Specific Target Sites Research Articles

Comprehensive Review of Hydrogel Synthesis, Characterization, and Emerging Applications

Hydrogels play a crucial role due to their high-water content and 3D structure, which make them ideal for various applications in biomedicine, sensing, and beyond. They can be prepared from a variety of biomaterials, polymers, and their combinations, allowing for versatility in properties and applications. Hydrogels include natural types derived from collagen, gelatin, alginate, and hyaluronic acid, as well as synthetic types based on polyethylene glycol (PEG), polyvinyl alcohol (PVA), and polyacrylamide (PAAm). Each type possesses distinct properties, such as mechanical strength, biodegradability, and biocompatibility, which can be tailored for applications such as wound healing, contact lenses, 3D bioprinting, and tissue engineering. The high-water content of hydrogels mimics natural tissue environments, promoting cell growth and allowing nutrient and waste exchange, which supports the development of functional tissues. They serve as scaffolds in tissue engineering applications, including wound healing, cartilage and bone regeneration, vascular tissue engineering, and organ-on-a-chip systems. Additionally, hydrogels can encapsulate and deliver therapeutic agents, such as growth factors or drugs, to specific target sites in the body. Hydrogels can be prepared through three primary methods: physical crosslinking, which relies on non-covalent interactions such as physical entanglements or hydrogen bonding; chemical crosslinking, which forms covalent bonds between polymer chains to create a stable structure; and irradiation-based crosslinking, where UV irradiation induces rapid hydrogel formation. The choice of crosslinking method depends on the desired properties and applications of the hydrogel. By providing a biomimetic environment, hydrogels facilitate cell growth and differentiation, support tissue formation, and aid in the regeneration of damaged or diseased tissues while delivering therapeutic agents. This review focuses on the critical advancements in processing routes for hydrogel development, summarizing the characterization and application of hydrogels. It also details key applications, including wound healing and cartilage and bone regeneration, as well as the challenges and future perspectives in the field.

Nanoformulations Insights: A Novel Paradigm for Antifungal Therapies and Future Perspectives.

Currently, fungal infections are becoming more prevalent worldwide. Subsequently, many antifungal agents are available to cure diseases like pemphigus, athlete's foot, acne, psoriasis, hyperpigmentation, albinism, and skin cancer. Still, they fall short due to pitfalls in physiochemical properties. Conventional medications like lotion, creams, ointments, poultices, and gels are available for antifungal therapy but present many shortcomings. They are associated with drug retention and poor penetration problems, resulting in drug resistance, hypersensitivity, and diminished efficacy. On the contrary, nanoformulations have gained tremendous potential in overcoming the drawbacks of conventional delivery. Furthermore, the potential breakthroughs of nanoformulations are site-specific targeting. It has improved bioavailability, patient-tailored approach, reduced drug retention and hypersensitivity, and improved skin penetration. Nowadays, nanoformulations are gaining popularity for antifungal therapy against superficial skin infections. Nanoformulations-based liposomes, niosomes, nanosponges, solid lipid nanoparticles, and potential applications have been explored for antifungal therapy due to enhanced activity and reduced toxicity. Researchers are now more focused on developing patient-oriented target-based nano delivery to cover the lacunas of conventional treatment with higher immune stimulatory effects. Future direction involves the construction of novel nanotherapeutic devices, nanorobotics, and robust methods. In addition, for the preparations of nanoformulations for clinical studies, animal modeling solves the problems of antifungal therapy. This review describes insights into various superficial fungal skin infections and their potential applications, nanocarrier-based drug delivery, and mechanism of action. In addition, it focuses on regulatory considerations, pharmacokinetic and pharmacodynamic studies, clinical trials, patents, challenges, and future inputs for researchers to improve antifungal therapy.

Reactive Oxygen Species-Responsive Pillararene-Embedded Covalent Organic Frameworks with Amplified Antimicrobial Photodynamic Therapy for the Targeted Elimination of Periodontitis Pathogens.

Reactive oxygen species (ROS)-responsive drug delivery systems possess immense potential for targeted delivery and controlled release of therapeutics. However, the rapid responsiveness to ROS and sustained release of antibacterial drugs are often limited by the challenging microenvironment of periodontitis. Integrating ROS-responsive drug delivery systems with photocatalytic technologies presents a strategic approach to overcome these limitations. Herein, a pillararene-embedded covalent organic framework (PCOF) incorporating the antibacterial prodrug thioacetal (TA) has been developed to treat periodontitis. This drug-loaded nanoplatform, namely TA-loaded PCOF, utilizes the self-amplifying ROS property to enhance therapeutic efficacy. PCOFs demonstrate exceptional photosensitivity and ROS generation capabilities when employed as drug carriers. When exposed to ROS, TA within the nanoplatform was activated and cleaved into cinnamaldehyde (CA), a highly potent antibacterial compound. By leveraging visible light to activate the site-specific infection targeting, TA-loaded PCOF effectively alleviated periodontitis, thereby advancing the field of antibacterial drug delivery systems.

