ZIF-8 was distributed orderly on the electrode after the embedding of the magnets inside the electrode, then the BSA was coated on the electrode with the electrodeposited AuNPs through Au-S bonding. The sensor constructed in this study achieved ultra-sensitive detection of norfloxacin with an effective area of 0.08433 cm2, a limit of detection (LOD) of 0.108 pmol·L−1, and a wide linear range (1 ∼ 100, 100 ∼ 1000 and 1000 ∼ 8000 pmol·L−1). The prepared sensors exhibited satisfactory performance in the detection of milk and environmental water, with acceptable recoveries ranging from 96.24 % to 104.88 %, and the relative standard deviation (RSD) was no more than 4.84 %.

Determination of Acetylcholinesterase Activity Based on Ratiometric Fluorescence Signal Sensing.

Acetylcholinesterase (AChE) plays an important role in the treatment of human diseases, environmental security and global food supply. In this study, the simple fluorescent indicators and MnO2 nanosheets were developed and integrated to establish a ratiometric fluorescence sensing system for the detection of AChE activity. Two fluorescence signals could be recorded independently at the same excitation wavelength, which extended the detection range and enhanced the visibility of results. Fluorescence of F-PDA was quenched by MnO2 nanosheets on account of inner filtering effect. Meanwhile, the nonfluorescent OPD was catalytically oxidized to 2,3-diaminophenazine by MnO2 nanosheets. The acetylcholine (ATCh) was catalytically hydrolyzed by AChE to enzymatic thiocholine, which decomposed MnO2 to Mn2+, recovered the fluorescence of F-PDA and reduced the emission of ox-OPD. Utilizing the fluorescence intensity ratio F468/F558 as the signal readout, the ratiometric fluorescence method was established to detect AChE activity. Under the excitation wavelength of 410nm, the ratio F460/F558 against the AChE concentration demonstrated two linear relationships in the range 0.05 -1.0 and 1.0-50 U·L- 1 with a limit of detection (LOD) of 0.073 U·L- 1. The method was applied to the detection of AChE activity and the analysis of the inhibitor Huperzine-A. Due to the advantages of high sensitivity and favorable selectivity, the method possesses an application prospect in the activity deteceion of AChE and the screening of inhibitors.

Chromosome Transplantation: Opportunities and Limitations.

There are thousands of rare genetic diseases that could be treated with classical gene therapy strategies such as the addition of the defective gene via viral or non-viral delivery or by direct gene editing. However, several genetic defects are too complex for these approaches. These "genomic mutations" include aneuploidies, intra and inter chromosomal rearrangements, large deletions, or inversion and copy number variations. Chromosome transplantation (CT) refers to the precise substitution of an endogenous chromosome with an exogenous one. By the addition of an exogenous chromosome and the concomitant elimination of the endogenous one, every genetic defect, irrespective of its nature, could be resolved. In the current review, we analyze the state of the art of this technique and discuss its possible application to human pathology. CT might not be limited to the treatment of human diseases. By working on sex chromosomes, we showed that female cells can be obtained from male cells, since chromosome-transplanted cells can lose either sex chromosome, giving rise to 46,XY or 46,XX diploid cells, a modification that could be exploited to obtain female gametes from male cells. Moreover, CT could be used in veterinary biology, since entire chromosomes containing an advantageous locus could be transferred to animals of zootechnical interest without altering their specific genetic background and the need for long and complex interbreeding. CT could also be useful to rescue extinct species if only male cells were available. Finally, the generation of "synthetic" cells could be achieved by repeated CT into a recipient cell. CT is an additional tool for genetic modification of mammalian cells.

The Exacerbating Effects of the Tumor Necrosis Factor in Cardiovascular Stenosis: Intimal Hyperplasia.

TNF-α functions as a master regulator of inflammation, and it plays a prominent role in several immunological diseases. By promoting important cellular mechanisms, such as cell proliferation, migration, and phenotype switch, TNF-α induces its exacerbating effects, which are the underlying cause of many proliferative diseases such as cancer and cardiovascular disease. TNF-α primarily alters the immune component of the disease, which subsequently affects normal functioning of the cells. Monoclonal antibodies and synthetic drugs that can target TNF-α and impair its effects have been developed and are currently used in the treatment of a few select human diseases. Vascular restenosis is a proliferative disorder that is initiated by immunological mechanisms. In this review, the role of TNF-α in exacerbating restenosis resulting from neointimal hyperplasia, as well as molecular mechanisms and cellular processes affected or induced by TNF-α, are discussed. As TNF-α-targeting drugs are currently not approved for the treatment of restenosis, the summation of the topics discussed here is anticipated to provide information that can emphasize on the use of TNF-α-targeting drug candidates to prevent vascular restenosis.

