scholarly journals Emergence of Nanotechnology to Fight HIV Sexual Transmission: The Trip of G2-S16 Polyanionic Carbosilane Dendrimer to Possible Pre-Clinical Trials

2020 ◽  
Vol 21 (24) ◽  
pp. 9403
Author(s):  
Ignacio Relaño-Rodríguez ◽  
Maria Ángeles Muñoz-Fernández
Keyword(s):  
Clinical Trials ◽  
Histopathological Examination ◽  
Early Stage ◽  
Sexual Transmission ◽  
Reaction Times ◽  
Vaginal Mucosa ◽  
Carbosilane Dendrimer ◽  
Anti Hiv

Development of new, safe, and effective microbicides to prevent human immunodeficiency virus HIV sexual transmission is needed. Unfortunately, most microbicides proved ineffective to prevent the risk of HIV-infection in clinical trials. We are working with G2-S16 polyanionic carbosilane dendrimer (PCD) as a new possible vaginal topical microbicide, based on its short reaction times, wide availability, high reproducibility, and quantitative yields of reaction. G2-S16 PCD exerts anti-HIV activity at an early stage of viral replication, by blocking gp120/CD4/CCR5 interaction, and providing a barrier against infection for long periods of time. G2-S16 PCD was stable at different pH values, as well as in the presence of seminal fluids. It maintained the anti-HIV activity against R5/X4 HIV over time, did not generate any type of drug resistance, and retained the anti-HIV effect when exposed to semen-enhanced viral infection. Importantly, G2-S16 PCD did not modify vaginal microbiota neither in vitro or in vivo. Histopathological examination did not show vaginal irritation, inflammation, lesions, or damage in the vaginal mucosa, after administration of G2-S16 PCD at different concentrations and times in female mice and rabbit animal models. Based on these promising data, G2-S16 PCD could become a good, safe, and readily available candidate to use as a topical vaginal microbicide against HIV.

scholarly journals Factors Important to the Prioritization and Development of Successful Topical Microbicides for HIV-1

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Karen W. Buckheit ◽  
Robert W. Buckheit
Keyword(s):  
Clinical Trials ◽  
Ex Vivo ◽  
Sexual Transmission ◽  
Virus Transmission ◽  
Preclinical Development ◽  
Sexual Transmission Of Hiv ◽  
The Right ◽  
Hiv 1

Significant advancements in topical microbicide development have occurred since the prevention strategy was first described as a means to inhibit the sexual transmission of HIV-1. The lack of clinical efficacy of the first generation microbicide products has focused development attention on specific antiretroviral agents, and these agents have proven partially successful in human clinical trials. With greater understanding of vaginal and rectal virus infection, replication, and dissemination, better microbicide products and delivery strategies should result in products with enhanced potency. However, a variety of development gaps exist which relate to product dosing, formulation and delivery, and pharmacokinetics and pharmacodynamics which must be better understood in order to prioritize microbicide products for clinical development. In vitro, ex vivo, and in vivo models must be optimized with regard to these development gaps in order to put the right product at the right place, at the right time, and at the right concentration for effective inhibition of virus transmission. As the microbicide field continues to evolve, we must harness the knowledge gained from unsuccessful and successful clinical trials and development programs to continuously enhance our preclinical development algorithms.

Traditional Medicines, HIV, and Related Infections

2011 ◽  
Vol 23 (1) ◽  
pp. 159-164 ◽  
Author(s):  
M. Patel ◽  
P. Bessong ◽  
H. Liu
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
Ethical Issues ◽  
Mechanisms Of Action ◽  
Antiretroviral Drugs ◽  
In Vivo Studies ◽  
Traditional Medicines ◽  
Anti Hiv

Traditional medicines are an integral part of health care worldwide, even though their efficacy has not been scientifically proven. HIV-infected individuals may use them singularly or in combination with conventional medicines. Many in vitro studies have proven the anti-HIV, anti- Candida, and anti–herpes simplex virus potential of traditional plants and identified some of the mechanisms of action. Very few in vivo studies are available that involve a small number of participants and show controversial results. In addition, knowledge is limited of the role of traditional medicines in the enhancement of the immune system. The use of traditional medicines with antiretroviral drugs (ARVs) has created a problem because drug interactions compromise the efficacy of ARVs. Several currently popular plants have been studied in the laboratory for their interaction with ARVs, with disadvantageous results. Unfortunately, no clinical trials are available. The science of traditional medicines is relatively new and is at present being modernized worldwide. However, there are still ethical issues regarding traditional medicines that need to be addressed—for example, regulations regarding quality control and standardization of medicines, regulation and education of healers who deliver these medicines, and unregulated clinical trials. The workshop addressed the following questions about traditional medicine and their use in HIV infection: What are the mechanisms of action of anti-HIV traditional medicines? Should traditional medicines be used in conjunction with ARV? Do traditional medicines enhance the immune system? Should medicinal plants be used for the control of oral infections associated with HIV? What are the ethical issues surrounding the use of traditional medicines for the treatment of HIV and associated infections?

