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1.
J Sci Food Agric ; 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-38988267

ABSTRACT

BACKGROUND: The stem of Abroma augusta contains mucilaginous polysaccharides having numerous ethnomedicinal properties. The present work aimed to develop a scalable ultrasonic-assisted aqueous Abroma augusta mucilage (AAM) extraction (UAE) method and further explores its emulsifying property and toxicity concern. RESULTS: The combination of ultrasonic power (750 W), solid-to-liquid ratio (1:15) and temperature (348 K) gave the highest extraction yield of 2.28% with a diffusivity value of 3.85 × 10-9 m2 s-1, which was higher than aqueous extraction method using a kinetic model based on Fick's second law of diffusion. The extracted polysaccharide showed no toxicity as measured through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay on RAW cell line. Additionally, the polysaccharide over its critical micelle concentration (400, 500, 600 and 700 µg mL-1) offered emulsifying properties with 0.5%, 1% and 5% oil (v/v). The emulsion with a polysaccharide concentration of 600 µg mL-1 with 5% oil (v/v) provides stability against coalescence for 3 days. CONCLUSION: The overall findings indicated that UAE of AAM polysaccharide can be used for an efficient extraction method, and the obtained polysaccharide is nontoxic in nature and bears emulsifying properties. © 2024 Society of Chemical Industry.

2.
Mini Rev Med Chem ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38982701

ABSTRACT

Globally, one of the most prevalent cancers is colorectal cancer (CRC). Chemotherapy and surgery are two common conventional CRC therapies that are frequently ineffective and have serious adverse effects. Thus, there is a need for complementary and different therapeutic approaches. The use of microbial metabolites to trigger epigenetic alterations as a way of preventing CRC is one newly emerging field of inquiry. Small chemicals called microbial metabolites, which are made by microbes and capable of altering host cell behaviour, are created. Recent research has demonstrated that these metabolites can lead to epigenetic modifications such as histone modifications, DNA methylation, and non-coding RNA regulation, which can control gene expression and affect cellular behaviour. This review highlights the current knowledge on the epigenetic modification for cancer treatment, immunomodulatory and anti-carcinogenic attributes of microbial metabolites, gut epigenetic targeting system, and the role of dietary fibre and gut microbiota in cancer treatment. It also focuses on short-chain fatty acids, especially butyrates (which are generated by microbes), and their cancer treatment perspective, challenges, and limitations, as well as state-of-the-art research on microbial metabolites-induced epigenetic changes for CRC inhibition. In conclusion, the present work highlights the potential of microbial metabolites-induced epigenetic modifications as a novel therapeutic strategy for CRC suppression and guides future research directions in this dynamic field.

3.
Med Rev (2021) ; 4(3): 235-238, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38919399

ABSTRACT

The protein, N-myc downstream-regulated gene 2 (NDRG2), a tumor suppressor, is significantly decreased or absent in many types of cancer. There is a significant negative correlation between the levels of NDRG2 and the development and progression of cancer tumor recurrence and tumor invasion, in different cancers. In contrast, the in vitro and in vivo overexpression of the NDRG2 protein decreases the proliferation, growth, adhesion and migration of many types of cancer cells. The in vitro overexpression of NDRG2 increases the efficacy of certain anticancer drugs in specific types of cancer cells. We hypothesize that the delivery of the mRNA of the NDRG2 protein, encapsulated by lipid nanoparticles, could represent a potential treatment of metastatic and drug-resistant cancers. This would be accomplished using a self-amplifying mRNA that encodes the NDRG2 protein and an RNA-dependent-RNA polymerase, obtained from an in vitrotranscribed (IVT) mRNA. The IVT mRNA would be encapsulated in a lipid nanoformulation. The efficacy of the nanoformulation would be determined in cultured cancer cells and if the results are positive, nude mice transplanted with either drug-resistant or metastatic drug-resistant cancer cells, would be treated with the nano- formulation and monitored for efficacy and adverse effects. If the appropriate preclinical studies indicate this formulation is efficacious and safe, it is possible it could be evaluated in clinical trials.