Evolution of the clinical-stage hyperactive TcBuster transposase as a platform for robust non-viral production of adoptive cellular therapies

Cellular therapies for the treatment of human diseases, such as chimeric antigen receptor (CAR) T and NK cells have shown remarkable clinical efficacy in treating hematological malignancies, however current methods mainly utilize viral vectors which are limited by their cargo size capacities, high cost, and long timelines for production of clinical reagent. Delivery of genetic cargo via DNA transposon engineering is a more timely and cost-effective approach, yet has been held back by less efficient integration rates. Here, we report the development of a novel hyperactive TcBuster (TcB-M) transposase engineered through structure guided and in vitro evolution approaches that achieves high-efficiency integration of large, multicistronic CAR-expression cassettes in primary human cells. Our proof of principle TcB-M engineering of CAR-NK and CAR-T cells show low integrated vector copy number, a safe insertion site profile, robust in vitro function, and improves survival in a Burkitt lymphoma xenograft model in vivo. Overall, TcB-M is a versatile, safe, efficient and open-source option for the rapid manufacture and preclinical testing of primary human immune cell therapies through delivery of multicistronic large cargo via transposition.

Biomedical significance of the therapeutic use of autophagy (literature review)

Autophagy, or is an intracellular degradation pathway for improperly functioning aggre-gation-prone proteins, damaged organelles, unwanted macromolecules, and invading patho-gens. The process is necessary for maintaining cell and tissue homeostasis, which contributes to the survival of the organism, and is actively studied. The purpose of this work was the search, selection and analysis of the literature on autophagy as one of the main mechanisms of maintaining cellular homeostasis under conditions of oxidative stress; cellular aging; calo-rie restriction; as well as about the targeted effect on autophagy in the conditions of various diseases. The following generalizations were made: 1) the ability to be directly activated in response to the intense formation of reactive oxygen species in cells allows us to consider autophagy as an important element of antioxidant protection, therefore, the study of ways and means of effective autophagy management is becoming relevant today; 2) dietary con-sumption of autophagy activators may promote health and extend lifespan through multiple mechanisms, including reduction of oxidative stress, induction of autophagy, and suppression of inflammation; 3) studies aimed at elucidating the role of sirtuins, which are key regulators of cellular metabolism and oxidative stress, are gaining relevance in the initiation of autoph-agy. Currently, sirtuin-dependent mechanisms of autophagy require research in experimental models using mammalian cells; 4) continuing the study of autophagy processes will allow a better understanding of physiological aspects and help ensure progress in the development of new strategies for the prevention and treatment of human diseases (including those related to age); 5) autophagy is crucial for cellular physiology, autophagy dysfunction is in-volved in the pathogenesis of various human diseases, and therefore the therapeutic use of autophagy has potential biomedical significance. Keywords: cell death, cellular homeostasis, oxidative stress, cellular aging, calorie restriction, targeted effect on autophagy.

General Synthesis of Conformationally Constrained Noncanonical Amino Acids with C(sp3)-Rich Benzene Bioisosteres.

Recent years have seen novel modalities emerge for the treatment of human diseases resulting in an increase in beyond rule of 5 (bRo5) chemical matter. As a result, synthetic innovations aiming to enable rapid access to complex bRo5 molecular entities have become increasingly valuable for medicinal chemists' toolkits. Herein, we report the general synthesis of a new class of noncanonical amino acids (ncAA) with a cyclopropyl backbone to achieve conformational constraint and bearing C(sp3)-rich benzene bioisosteres. We also demonstrate preliminary studies toward utilities of these ncAA as building blocks for medicinal chemistry research.

Biomaterial-Based CRISPR/Cas9 Delivery Systems for Tumor Treatment.