The Association and Prognostic Implications of Long Non-Coding RNAs in Major Psychiatric Disorders, Alzheimer's Diseases and Parkinson's Diseases: A Systematic Review.

The prevalence of psychiatric disorders and neurodegenerative diseases is steadily increasing, placing a significant burden on both society and individuals. Given the intricate and multifaceted nature of these diseases, the precise underlying mechanisms remain elusive. Consequently, there is an increasing imperative to investigate the mechanisms, identify specific target sites for effective treatment, and provide for accurate diagnosis of patients with these diseases. Numerous studies have revealed significant alterations in the expression of long non-coding RNAs (lncRNAs) in psychiatric disorders and neurodegenerative diseases, suggesting their potential to increase the probability of these diseases. Moreover, these findings propose that lncRNAs could be used as highly valuable biomarkers in diagnosing and treating these diseases, thereby offering novel insights for future clinical interventions. The review presents a comprehensive summary of the origin, biological functions, and action mechanisms of lncRNAs, while exploring their implications in the pathogenesis of psychiatric disorders and neurodegenerative diseases and their potential utility as biomarkers.

Binding site redundancy is critical for the regulation of fas by miR-30c in blunt snout bream (Megalobrama amblycephala)

MiR-30c and fatty acid synthase (fas) both play important roles in physiological processes such as lipid synthesis and fat metabolism. Predictive analysis revealed that fas is a target gene of miR-30c with multiple seed sites. Seed sites are useful to predict miRNA targeting relationships; however, detailed analyses of seed sites in fish genomes remain poorly studied. In this study, the regulatory relationship between miR-30c and fas, number and effect of seed regions, and mechanism by which miR-30c regulates lipid metabolism were evaluated in blunt snout bream (Megalobrama amblycephala). Four miR-30c target sites for fas were identified using various prediction tools. miR-30c mimics were transfected into 293 T cells, and dual-luciferase reporter assays were used to evaluate the roles of different fas target sites. When a single target site was mutated, relative luciferase activity was higher than that in the control group, with different activity levels depending on the mutation site. When multiple target sites were mutated, relative luciferase activity increased significantly as the number of mutation sites increased and was the highest when the four sites were mutated simultaneously. The miR-30c agomir was injected into the abdominal cavity of M. amblycephala at various concentrations for analyses of physiological and biochemical parameters in the liver and blood and the expression of genes related to lipid metabolism in the liver. Total cholesterol, free fatty acid, triglyceride, and low density lipoprotein levels were significantly lower after miR-30c agomir injection comparing to the control (P < 0.05). Additionally, the expression levels of genes related to lipid metabolism were significantly lower after miR-30c agomir injection than in the control (P < 0.05). In summary, this study identified four specific miR-30c target sites in the 3′ UTR of fas mRNA; the effects of these sites are cumulative, and the redundancy ensures the accurate regulation of fas during evolution. In addition, miR-30c has a negative regulatory effect on fas and regulates lipid metabolism via various genes related to this process. Therefore, the regulation of miR-30c can effectively ameliorate the side effects of a high-fat diet on liver function in M. amblycephala.

Poly(malic acid) Nanoconjugates of Pyrazinoic Acid for Lung Delivery in the Treatment of Tuberculosis.

Tuberculosis (TB) remains a major global infection, and TB treatments could be improved by site-specific targeting with delivery systems that allow tissue and cell uptake. To increase the drug concentration at the target sites following lung delivery, polymeric nanoconjugates based on biodegradable poly(malic acid) were designed. Pyrazinoic acid (POA), the active moiety of pyrazinamide─a first-line antituberculosis drug─was covalently bound to poly(malic acid) using a hydrophobic linker at mole ratios of 25%, 50%, and 75%. Three linkers, hexanediol, octanediol, and decanediol, were considered. Independently of the linker or ratio, all the conjugates were able to self-assemble, forming nanoconjugates (NCs) in water with 130-190 nm in diameter. Pyrazinoic acid could be released in a controlled manner without any burst release effect. Its kinetics can be adjusted by modifying the grafting ratio and linker length. No cytotoxicity was observed on RAW 264.7 macrophages up to ∼14 μg/mL of POA. In addition, the nanoconjugates were efficiently taken up by these cells over 5 h. Thanks to their high loading capacity and modulable release profiles, these nanoconjugates hold great promise for more effective treatment of tuberculosis.