4.
Gastroenterol Rep (Oxf) ; 12: goae033, 2024.
Article in English | MEDLINE | ID: mdl-38690290

ABSTRACT

Evidence-based research has confirmed the role of gastrointestinal microbiota in regulating intestinal inflammation. These data have generated interest in developing microbiota-based therapies for the prevention and management of inflammatory bowel disease (IBD). Despite in-depth understanding of the etiology of IBD, it currently lacks a cure and requires ongoing management. Accumulating data suggest that an aberrant gastrointestinal microbiome, often referred to as dysbiosis, is a significant environmental instigator of IBD. Novel microbiome-targeted interventions including prebiotics, probiotics, fecal microbiota transplant, and small molecule microbiome modulators are being evaluated as therapeutic interventions to attenuate intestinal inflammation by restoring a healthy microbiota composition and function. In this review, the effectiveness and challenges of microbiome-centered interventions that have the potential to alleviate intestinal inflammation and improve clinical outcomes of IBD are explored.

5.
Cancer Rep (Hoboken) ; 7(5): e2051, 2024 May.
Article in English | MEDLINE | ID: mdl-38702989

ABSTRACT

BACKGROUND: Glioblastomas are characterized by aggressive behavior. Surgery, radiotherapy, and alkylating agents, including temozolomide are the most common treatment options for glioblastoma. Often, conventional therapies fail to treat these tumors since they develop drug resistance. There is a need for newer agents to combat this deadly tumor. Natural products such as gedunin have shown efficacy in several human diseases. A comprehensive study of gedunin, an heat shock protein (HSP)90 inhibitor, has not been thoroughly investigated in glioblastoma cell lines with different genetic modifications. AIMS: A key objective of this study was to determine how gedunin affects the biological and signaling mechanisms in glioblastoma cells, and to determine how those mechanisms affect the proliferation and apoptosis of glioblastoma cells. METHODS: The viability potentials of gedunin were tested using MTT, cell counts, and wound healing assays. Gedunin's effects on glioma cells were further validated using LDH and colony formation assays. In addition, we investigated the survival and apoptotic molecular signaling targets perturbed by gedunin using Western blot analysis and flow cytometry. RESULTS: Our results show that there was a reduction in cell viability and inhibition of wound healing in the cells tested. Western blot analysis of the gene expression data revealed genes such as EGFR and mTOR/Akt/NF kappa B to be associated with gedunin sensitivity. Gedunin treatment induced apoptosis by cleaving poly ADP-ribose polymerase, activating caspases, and downregulating BCL-xL. Based on these results, gedunin suppressed cell growth and HSP client proteins, resulting in apoptosis in glioblastoma cell lines. CONCLUSION: Our data provide in vitro support for the anticancer activity of gedunin in glioma cells by downregulating cancer survival proteins.


Subject(s)
Apoptosis , Cell Proliferation , Glioblastoma , Limonins , Humans , Glioblastoma/pathology , Glioblastoma/drug therapy , Glioblastoma/metabolism , Apoptosis/drug effects , Cell Proliferation/drug effects , Cell Line, Tumor , Signal Transduction/drug effects , HSP90 Heat-Shock Proteins/metabolism , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Brain Neoplasms/pathology , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Cell Survival/drug effects , Antineoplastic Agents/pharmacology
6.
Article in English | MEDLINE | ID: mdl-38784601

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. While there is currently no cure for AD, several pharmacotherapeutic targets and management strategies have been explored. Additionally, traditional medicinal plants have gained attention for their potential role in AD management. Pharmacotherapeutic targets in AD include amyloid-beta (Aß) aggregation, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, and cholinergic dysfunction. Traditional medicinal plants, such as Ginkgo biloba, Huperzia serrata, Curcuma longa (turmeric), and Panax ginseng, have demonstrated the ability to modulate these targets through their bioactive compounds. Ginkgo biloba, for instance, contains flavonoids and terpenoids that exhibit neuroprotective effects by reducing Aß deposition and enhancing cerebral blood flow. Huperzia serrata, a natural source of huperzine A, has acetylcholinesterase-inhibiting properties, thus improving cholinergic function. Curcuma longa, enriched with curcumin, exhibits anti-inflammatory and antioxidant effects, potentially mitigating neuroinflammation and oxidative stress. Panax ginseng's ginsenosides have shown neuroprotective and anti-amyloidogenic properties. The investigation of traditional medicinal plants as a complementary approach to AD management offers several advantages, including a lower risk of adverse effects and potential multi-target interactions. Furthermore, the cultural knowledge and utilization of these plants provide a rich source of information for the development of new therapies. However, further research is necessary to elucidate the precise mechanisms of action, standardize preparations, and assess the safety and efficacy of these natural remedies. Integrating traditional medicinal-plant-based therapies with modern pharmacotherapies may hold the key to a more comprehensive and effective approach to AD treatment. This review aims to explore the pharmacotherapeutic targets in AD and assess the potential of traditional medicinal plants in its management.

