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Pharmaceutics May 2024This review explores the intersection of microfluidic technology and complex emulsion development as a promising solution to the challenges of formulations in multi-drug... (Review)
Review
This review explores the intersection of microfluidic technology and complex emulsion development as a promising solution to the challenges of formulations in multi-drug therapy (MDT) and polypharmacy. The convergence of microfluidic technology and complex emulsion fabrication could herald a transformative era in multi-drug delivery systems, directly confronting the prevalent challenges of polypharmacy. Microfluidics, with its unparalleled precision in droplet formation, empowers the encapsulation of multiple drugs within singular emulsion particles. The ability to engineer emulsions with tailored properties-such as size, composition, and release kinetics-enables the creation of highly efficient drug delivery vehicles. Thus, this innovative approach not only simplifies medication regimens by significantly reducing the number of necessary doses but also minimizes the pill burden and associated treatment termination-issues associated with polypharmacy. It is important to bring forth the opportunities and challenges of this synergy between microfluidic-driven complex emulsions and multi-drug therapy poses. Together, they not only offer a sophisticated method for addressing the intricacies of delivering multiple drugs but also align with broader healthcare objectives of enhancing treatment outcomes, patient safety, and quality of life, underscoring the importance of dosage form innovations in tackling the multifaceted challenges of modern pharmacotherapy.
PubMed: 38931830
DOI: 10.3390/pharmaceutics16060707 -
Molecules (Basel, Switzerland) Jun 2024Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a crucial tumor suppressor protein with frequent mutations and alterations. Although protein...
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a crucial tumor suppressor protein with frequent mutations and alterations. Although protein therapeutics are already integral to numerous medical fields, their potential remains nascent. This study aimed to investigate the impact of stable, unphosphorylated recombinant human full-length PTEN and its truncated variants, regarding their tumor suppression activity with multiwalled-carbon nanotubes (MW-CNTs) as vehicles for their delivery in breast cancer cells (T-47D, ZR-75-1, and MCF-7). The cloning, overexpression, and purification of PTEN variants were achieved from , followed by successful binding to CNTs. Cell incubation with protein-functionalized CNTs revealed that the full-length PTEN-CNTs significantly inhibited cancer cell growth and stimulated apoptosis in ZR-75-1 and MCF-7 cells, while truncated PTEN fragments on CNTs had a lesser effect. The N-terminal fragment, despite possessing the active site, did not have the same effect as the full length PTEN, emphasizing the necessity of interaction with the C2 domain in the C-terminal tail. Our findings highlight the efficacy of full-length PTEN in inhibiting cancer growth and inducing apoptosis through the alteration of the expression levels of key apoptotic markers. In addition, the utilization of carbon nanotubes as a potent PTEN protein delivery system provides valuable insights for future applications in in vivo models and clinical studies.
Topics: PTEN Phosphohydrolase; Nanotubes, Carbon; Humans; Breast Neoplasms; Female; Apoptosis; Cell Line, Tumor; Cell Proliferation; MCF-7 Cells; Antineoplastic Agents
PubMed: 38930850
DOI: 10.3390/molecules29122785 -
International Journal of Environmental... May 2024Drugged driving, the act of driving a vehicle under the influence of illicit drugs, by adolescents is a serious public health concern. Many factors contribute to this...
Drugged driving, the act of driving a vehicle under the influence of illicit drugs, by adolescents is a serious public health concern. Many factors contribute to this risk behavior, but much less is known regarding the role of parenting behaviors in this phenomenon. The purpose of this study was to examine specific parenting behaviors and their influence among a nationally representative sample of adolescents. Pooled data from the 2016-2019 National Survey on Drug Use and Health (NSDUH) among 17,520 adolescents ages 16-17 years old were analyzed. Differences were found in specific parenting behaviors and adolescent drugged/drunk driving, with parents not checking homework and not telling their children they are proud of them being the most influential. Findings from the present study may inform drugged driving prevention programs for parents and adolescents and enhance road safety interventions.
Topics: Humans; Adolescent; Parenting; United States; Female; Male; Driving Under the Influence; Adolescent Behavior; Automobile Driving; Risk-Taking; Substance-Related Disorders
PubMed: 38928941
DOI: 10.3390/ijerph21060695 -
International Journal of Molecular... Jun 2024Oil-Gan is the fruit of the genus L. The fruits have excellent effects on health care and development values. There are many methods for the management of diabetic...