CRISPR/Cas9 gene editing technology is characterized by high specificity and efficiency, and has been applied to the treatment of human diseases, especially tumors involving multiple genetic modifications. However, the clinical application of CRISPR/Cas9 still faces some major challenges, the most urgent of which is the development of optimized delivery vectors. Biomaterials are currently the best choice for use in CRISPR/Cas9 delivery vectors owing to their tunability, biocompatibility, and efficiency. As research on biomaterial vectors continues to progress, hope for the application of the CRISPR/Cas9 system for clinical oncology therapy builds. In this review, we first detail the CRISPR/Cas9 system and its potential applications in tumor therapy. Then, we introduce the different delivery forms and compare the physical, viral, and non-viral vectors. In addition, we analyze the characteristics of different types of biomaterial vectors. We further review recent research progress in the use of biomaterials as vectors for CRISPR/Cas9 delivery to treat specific tumors. Finally, we summarize the shortcomings and prospects of biomaterial-based CRISPR/Cas9 delivery systems.

MUSCLE: multi-view and multi-scale attentional feature fusion for microRNA-disease associations prediction.

MicroRNAs (miRNAs) synergize with various biomolecules in human cells resulting in diverse functions in regulating a wide range of biological processes. Predicting potential disease-associated miRNAs as valuable biomarkers contributes to the treatment of human diseases. However, few previous methods take a holistic perspective and only concentrate on isolated miRNA and disease objects, thereby ignoring that human cells are responsible for multiple relationships. In this work, we first constructed a multi-view graph based on the relationships between miRNAs and various biomolecules, and then utilized graph attention neural network to learn the graph topology features of miRNAs and diseases for each view. Next, we added an attention mechanism again, and developed a multi-scale feature fusion module, aiming to determine the optimal fusion results for the multi-view topology features of miRNAs and diseases. In addition, the prior attribute knowledge of miRNAs and diseases was simultaneously added to achieve better prediction results and solve the cold start problem. Finally, the learned miRNA and disease representations were then concatenated and fed into a multi-layer perceptron for end-to-end training and predicting potential miRNA-disease associations. To assess the efficacy of our model (called MUSCLE), we performed 5- and 10-fold cross-validation (CV), which got average the Area under ROC curves of 0.966${\pm }$0.0102 and 0.973${\pm }$0.0135, respectively, outperforming most current state-of-the-art models. We then examined the impact of crucial parameters on prediction performance and performed ablation experiments on the feature combination and model architecture. Furthermore, the case studies about colon cancer, lung cancer and breast cancer also fully demonstrate the good inductive capability of MUSCLE. Our data and code are free available at a public GitHub repository: https://github.com/zht-code/MUSCLE.git.

The reverse zoonosis transfer cycle from the human-animal-plant-environment interface: How antibiotic-resistant bacteria from humans threaten the environment and fuel the rise of superbugs

The uncontrolled use of antibiotics for the treatment of human diseases and animal farming led to a global crisis in the form of the re-emergence of antibiotic-resistant bacteria (ARB). This paper critically explores the reverse zoonosis transfer cycle and highlights facts about ARB in the environment and re-infections in humans. ARB shed by humans through various routes contaminates the environment, where it can persist and even thrive. The contaminated reservoir and various environmental sources aid ARB strains to re-enter the human vicinity and re-infect human populations, where they may be in the healthcare system in the form of resistance to multiple antibiotics. These strains are called “superbugs,” leading to potentially untreatable infections. This paper discusses the evidence for this hypothesis, highlighting the consequences for public health and the environment. Hence, it explores the implications for antibiotic stewardship and emphasizes the urgency of developing alternative strategies to combat antibiotic resistance (AR) and the reverse zoonosis transfer cycle (RZTC).

Current status and progress of research on the ADP-dependent glucokinase gene.

ADP-dependent glucokinase (ADPGK) produces glucose-6-phosphate with adenosine diphosphate (ADP) as the phosphate group donor, in contrast to ATP-dependent hexokinases (HKs). Originally found in archaea, ADPGK is involved in glycolysis. However, its biological function in most eukaryotic organisms is still unclear, and the molecular mechanism of action requires further investigation. This paper provides a concise overview of ADPGK's origin, biological function and clinical application. It aims to furnish scientific information for the diagnosis and treatment of human metabolic diseases, neurological disorders, and malignant tumours, and to suggest new strategies for the development of targeted drugs.