M6ATM: a deep learning framework for demystifying the m6A epitranscriptome with Nanopore long-read RNA-seq data.

N6-methyladenosine (m6A) is one of the most abundant and well-known modifications in messenger RNAs since its discovery in the 1970s. Recent studies have demonstrated that m6A is involved in various biological processes, such as alternative splicing and RNA degradation, playing an important role in a variety of diseases. To better understand the role of m6A, transcriptome-wide m6A profiling data are indispensable. In recent years, the Oxford Nanopore Technology Direct RNA Sequencing (DRS) platform has shown promise for RNA modification detection based on current disruptions measured in transcripts. However, decoding current intensity data into modification profiles remains a challenging task. Here, we introduce the m6A Transcriptome-wide Mapper (m6ATM), a novel Python-based computational pipeline that applies deep neural networks to predict m6A sites at a single-base resolution using DRS data. The m6ATM model architecture incorporates a WaveNet encoder and a dual-stream multiple-instance learning model to extract features from specific target sites and characterize the m6A epitranscriptome. For validation, m6ATM achieved an accuracy of 80% to 98% across in vitro transcription datasets containing varying m6A modification ratios and outperformed other tools in benchmarking with human cell line data. Moreover, we demonstrated the versatility of m6ATM in providing reliable stoichiometric information and used it to pinpoint PEG10 as a potential m6A target transcript in liver cancer cells. In conclusion, m6ATM is a high-performance m6A detection tool, and our results pave the way for future advancements in epitranscriptomic research.

Potential of Dendrimers in Drug Delivery: An Updated Review

Dendrimers have become a choice, for delivering drugs at the nano level thanks to their structure that allows precise control over size, shape, and surface features. This summary gives an update on progress in using dendrimers for drug delivery. To start with it talks about the ways dendrimers are customized for drug delivery needs like modifying their surfaces to make them more compatible with the body and targeting specific delivery sites. By adding elements that respond to conditions like pH or temperature they can release drugs in a controlled manner when needed. The summary also looks at developments using dendrimer-based formulations for types of therapeutic substances such as small molecules, peptides, proteins, and genetic material. These formulations have shown performance in how drugs move through the body, effectiveness in treating illnesses, and fewer side effects compared to methods of drug delivery. It also covers studies done before applying these systems in real-life blood-brain situations and how they could help get past barriers within the body like the blood-brain barrier or deliver drugs directly to tissues or cells - improving treatments while reducing overall harm. Lastly, it touches on obstacles and future paths, for research involving dendrimers like making them more scalable and consistent well as meeting regulatory standards. It is essential to overcome these obstacles to successfully transition dendrimer-based drug delivery systems, from research labs to use thereby harnessing their capabilities to transform drug delivery and personalized medicine.

Emerging Applications of Herbal-Based Nanocosmeceuticals for Beauty and Skin Therapy

: Herbal cosmeceuticals are a rapidly expanding sector of the personal care industry, and their use has greatly expanded over time. The advancement of research and development is demonstrated by nanotechnology, which boosts product efficacy by delivering innovative solutions. The application of nanotechnology is growing in the field of cosmeceuticals to address numerous shortcomings of conventional herbal products. Lower penetration and high compound instability of various cosmetic products for prolonged and enhanced compound delivery to beauty-based skin therapy are the main problems with the use of phyto-based cosmeceuticals. Nanosized delivery technologies are currently being used in cosmeceutical industries and products for prolonged and improved delivery of phyto-derived bioactive chemicals to solve these drawbacks. The aseptic sensation of many cosmeceutical products is improved by nanosizing phytocompounds, which also improve skin-protective properties and sustained delivery. Nanocosmeceuticals are now commonly utilized on skin, hair, lips, and nails to treat disorders including wrinkles, photoaging, hyperpigmentations, dandruff, hair damage, chapped lips, etc. Some of the cutting-edge nanotechnologies now being used for improved delivery of the phytoconstituents in skin care therapy include liposomes, ethosomes, glycerosomes, transferosomes, niosomes, phytosomes, nanostructured lipid carriers, solid lipid nanoparticles, polymeric nanoparticles, nanoemulsions, nanogels, etc. The advantages of these novel nanocarriers include improved skin penetration, controlled and prolonged drug release, increased stability, site-specific targeting, high entrapment efficiency, and improved bioavailability. Several phytoconstituents such as curcumin, aloe vera, resveratrol, lycopene, tocopherol, quercetin, catechins, and lutein have been successfully nanosized by employing various delivery technologies and incorporated in various gels, lotions, and creams for skin, lip, hair, and nail care for their sustained effects. The present article primarily focuses on the use of phytocompounds in various cosmeceutical products, diverse classes of innovative nanocarriers employed for delivering herbal nanocosmeceuticals, and the use of various phytobioactive compounds in novel nanocosmeceutical formulations to improve skin-based therapy.