7.
Expert Opin Drug Deliv ; 21(5): 695-712, 2024 May.
Article in English | MEDLINE | ID: mdl-38787783

ABSTRACT

INTRODUCTION: Retinal drug delivery has witnessed significant advancements in recent years, mainly driven by the prevalence of retinal diseases and the need for more efficient and patient-friendly treatment strategies. AREAS COVERED: Advancements in nanotechnology have introduced novel drug delivery platforms to improve bioavailability and provide controlled/targeted delivery to specific retinal layers. This review highlights various treatment options for retinal diseases. Additionally, diverse strategies aimed at enhancing delivery of small molecules and antibodies to the posterior segment such as implants, polymeric nanoparticles, liposomes, niosomes, microneedles, iontophoresis and mixed micelles were emphasized. A comprehensive overview of the special technologies currently under clinical trials or already in the clinic was provided. EXPERT OPINION: Ideally, drug delivery system for treating retinal diseases should be less invasive in nature and exhibit sustained release up to several months. Though topical administration in the form of eye drops offers better patient compliance, its clinical utility is limited by nature of the drug. There is a wide range of delivery platforms available, however, it is not easy to modify any single platform to accommodate all types of drugs. Coordinated efforts between ophthalmologists and drug delivery scientists are necessary while developing therapeutic compounds, right from their inception.


Subject(s)
Drug Delivery Systems , Retinal Diseases , Humans , Retinal Diseases/drug therapy , Animals , Nanotechnology , Biological Availability , Ophthalmic Solutions/administration & dosage , Administration, Ophthalmic , Pharmaceutical Preparations/administration & dosage , Delayed-Action Preparations , Nanoparticles
8.
Crit Rev Ther Drug Carrier Syst ; 41(5): 111-150, 2024.
Article in English | MEDLINE | ID: mdl-38608134

ABSTRACT

Meloxicam, a selective COX-2 inhibitor, has demonstrated clinical effectiveness in managing inflammation and acute pain. Although available in oral and parenteral formulations such as capsule, tablet, suspension, and solution, frequent administration is necessary to maintain therapeutic efficacy, which can increase adverse effects and patient non-compliance. To address these issues, several sustained drug delivery strategies such as oral, transdermal, transmucosal, injectable, and implantable drug delivery systems have been developed for meloxicam. These sustained drug delivery strategies have the potential to improve the therapeutic efficacy and safety profile of meloxicam, thereby reducing the frequency of dosing and associated gastrointestinal side effects. The choice of drug delivery system will depend on the desired release profile, the target site of inflammation, and the mode of administration. Overall, meloxicam sustained delivery systems offer better patient compliance, and reduce the side effects, thereby improving the clinical applications of this drug. Herein, we discuss in detail different strategies for sustained delivery of meloxicam.


Subject(s)
Acute Pain , Analgesics , Humans , Meloxicam , Drug Delivery Systems , Inflammation
9.
Cancer Rep (Hoboken) ; 7(4): e2074, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38627904