Oil-Gan is the fruit of the genus L. The fruits have excellent effects on health care and development values. There are many methods for the management of diabetic nephropathy (DN). However, there is a lack of effective drugs for treating DN throughout the disease course. The primary aim of this study was to examine the protective effects (including analyses of urine and blood, and inflammatory cytokine levels) and mechanisms of the ethyl acetate extract of (EPE) on db/db mice, an animal model of diabetic nephropathy; the secondary aim was to examine the expression levels of p- protein kinase Cα (PKCα)/t-PKCα in the kidney and its downregulation of vascular endothelial growth factor (VEGF) and fibrosis gene transforming growth factor-β1 (TGF-β1) by Western blot analyses. Eight db/m mice were used as the control group. Forty db/db mice were randomly divided into five groups. Treatments included a vehicle, EPE1, EPE2, EPE3 (at doses of 100, 200, or 400 mg/kg EPE), or the comparative drug aminoguanidine for 8 weeks. After 8 weeks of treatment, the administration of EPE to db/db mice effectively controlled hyperglycemia and hyperinsulinemia by markedly lowering blood glucose, insulin, and glycosylated HbA1c levels. The administration of EPE to db/db mice decreased the levels of BUN and creatinine both in blood and urine and reduced urinary albumin excretion and the albumin creatine ratio (UACR) in urine. Moreover, EPE treatment decreased the blood levels of inflammatory cytokines, including kidney injury molecule-1 (KIM-1), C-reactive protein (CRP), and NLR family pyrin domain containing 3 (NLRP3). Our findings showed that EPE not only had antihyperglycemic effects but also improved renal function in db/db mice. A histological examination of the kidney by immunohistochemistry indicated that EPE can improve kidney function by ameliorating glomerular morphological damage following glomerular injury; alleviating proteinuria by upregulating the expression of nephrin, a biomarker of early glomerular damage; and inhibiting glomerular expansion and tubular fibrosis. Moreover, the administration of EPE to db/db mice increased the expression levels of p- PKCα/t-PKCα but decreased the expression levels of VEGF and renal fibrosis biomarkers (TGF-β1, collagen IV, p-Smad2, p-Smad3, and Smad4), as shown by Western blot analyses. These results implied that EPE as a supplement has a protective effect against renal dysfunction through the amelioration of insulin resistance as well as the suppression of nephritis and fibrosis in a DN model.
Topics: Animals; Diabetic Nephropathies; Plant Extracts; Mice; Phyllanthus emblica; Male; Disease Models, Animal; Diabetes Mellitus, Experimental; Acetates; Vascular Endothelial Growth Factor A; Kidney; Transforming Growth Factor beta1; Protein Kinase C-alpha; Blood Glucose
PubMed: 38928391
DOI: 10.3390/ijms25126686 -
International Journal of Molecular... Jun 2024Ruthenium chloride (RuCl) is widely utilized for synthesis and catalysis of numerous compounds in academia and industry and is utilized as a key molecule in a variety of...
Ruthenium chloride (RuCl) is widely utilized for synthesis and catalysis of numerous compounds in academia and industry and is utilized as a key molecule in a variety of compounds with medical applications. Interestingly, RuCl has been demonstrated to modulate human plasmatic coagulation and serves as a constituent of a compounded inorganic antivenom that neutralizes the coagulopathic effects of snake venom in vitro and in vivo. Using thrombelastography, this investigation sought to determine if RuCl inhibition of the fibrinogenolytic effects of venom could be modulated by vehicle composition in human plasma. Venom was exposed to RuCl in 0.9% NaCl, phosphate-buffered saline (PBS), or 0.9% NaCl containing 1% dimethyl sulfoxide (DMSO). RuCl inhibited venom-mediated delay in the onset of thrombus formation, decreased clot growth velocity, and decreased clot strength. PBS and DMSO enhanced the effects of RuCl. It is concluded that while a Ru-based cation is responsible for significant inhibition of venom activity, a combination of Ru-based ions containing phosphate and DMSO enhances RuCl-mediated venom inhibition. Additional investigation is indicated to determine what specific Ru-containing molecules cause venom inhibition and what other combinations of inorganic/organic compounds may enhance the antivenom effects of RuCl.
Topics: Humans; Dimethyl Sulfoxide; Antivenins; Crotalid Venoms; Animals; Blood Coagulation; Crotalus; Ruthenium Compounds; Sodium Chloride; Thrombelastography; Venomous Snakes
PubMed: 38928132
DOI: 10.3390/ijms25126426 -
Biomedicines May 2024A sodium current (I) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia...