scholarly journals Exosomes Transport Anti-Human Immunodeficiency Virus Factors from Human Cervical Epithelial Cells to Macrophages

2021 ◽  
pp. 1-11
Author(s):  
Xi-Qiu Xu ◽  
Biao Zhang ◽  
Le Guo ◽  
Yu Liu ◽  
Feng-Zhen Meng ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Hiv Infection ◽  
Reproductive Tract ◽  
Sexual Transmission ◽  
Female Reproductive Tract ◽  
In Vivo Studies ◽  
Cervical Epithelial Cells ◽  
Anti Hiv

The female reproductive tract (FRT) is a major site of HIV sexual transmission. As the outermost layer of cells in the FRT, the human cervical epithelial cells (HCEs) have direct contact with HIV or infected cells. Our early work showed that supernatant (SN) from TLR3-activated HCEs contain the antiviral factors that could potently inhibit HIV replication in macrophages. However, it remains to be determined how HCEs transport the anti-HIV factors to macrophages. This follow-up study examined the role of exosomes in HCE-mediated anti-HIV activity. We found that TLR3 activation of HCEs resulted in the release of exosomes that contained multiple IFN-stimulated genes (ISGs: <i>ISG56</i>, <i>OAS1</i>, <i>MxA,</i> and <i>Mx2</i>) and the HIV restriction microRNAs (miR-28, miR-29 family members, miR-125b, miR-150, miR-382, miR-223, miR-20a, and miR-198). The depletion of exosomes from SN of TLR3-activated HCEs diminished HCE-mediated anti-HIV activity in macrophages, indicating that HCE-derived exosomes are responsible for transporting the antiviral molecules to macrophages. These in vitro findings suggest a novel antiviral mechanism by which HCEs participate in the FRT innate immunity against HIV infection. Further in vivo studies are necessary in order to develop an exosome-based delivery system for prevention and treatment of HIV infection through sexual transmission.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

scholarly journals High-throughput screening and rational design of biofunctionalized surfaces with optimized biocompatibility and antimicrobial activity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhou Fang ◽  
Junjian Chen ◽  
Ye Zhu ◽  
Guansong Hu ◽  
Haoqian Xin ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Rational Design ◽  
Click Reaction ◽  
Reaction Times ◽  
Great Promise ◽  
Biomaterial Surfaces

AbstractPeptides are widely used for surface modification to develop improved implants, such as cell adhesion RGD peptide and antimicrobial peptide (AMP). However, it is a daunting challenge to identify an optimized condition with the two peptides showing their intended activities and the parameters for reaching such a condition. Herein, we develop a high-throughput strategy, preparing titanium (Ti) surfaces with a gradient in peptide density by click reaction as a platform, to screen the positions with desired functions. Such positions are corresponding to optimized molecular parameters (peptide densities/ratios) and associated preparation parameters (reaction times/reactant concentrations). These parameters are then extracted to prepare nongradient mono- and dual-peptide functionalized Ti surfaces with desired biocompatibility or/and antimicrobial activity in vitro and in vivo. We also demonstrate this strategy could be extended to other materials. Here, we show that the high-throughput versatile strategy holds great promise for rational design and preparation of functional biomaterial surfaces.

scholarly journals G2-S16 Polyanionic Carbosilane Dendrimer Can Reduce HIV-1 Reservoir Formation by Inhibiting Macrophage Cell to Cell Transmission

2021 ◽  
Vol 22 (16) ◽  
pp. 8366
Author(s):  
Ignacio Relaño-Rodríguez ◽  
María de la Sierra Espinar-Buitrago ◽  
Vanessa Martín-Cañadilla ◽  
Rafael Gómez-Ramírez ◽  
María Ángeles Muñoz-Fernández
Keyword(s):  
T Cells ◽  
Developed Countries ◽  
Main Role ◽  
Viral Particles ◽  
Carbosilane Dendrimer ◽  
Science Community ◽  
New Compounds ◽  
Hiv 1

Human immunodeficiency virus (HIV-1) is still a major problem, not only in developing countries but is also re-emerging in several developed countries, thus the development of new compounds able to inhibit the virus, either for prophylaxis or treatment, is still needed. Nanotechnology has provided the science community with several new tools for biomedical applications. G2-S16 is a polyanionic carbosilane dendrimer capable of inhibiting HIV-1 in vitro and in vivo by interacting directly with viral particles. One of the main barriers for HIV-1 eradication is the reservoirs created in primoinfection. These reservoirs, mainly in T cells, are untargetable by actual drugs or immune system. Thus, one approach is inhibiting HIV-1 from reaching these reservoir cells. In this context, macrophages play a main role as they can deliver viral particles to T cells establishing reservoirs. We showed that G2-S16 dendrimer is capable of inhibiting the infection from infected macrophages to healthy T CD4/CD8 lymphocytes by eliminating HIV-1 infectivity inside macrophages, so they are not able to carry infectious particles to other body locations, thus preventing the reservoirs from forming.