ABSTRACT

BACKGROUND: Iatrogenesis is an inevitable global threat to healthcare that drastically increases morbidity and mortality. Cancer is a fatal pathological condition that affects people of different ages, sexes, and races around the world. In addition to the detrimental cancer pathology, one of the most common contraindications and challenges observed in cancer patients is severe adverse drug effects and hypersensitivity reactions induced by chemotherapy. Chemotherapy-induced cognitive neurotoxicity is clinically referred to as Chemotherapy-induced cognitive impairment (CICI), chemobrain, or chemofog. In addition to CICI, chemotherapy also causes neuropsychiatric issues, mental disorders, hyperarousal states, and movement disorders. A synergistic chemotherapy regimen of Doxorubicin (Anthracycline-DOX) and Cyclophosphamide (Alkylating Cytophosphane-CPS) is indicated for the management of various cancers (breast cancer, lymphoma, and leukemia). Nevertheless, there are limited research studies on Doxorubicin and Cyclophosphamide's pharmacodynamic and toxicological effects on dopaminergic neuronal function. AIM: This study evaluated the dopaminergic neurotoxic effects of Doxorubicin and Cyclophosphamide. METHODS AND RESULTS: Doxorubicin and Cyclophosphamide were incubated with dopaminergic (N27) neurons. Neuronal viability was assessed using an MTT assay. The effect of Doxorubicin and Cyclophosphamide on various prooxidants, antioxidants, mitochondrial Complex-I & IV activities, and BAX expression were evaluated by Spectroscopic, Fluorometric, and RT-PCR methods, respectively. Prism-V software (La Jolla, CA, USA) was used for statistical analysis. Chemotherapeutics dose-dependently inhibited the proliferation of the dopaminergic neurons. The dopaminergic neurotoxic mechanism of Doxorubicin and Cyclophosphamide was attributed to a significant increase in prooxidants, a decrease in antioxidants, and augmented apoptosis without affecting mitochondrial function. CONCLUSION: This is one of the first reports that reveal Doxorubicin and Cyclophosphamide induce significant dopaminergic neurotoxicity. Thus, Chemotherapy-induced adverse drug reaction issues substantially persist during and after treatment and sometimes never be completely resolved clinically. Consequently, failure to adopt adequate patient care measures for cancer patients treated with certain chemotherapeutics might substantially raise the incidence of numerous movement disorders.


Subject(s)
Breast Neoplasms , Drug-Related Side Effects and Adverse Reactions , Movement Disorders , Humans , Female , Cyclophosphamide/adverse effects , Anthracyclines/therapeutic use , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Antibiotics, Antineoplastic , Doxorubicin/pharmacology , Breast Neoplasms/pathology , Movement Disorders/drug therapy
10.
Environ Sci Pollut Res Int ; 31(19): 27509-27530, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38573572

ABSTRACT

Catastrophic oil spill is one of the major issues to the environment. Various methods have been used to treat oil spillage including in situ burning, the use of skimmers, dispersants, bioremediation, dispersing agents, oil sorbents, and biological agents. Application of oil sorbent is one of the effective solutions in oil spill clean-up. Polymers are sustainable extraordinary materials for the treatment of oil spillage due to their special physicochemical characteristics such as high porosity, good hydrophobicity, and reusability. Polymers are modified using suitable chemical reagents and their hydrophobicity is enhanced, making them suitable for oil spill clean-up. The present manuscript is an attempt to summarize the study of chemical modifications done on a polymer polyurethane (PU) for achieving the desirable properties, for efficient oil spill clean-up. A patent analysis has been carried out for the leading countries, top inventors, leading assignees, trends of patent publications, citation analysis, and summary of granted patents in the area of the use of a polymer Polyurethane (PU) for oil spill clean-up.


Subject(s)
Environmental Restoration and Remediation , Petroleum Pollution , Polyurethanes , Polyurethanes/chemistry , Environmental Restoration and Remediation/methods
11.
AAPS PharmSciTech ; 25(2): 28, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38302687

ABSTRACT

Cyclosporine A (CsA) is a cyclic peptide immunosuppressant drug that is beneficial in the treatment of various ocular diseases. However, its ocular bioavailability in the posterior eye is limited due to its poor aqueous solubility. Conventional CsA formulations such as a solution or emulsion permeate poorly across the eye due to various static and dynamic barriers of the eye. Dissolvable microneedle (MN)-based patches can be used to overcome barrier properties and, thus, enhance the ocular bioavailability of CsA in the posterior eye. CsA-loaded dissolvable MN patches were fabricated using polyvinylpyrrolidone (PVP) and characterized for MN uniformity and sharpness using SEM. Further characterization for its failure force, penetration force, and depth of penetration were analyzed using a texture analyzer. Finally, the dissolution time, ex vivo permeation, and ocular distribution of cyclosporine were determined in isolated porcine eyes. PVP MNs were sharp, uniform with good mechanical properties, and dissolved within 5 min. Ocular distribution of CsA in a whole porcine eye perfusion model showed a significant increase of CsA levels in various posterior segment ocular tissues as compared to a topically applied ophthalmic emulsion (Restasis®) (P < 0.001). Dissolving MNs of CsA were prepared, and the MN arrays can deliver CsA to the back of the eye offering potential for treating various inflammatory diseases.