A sodium current (I) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia risks. The sodium channel blocker mexiletine has been shown to restore the trafficking of mutant sodium channels to the membrane. However, these studies were mostly performed in heterologous expression systems using high mexiletine concentrations. Moreover, the chronic effects on I in a non-diseased cardiomyocyte environment remain unknown. In this paper, we investigated the chronic and acute effects of a therapeutic dose of mexiletine on I and the action potential (AP) characteristics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of a healthy individual. Control hiPSC-CMs were incubated for 48 h with 10 µM mexiletine or vehicle. Following the wash-out of mexiletine, patch clamp analysis and immunocytochemistry experiments were performed. The incubation of hiPSC-CMs for 48 h with mexiletine (followed by wash-out) induced a significant increase in peak I of ~75%, without any significant change in the voltage dependence of (in)activation. This was accompanied by a significant increase in AP upstroke velocity, without changes in other AP parameters. The immunocytochemistry experiments showed a significant increase in membrane Na1.5 fluorescence following a 48 h incubation with mexiletine. The acute re-exposure of hiPSC-CMs to 10 µM mexiletine resulted in a small but significant increase in AP duration, without changes in AP upstroke velocity, peak I density, or the I voltage dependence of (in)activation. Importantly, the increase in the peak I density and resulting AP upstroke velocity induced by chronic mexiletine incubation was not counteracted by the acute re-administration of the drug. In conclusion, the chronic administration of a clinically relevant concentration of mexiletine increases I density in non-diseased hiPSC-CMs, likely by enhancing the membrane trafficking of sodium channels. Our findings identify mexiletine as a potential therapeutic strategy to enhance and/or restore I and cardiac conduction.
PubMed: 38927420
DOI: 10.3390/biomedicines12061212 -
Biomedicines May 2024Glioblastoma (GBM) is a fatal astrocytic glioma with poor prognosis and treatment resistance. Repurposing potential FDA-approved drugs like anti-psychotics can address...
Glioblastoma (GBM) is a fatal astrocytic glioma with poor prognosis and treatment resistance. Repurposing potential FDA-approved drugs like anti-psychotics can address the concerns in a timely and cost-effective manner. Epidemiological studies have shown that patients with schizophrenic using anti-psychotics have a low incidence of GBM. Therefore, we aimed to investigate the therapeutic potential of atypical anti-psychotic Iloperidone (ILO) alone and in combination with Temozolomide (TMZ) against GBM. The study assessed the growth inhibitory effect of ILO, TMZ, and their combination (ILO + TMZ) on U-87MG and T-98G cell lines using an MTT assay. The drug interaction coefficient (CDI) was determined, and doses with synergistic effects were used for subsequent experiments, including migratory, invasion, and TUNEL assays. The expressions of DRD2, β-catenin, Dvl2, Twist, and Slug were assessed by RTq-PCR, whereas the β-catenin protein expression was also determined by immunocytochemistry. ILO ( < 0.05) and TMZ ( < 0.01) significantly inhibited the growth of U-87MG cells at all tested doses. The combination of 60 µM of both drugs showed synergistic activity with CDI < 1. The inhibition of migration and apoptosis was more pronounced in the case of combination treatment ( < 0.001). Inhibition of the invading cells was also found to be significant in ILO- and combination-treated groups ( < 0.001). ILO and combination treatment also significantly downregulated the expression of DRD2, while TMZ upregulated the expression ( < 0.001). The expressions of β-catenin ( < 0.001), Dvl2 ( < 0.001), Twist ( < 0.001), and Slug ( < 0.001) were also significantly downregulated in all treatment groups as compared to the vehicle control. The data suggest that ILO possesses strong growth inhibitory activity, possibly due to its effect on DRD2 and β-catenin expression and has the potential to be repurposed against GBM.
PubMed: 38927341
DOI: 10.3390/biomedicines12061134 -
Biomolecules Jun 2024Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of...
Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4 T cells, CD8 T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1β and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1β and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease.
Topics: Animals; Angiotensin II; Aortic Aneurysm, Abdominal; Mice; Male; Sulfonamides; Apolipoproteins E; Phosphate-Binding Proteins; Disease Models, Animal; Mice, Inbred C57BL; Macrophages; Indoles; Mice, Knockout, ApoE; Gasdermins
PubMed: 38927129
DOI: 10.3390/biom14060726 -
Journal of Nanobiotechnology Jun 2024The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell...
BACKGROUND
The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell transplantation, thus making exosomes promising candidates for large-scale clinical implementation and commercialization. However, exosome extraction and purification efficiencies are relatively low, and therapeutic heterogeneity is high due to differences in culture conditions and cell viability. Therefore, in this study, we investigated a priming procedure to enhance the production and therapeutic effects of exosomes from human umbilical cord mesenchymal stem cells (hucMSCs). After preconditioning hucMSCs with agonists/inhibitors that target the Wnt/β-catenin pathway, we assessed both the production of exosomes and the therapeutic efficacy of the optimized exosomes in the context of diabetic wound healing, hoping to provide a safer, more stable and more effective option for clinical application.