scholarly journals Development of Triamcinolone Acetonide-Loaded Microemulsion as a Prospective Ophthalmic Delivery System for Treatment of Uveitis: In Vitro and In Vivo Evaluation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 444
Author(s):  
Alaa Mahran ◽  
Sayed Ismail ◽  
Ayat A. Allam
Keyword(s):  
Triamcinolone Acetonide ◽  
Delivery System ◽  
Histopathological Examination ◽  
Rabbit Model ◽  
Subconjunctival Injection ◽  
In Vivo Evaluation ◽  
Ternary Phase Diagrams ◽  
Ophthalmic Delivery

Treatment of uveitis (i.e., inflammation of the uvea) is challenging due to lack of convenient ophthalmic dosage forms. This work is aimed to determine the efficiency of triamcinolone acetonide (TA)-loaded microemulsion as an ophthalmic delivery system for the treatment of uveitis. Water titration method was used to construct different pseudo-ternary phase diagrams. Twelve microemulsion formulations were prepared using oleic acid, Cremophor EL, and propylene glycol. Among all tested formulations, Formulation F3, composed of oil: surfactant-co-surfactant (1:1): water (15:35:50% w/w, respectively), was found to be stable and showed acceptable pH, viscosity, conductivity, droplet size (211 ± 1.4 nm), and zeta potential (−25 ± 1.7 mV) and almost complete in vitro drug release within 24 h. The in vivo performance of the optimized formulation was evaluated in experimentally uveitis-induced rabbit model and compared with a commercial TA suspension (i.e., Kenacort®-A) either topically or by subconjunctival injection. Ocular inflammation was evaluated by clinical examination, white blood cell count, protein content measurement, and histopathological examination. The developed TA-loaded microemulsion showed superior therapeutic efficiency in the treatment of uveitis with high patient compliance compared to commercial suspension. Hence, it could be considered as a potential ocular treatment option in controlling of uveitis.

scholarly journals Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2506
Author(s):  
Wamidh H. Talib ◽  
Ahmad Riyad Alsayed ◽  
Alaa Abuawad ◽  
Safa Daoud ◽  
Asma Ismail Mahmod
Keyword(s):  
Clinical Trials ◽  
Current Knowledge ◽  
Biological Activities ◽  
Experimental Studies ◽  
Therapeutic Effects ◽  
Cell Proliferation Inhibition ◽  
Different Types ◽  
Solid Foundation

Melatonin is a pleotropic molecule with numerous biological activities. Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies. This review summarized melatonin biosynthesis, availability from natural sources, metabolism, bioavailability, anticancer mechanisms of melatonin, its use in clinical trials, and pharmaceutical formulation. Studies discussed in this review will provide a solid foundation for researchers and physicians to design and develop new therapies to treat and prevent cancer using melatonin.

scholarly journals Upregulations of Clcn3 and P-Gp Provoked by Lens Osmotic Expansion in Rat Galactosemic Cataract

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
Lixia Ji ◽  
Lixia Cheng ◽  
Zhihong Yang
Keyword(s):  
Osmotic Stress ◽  
Early Stage ◽  
Lens Epithelial Cells ◽  
Anterior Capsule ◽  
Glycoprotein P ◽  
Protein Levels ◽  
P Glycoprotein ◽  
Sugar Cataract

Objective.Lens osmotic expansion, provoked by overactivated aldose reductase (AR), is the most essential event of sugar cataract. Chloride channel 3 (Clcn3) is a volume-sensitive channel, mainly participating in the regulation of cell fundamental volume, and P-glycoprotein (P-gp) acts as its modulator. We aim to study whether P-gp and Clcn3 are involved in lens osmotic expansion of galactosemic cataract.Methods and Results.In vitro, lens epithelial cells (LECs) were primarily cultured in gradient galactose medium (10–60 mM), more and more vacuoles appeared in LEC cytoplasm, and mRNA and protein levels of AR, P-gp, and Clcn3 were synchronously upregulated along with the increase of galactose concentration. In vivo, we focused on the early stage of rat galactosemic cataract, amount of vacuoles arose from equatorial area and scattered to the whole anterior capsule of lenses from the 3rd day to the 9th day, and mRNA and protein levels of P-gp and Clcn3 reached the peak around the 9th or 12th day.Conclusion. Galactosemia caused the osmotic stress in lenses; it also markedly leads to the upregulations of AR, P-gp, and Clcn3 in LECs, together resulting in obvious osmotic expansion in vitro and in vivo.

Focus on the therapeutic efficacy of 3BNC117 against HIV-1: In vitro studies, in vivo studies, clinical trials and challenges

2017 ◽  
Vol 52 ◽  
pp. 44-50 ◽  
Author(s):  
Zhi-Jun Liu ◽  
Jing Bai ◽  
Feng-Li Liu ◽  
Xiang-Yang Zhang ◽  
Jing-Zhang Wang
Keyword(s):  
Clinical Trials ◽  
Therapeutic Efficacy ◽  
In Vitro Studies ◽  
In Vivo Studies ◽  
Hiv 1
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