Subject(s)
Cyclosporine , Eye , Animals , Swine , Emulsions , Immunosuppressive Agents , Drug Delivery Systems
12.
Mini Rev Med Chem ; 24(15): 1449-1468, 2024.
Article in English | MEDLINE | ID: mdl-38343053

ABSTRACT

Chemotherapy is still the major method of treatment for many types of cancer. Curative cancer therapy is hampered significantly by medication resistance. Acidic organelles like lysosomes serve as protagonists in cellular digestion. Lysosomes, however, are gaining popularity due to their speeding involvement in cancer progression and resistance. For instance, weak chemotherapeutic drugs of basic nature permeate through the lysosomal membrane and are retained in lysosomes in their cationic state, while extracellular release of lysosomal enzymes induces cancer, cytosolic escape of lysosomal hydrolases causes apoptosis, and so on. Drug availability at the sites of action is decreased due to lysosomal drug sequestration, which also enhances cancer resistance. This review looks at lysosomal drug sequestration mechanisms and how they affect cancer treatment resistance. Using lysosomes as subcellular targets to combat drug resistance and reverse drug sequestration is another method for overcoming drug resistance that is covered in this article. The present review has identified lysosomal drug sequestration as one of the reasons behind chemoresistance. The article delves deeper into specific aspects of lysosomal sequestration, providing nuanced insights, critical evaluations, or novel interpretations of different approaches that target lysosomes to defect cancer.


Subject(s)
Antineoplastic Agents , Drug Resistance, Neoplasm , Lysosomes , Neoplasms , Humans , Lysosomes/metabolism , Lysosomes/drug effects , Drug Resistance, Neoplasm/drug effects , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Animals
13.
Mini Rev Med Chem ; 24(15): 1409-1426, 2024.
Article in English | MEDLINE | ID: mdl-38385496

ABSTRACT

Prostate cancer is a widespread malignancy among men, with a substantial global impact on morbidity and mortality. Despite advances in conventional therapies, the need for innovative and less toxic treatments remains a priority. Emerging evidence suggests that dietary plant metabolites possess epigenetic-modifying properties, making them attractive candidates for prostate cancer treatment. The present work reviews the epigenetic effects of dietary plant metabolites in the context of prostate cancer therapy. We first outline the key epigenetic mechanisms involved in prostate cancer pathogenesis, including histone modifications, DNA methylation, and miRNA or Long Noncoding RNA (lncRNA) dysregulation. Next, we delve into the vast array of dietary plant metabolites that have demonstrated promising anti-cancer effects through epigenetic regulation. Resveratrol, minerals, isothiocyanates, curcumin, tea polyphenols, soy isoflavones and phytoestrogens, garlic compounds, anthocyanins, lycopene, and indoles are among the most extensively studied compounds. These plant-derived bioactive compounds have been shown to influence DNA methylation patterns, histone modifications, and microRNA expression, thereby altering the gene expression allied with prostate cancer progression, cell proliferation, and apoptosis. We also explore preclinical and clinical studies investigating the efficacy of dietary plant metabolites as standalone treatments or in combination with traditional treatments for people with prostate cancer. The present work highlights the potential of dietary plant metabolites as epigenetic modulators to treat prostate cancer. Continued research in this field may pave the way for personalized and precision medicine approaches, moving us closer to the goal of improved prostate cancer management.


Subject(s)
Epigenesis, Genetic , Prostatic Neoplasms , Male , Humans , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Epigenesis, Genetic/drug effects , DNA Methylation/drug effects , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry
14.
Curr Top Med Chem ; 24(6): 523-540, 2024.
Article in English | MEDLINE | ID: mdl-38258788