RESULTS
The Wnt signalling pathway agonist CHIR99021 increased exosome production by 1.5-fold without causing obvious changes in the characteristics of the hucMSCs or the size of the exosome particles. Further studies showed that CHIR99021 promoted the production of exosomes by facilitating exocytosis. This process was partly mediated by SNAP25. To further explore whether CHIR99021 changed the cargo that was loaded into the exosomes and its therapeutic effects, we performed proteomic and transcriptomic analyses of exosomes from primed and control hucMSCs. The results showed that CHIR99021 significantly upregulated the expression of proteins that are associated with cell migration and wound healing. Animal experiments confirmed that, compared to control hucMSC-derived exosomes, CHIR99021-pretreated hucMSC-derived exosomes (CHIR-Exos) significantly accelerated wound healing in diabetic mice, enhanced local collagen deposition, promoted angiogenesis, and reduced chronic inflammation. Subsequent in vitro experiments confirmed that the CHIR-Exos promoted wound healing by facilitating cell migration, inhibiting oxidative stress-induced apoptosis, and preventing cell cycle arrest.
CONCLUSIONS
The Wnt agonist CHIR99021 significantly increased exosome secretion by hucMSCs, which was partly mediated by SNAP25. Notably, CHIR99021 treatment also significantly increased the exosomal levels of proteins that are associated with wound healing and cell migration, resulting in enhanced acceleration of wound healing. All of these results suggested that pretreatment of hucMSCs with CHIR99021 not only promoted exosome production but also improved the exosome therapeutic efficacy, thus providing a promising option for large-scale clinical implementation and commercialization.
Topics: Exosomes; Wound Healing; Mesenchymal Stem Cells; Humans; Animals; Wnt Signaling Pathway; Mice; Umbilical Cord; Pyridines; Diabetes Mellitus, Experimental; Pyrimidines; Male; Cells, Cultured; Cell Movement
PubMed: 38926800
DOI: 10.1186/s12951-024-02650-x -
Discovery Medicine Jun 2024Alzheimer's disease (AD) affects the brain and causes difficulties with cognition and emotions. At present, there are no viable therapies to halt or slow down the...
BACKGROUND
Alzheimer's disease (AD) affects the brain and causes difficulties with cognition and emotions. At present, there are no viable therapies to halt or slow down the advancement of AD. Metallothionein III (MT-III) exhibits antioxidant and anti-inflammatory characteristics, indicating possible therapeutic benefits. This study aimed to explore the influence of MT-III on AD pathological alterations and cognitive abilities.
METHODS
In this research, we employed the universally accepted AD mouse models (3xTg-AD) as test subjects and administrated vehicle or MT-III. The mice were subjected to the Morris water maze test to assess their spatial learning and memory capabilities. Moreover, to evaluate the consequent effects on neuronal groups in the hippocampus, the Nissl staining and neuronal nuclear antigen (NeuN) immunohistochemistry were used to identify the cellular morphology changes and density. Immunohistochemistry was also used to detect β-amyloid (Aβ) and glial fibrillary acidic protein (GFAP) to measure Aβ accumulation and astrocyte growth. Western blot was also used to measure Tau pathology-related PHD finger protein 1 (PHF-1), phosphorylated Tau (AT-8), and total Tau protein.
RESULTS
The administration of MT-III notably enhanced spatial learning and memory function in 3xTg-AD mice, as evidenced by the Morris water maze test ( < 0.01). According to immunohistochemistry and the obtained findings, it was observed that brain tissues of mice treated with MT-III showed a notable increase of Nissl bodies and NeuN intensity ( < 0.01) while a remarkable decrease in Aβ accumulation and GFAP ( < 0.01). Additionally, MT-III largely decreased levels of Tau phosphorylation-related PHF-1 and AT-8 ( < 0.01) and slightly reduced the level of Tau 5 ( < 0.05).
CONCLUSION
In summary, our research indicates that MT-III has the capacity to ameliorate pathological alterations in AD mouse models and safeguard their cognitive and emotional abilities. By decreasing β-amyloid accumulation and reducing the intensity of Tau pathology, MT-III protected hippocampal subfield neurons against pathological harm. Furthermore, MT-III reduced inflammation by inhibiting abnormal proliferation of astrocytes. Of utmost importance, MT-III greatly enhanced the cognitive abilities related to spatial learning and memory in mice, suggesting its promising therapeutic properties for AD.
Topics: Animals; Alzheimer Disease; Astrocytes; Mice; Disease Models, Animal; Metallothionein 3; Cell Proliferation; tau Proteins; Mice, Transgenic; Hippocampus; Amyloid beta-Peptides; Male; Humans; Maze Learning; Spatial Learning; Glial Fibrillary Acidic Protein
PubMed: 38926108
DOI: 10.24976/Discov.Med.202436185.112