A Multi-Modal Contrastive Diffusion Model for Therapeutic Peptide Generation

Therapeutic peptides represent a unique class of pharmaceutical agents crucial for the treatment of human diseases. Recently, deep generative models have exhibited remarkable potential for generating therapeutic peptides, but they only utilize sequence or structure information alone, which hinders the performance in generation. In this study, we propose a Multi-Modal Contrastive Diffusion model (MMCD), fusing both sequence and structure modalities in a diffusion framework to co-generate novel peptide sequences and structures. Specifically, MMCD constructs the sequence-modal and structure-modal diffusion models, respectively, and devises a multi-modal contrastive learning strategy with inter-contrastive and intra-contrastive in each diffusion timestep, aiming to capture the consistency between two modalities and boost model performance. The inter-contrastive aligns sequences and structures of peptides by maximizing the agreement of their embeddings, while the intra-contrastive differentiates therapeutic and non-therapeutic peptides by maximizing the disagreement of their sequence/structure embeddings simultaneously. The extensive experiments demonstrate that MMCD performs better than other state-of-the-art deep generative methods in generating therapeutic peptides across various metrics, including antimicrobial/anticancer score, diversity, and peptide-docking.

CRISPR/Cas9 Mechanism and Applications Progression

CRISPR (short for Clustered Regularly Interspaced Short Palindromic Repeats) and the accompanying endonuclease Cas9 are potent tools for gene editing in many applied disciplines. The CRISPR/Cas9 system primarily functions through two components, in which the single guide RNA (sgRNA) directs the Cas9 protein with endonuclease activity to carry out precise DNA cleavage. The cell's inherent repair mechanisms allow it to complete the subsequent reconnection of the broken genes. Gene knock-in or knock-out can therefore be achieved via this approach. This system was typically applied to prokaryotes in early studies. Its role as a component of their defense mechanism has been thoroughly studied. With rapid development over the past ten years, this system can now be effectively used in a multitude of eukaryotic cells, including yeast cells and mammalian cells. Because of its accuracy, effectiveness, and low cost, CRISPR/Cas9 has been widely used for human disease treatment and has shown great potential in gene therapies for hereditary diseases. However, since more late-stage clinical trials are required to validate its safety, its applications still face many challenges. This review investigates the mechanism of CRISPR/Cas9-mediated gene editing technology and highlights its recent applications in Alzheimer's disease, Sickle cell disease, and Duchenne muscular dystrophy, which are difficult to treat with current approaches. Some challenges the CRISPR/Cas9 system has encountered at this stage are described, and its prospects are also examined.

Phytochemical Analysis and Potential Inhibitory Property of Tubli (Derris elliptica Benth) Root Extract on Escherichia coli and Staphylococcus aureus

Medicinal plants contain bioactive compounds which are used for the treatment of various human diseases. One of these plants is the Tubli (Derris elliptica Benth) which comes from the genus of the family Papilionaceae locally known in Southeast Asian Countries as "Derris" or Tuba" and "Tubli" or "Tugling-pula" in Philippines. In this paper, is reported inhibitory property of this plant which had been studied against Escherichia coli and Staphylococcus aureus to find new substances with antimicrobial properties. The main purpose of the study was to identify the biochemical compounds of Tubli (Derris elliptica Benth) that inhibit the growth of Escherichia coli and Staphylococcus aureus; to determine the result of the mean average of zone inhibition between Escherichia coli and Staphylococcus aureus and to differentiate the mean average of zone of inhibition between Escherichia coli and Staphylococcus aureus. The experiments conducted used the Completely Randomized Designed (CRD). The data were analyzed using T-Test. Phytochemical analysis of Tubli (D. elliptica Benth) revealed the presence of tannins, flavonoids, alkaloids, saponins, and steroids which contributed to the antimicrobial ability of the root extract. It was found out that Tubli (D. elliptica Benth) was more active against the S. aureus having the total average zone of inhibition of 24.66 mm than the E. coli having the total average zone of inhibition of 20 mm. T-Test revealed that there is a significant difference on zone of inhibitions of the S. aureus and E. coli tested under Tubli (D. elliptica Benth) ethanolic root extract. The presence of phytochemicals suggests that D. elliptica has a potential antimicrobial property that could serve as a natural source of traditional medicine for treatment of various diseases.