ABSTRACT

Scientists are constantly researching and launching potential chemotherapeutic agents as an irreplaceable weapon to fight the battle against cancer. Despite remarkable advancement over the past several decades to wipe out cancer through early diagnosis, proper prevention, and timely treatment, cancer is not ready to give up and leave the battleground. It continuously tries to find some other way to give a tough fight for its survival, either by escaping from the effect of chemotherapeutic drugs or utilising its own chemical messengers like cytokines to ensure resistance. Cytokines play a significant role in cancer cell growth and progression, and the present article highlights their substantial contribution to mechanisms of resistance toward therapeutic drugs. Multiple clinical studies have even described the importance of specific cytokines released from cancer cells as well as stromal cells in conferring resistance. Herein, we discuss the different mechanism behind drug resistance and the crosstalk between tumor development and cytokines release and their contribution to showing resistance towards chemotherapeutics. As a part of this review, different approaches to cytokines profile have been identified and employed to successfully target new evolving mechanisms of resistance and their possible treatment options.


Subject(s)
Antineoplastic Agents , Cytokines , Drug Resistance, Neoplasm , Neoplasms , Humans , Drug Resistance, Neoplasm/drug effects , Cytokines/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry
15.
Immunol Rev ; 321(1): 228-245, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37903748

ABSTRACT

Ferroptosis is a novel form of programmed cell death morphologically, genetically, and biochemically distinct from other cell death pathways and characterized by the accumulation of iron-dependent lipid peroxides and oxidative damage. It is now understood that ferroptosis plays an essential role in various biological processes, especially in the metabolism of iron, lipids, and amino acids. Gastric cancer (GC) is a prevalent malignant tumor worldwide with low early diagnosis rates and high metastasis rates, accounting for its relatively poor prognosis. Although chemotherapy is commonly used to treat GC, drug resistance often leads to poor therapeutic outcomes. In the last several years, extensive research on ferroptosis has highlighted its significant potential in GC therapy, providing a promising strategy to address drug resistance associated with standard cancer therapies. In this review, we offer an extensive summary of the key regulatory factors related to the mechanisms underlying ferroptosis. Various inducers and inhibitors specifically targeting ferroptosis are uncovered. Additionally, we explore the prospective applications and outcomes of these agents in the field of GC therapy, emphasizing their capacity to improve the outcomes of this patient population.


Subject(s)
Ferroptosis , Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Amino Acids , Apoptosis , Iron
16.
Clin Genet ; 105(2): 226-227, 2024 02.
Article in English | MEDLINE | ID: mdl-37849383

ABSTRACT

We report the third case of FADS due to biallelic DOK7 variants, which further strengthens the association of DOK7 with this lethal phenotype and lack of genotype phenotype correlation.


Subject(s)
Arthrogryposis , Humans , Arthrogryposis/genetics , Phenotype , Muscle Proteins/genetics
17.
Mol Cancer Ther ; 23(4): 464-477, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38151817

ABSTRACT

Histone deacetylase inhibitors (HDACi) are part of a growing class of epigenetic therapies used for the treatment of cancer. Although HDACis are effective in the treatment of T-cell lymphomas, treatment of solid tumors with this class of drugs has not been successful. Overexpression of the multidrug resistance protein P-glycoprotein (P-gp), encoded by ABCB1, is known to confer resistance to the HDACi romidepsin in vitro, yet increased ABCB1 expression has not been associated with resistance in patients, suggesting that other mechanisms of resistance arise in the clinic. To identify alternative mechanisms of resistance to romidepsin, we selected MCF-7 breast cancer cells with romidepsin in the presence of the P-gp inhibitor verapamil to reduce the likelihood of P-gp-mediated resistance. The resulting cell line, MCF-7 DpVp300, does not express P-gp and was found to be selectively resistant to romidepsin but not to other HDACis such as belinostat, panobinostat, or vorinostat. RNA-sequencing analysis revealed upregulation of the mRNA coding for the putative methyltransferase, METTL7A, whose paralog, METTL7B, was previously shown to methylate thiol groups on hydrogen sulfide and captopril. As romidepsin has a thiol as the zinc-binding moiety, we hypothesized that METTL7A could inactivate romidepsin and other thiol-based HDACis via methylation of the thiol group. We demonstrate that expression of METTL7A or METTL7B confers resistance to thiol-based HDACis and that both enzymes are capable of methylating thiol-containing HDACis. We thus propose that METTL7A and METTL7B confer resistance to thiol-based HDACis by methylating and inactivating the zinc-binding thiol.


Subject(s)
Histone Deacetylase Inhibitors , Neoplasms , Humans , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Methyltransferases/metabolism , Neoplasms/drug therapy , Panobinostat/pharmacology , Panobinostat/therapeutic use , Zinc
18.
Curr Microbiol ; 81(1): 1, 2023 Nov 08.
Article in English | MEDLINE | ID: mdl-37935938

ABSTRACT

Consumption of probiotics, which are beneficial live microorganisms, has received a lot of attention because of their potential to improve health and wellness. Robust quality control measures are necessary to ensure the safety of probiotics and maximize their health effects. This review delves into the topic of quality management in probiotics, highlighting the significance of sticking to strict guidelines from manufacture to storage to distribution. Probiotic quality standards, Good Manufacturing Practices (GMP) implementation, quality control and testing techniques, and documentation and traceability systems are all discussed in detail. The importance of taking precautions to avoid microbial contamination, meeting all applicable regulations, and clearly marking and packaging probiotic products is also emphasized. In addition, it reviews the clinical evidence supporting the possible health advantages of probiotics and investigates the processes through which probiotics enhance health. The review continues by stressing the significance of educating and informing consumers about probiotics and their proper use in order to maximize health benefits. Probiotics' potential health benefits can be maximized and consumer faith in these helpful microbes can be bolstered by adopting thorough quality management measures to ensure their safety, efficacy, and consistency.


Subject(s)
Probiotics , Probiotics/standards
19.
Eur J Med Genet ; 66(12): 104888, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37993095

ABSTRACT

Non-immune hydrops fetalis (NIHF) is abnormal accumulation of serous fluid in ≥2 interstitial spaces with no evidence of maternal red cell alloimmunization. Leaving a few treatable conditions, it is generally considered as a sign of poor fetal outcome. Bi-allelic variants in THSD1 have been found to be to be associated with phenotypes ranging from lethal NIHF to persistent edema. Here, we report a family with non-immune hydrops in two successive pregnancies. Whole exome sequencing in second pregnancy identified a homozygous truncating variant in THSD1 (NM_018676:c.892G>T:p.Glu298Ter). Postnatal follow up showed gradual resolution of the accumulated fluid and normal development. This report further strengthens the association of variants in THSD1 with NIHF.


Subject(s)
Fetus , Hydrops Fetalis , Pregnancy , Female , Humans , Hydrops Fetalis/genetics , Exome Sequencing , Homozygote , Phenotype
20.
AAPS PharmSciTech ; 24(7): 200, 2023 Oct 02.
Article in English | MEDLINE | ID: mdl-37783858

ABSTRACT

Diet-induced obesity and hyperlipidemia are a growing public health concern leading to various metabolic disorders. Capsaicin, a major bioactive compound obtained from natural chili peppers, has demonstrated its numerous beneficial roles in treating obesity and weight loss. Current treatment involves either administration of antiobesity drugs or surgical procedures such as Roux-en-Y-gastric bypass or sleeve gastrectomy, both of which are associated with serious side effects and poor patient acceptance. Capsaicin, a pungent molecule, has low oral bioavailability. Therefore, there is a need for the development of site-specific drug delivery system for capsaicin. The present study is aimed at preparing and characterizing 3D-printed capsaicin-loaded rod-shaped implants by thermoplastic extrusion-based 3D printing technology. The implants were printed with capsaicin-loaded into a biodegradable polymer, polycaprolactone, at different drug loadings and infill densities. The surface morphology revealed a smooth and uniform external surface without any capsaicin crystals. DSC thermograms showed no significant changes/exothermic events among the blends suggesting no drug polymer interactions. The in vitro release studies showed a biphasic release profile for capsaicin, and the release was sustained for more than three months (~ 85% released) irrespective of drug loading and infill densities. The HPLC method was stability-indicating and showed good resolution for its analogs, dihydrocapsaicin and nordihydrocapsaicin. The implants were stable for three months at accelerated conditions (40°C) without any significant decrease in the assay of capsaicin. Therefore, capsaicin-loaded implants can serve as a long-acting injectable formulation for targeting the adipose tissue region in obese patients.


Subject(s)
Capsaicin , Obesity , Humans , Capsaicin/chemistry , Obesity/drug therapy , Drug Delivery Systems , Printing, Three-Dimensional , Polymers/therapeutic use , Drug Liberation
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