MicroRNAs as promising drug delivery target to ameliorate chronic obstructive pulmonary disease using nano-carriers: a comprehensive review.

Chronic obstructive pulmonary disease (COPD) is a deteriorating condition triggered by various factors, such as smoking, free radicals, and air pollution. This worsening disease is characterized by narrowing and thickening of airways, painful cough, and dyspnea. In COPD, numerous genes as well as microRNA (miRNA) play a significant role in the pathogenesis of the disease. Many in vivo and in vitro studies suggest that upregulation or suppression of certain miRNAs are effective treatment options for COPD. They have been proven to be more beneficial than the current symptomatic treatments, such as bronchodilators and corticosteroids. MiRNAs play a crucial role in immune cell development and regulate inflammatory responses in various tissues. MiRNA treatment thus allows for precision therapy with improved outcomes. Nanoparticle drug delivery systems such as polymeric nanoparticles, inorganic nanoparticles, dendrimers, polymeric micelles, and liposomes are an efficient method to ensure the biodistribution of the miRNAs to the target site. Identification of the right nanoparticle depending on the requirements and compatibility is essential for achieving maximum therapeutic effect. In this review, we offer a thorough comprehension of the pathology and genetics of COPD and the significance of miRNAs concerning various pathologies of the lung, as potential targets for treating the disease. The present review offers the latest insights into the nanoparticle drug delivery systems that can efficiently carry and deliver miRNA or antagomirs to the specific target site and hence help in effective management of COPD.

Dual Chemotherapeutic Loading in Oxalate Transferrin-Conjugated Polymersomes Incorporated into Chitosan Hydrogels for Site-Specific Targeting of Melanoma Cells.

In this work, we developed a smart drug delivery system composed of poly (ethylene glycol)-block-poly (ε-caprolactone) (PEG-PCL)-based polymersomes (Ps) loaded with doxorubicin (DOX) and vemurafenib (VEM). To enhance targeted delivery to malignant melanoma cells, these drug-loaded nanovesicles were conjugated to the oxalate transferrin variant (oxalate Tf) and incorporated into three-dimensional chitosan hydrogels. This innovative approach represents the first application of oxalate Tf for the precision delivery of drug-loaded polymersomes within a semi-solid dosage form based on chitosan hydrogels. These resulting semi-solids exhibited a sustained release profile for both encapsulated drugs. To evaluate their potency, we compared the cytotoxicity of native Tf-Ps with oxalate Tf-Ps. Notably, the oxalate Tf-Ps demonstrated a 3-fold decrease in cell viability against melanoma cells compared to normal cells and were 1.6-fold more potent than native Tf-Ps, indicating the greater potency of this nanoformulation. These findings suggest that dual-drug delivery using an oxalate-Tf-targeting ligand significantly enhances the drug delivery efficiency of Tf-conjugated nanovesicles and offers a promising strategy to overcome the challenge of multidrug resistance in melanoma therapy.

IGF2BP3 promotes mRNA degradation through internal m7G modification

Recent studies have suggested that mRNA internal m7G and its writer protein METTL1 are closely related to cell metabolism and cancer regulation. Here, we identify that IGF2BP family proteins IGF2BP1-3 can preferentially bind internal mRNA m7G. Such interactions, especially IGF2BP3 with m7G, could promote the degradation of m7G target transcripts in cancer cells. IGF2BP3 is more responsive to changes of m7G modification, while IGF2BP1 prefers m6A to stabilize the bound transcripts. We also demonstrate that p53 transcript, TP53, is m7G-modified at its 3’UTR in cancer cells. In glioblastoma, the methylation level and the half lifetime of the modified transcript could be modulated by tuning IGF2BP3, or by site-specific targeting of m7G through a dCas13b-guided system, resulting in modulation of cancer progression and chemosensitivity.

Role of nucleobase-specific interactions in the binding and bending of DNA by human male sex determination factor SRY

Y-chromosome-encoded master transcription factor SRY functions in the embryogenesis of therian mammals to initiate male development. Through interactions of its conserved high mobility-group (HMG) box within a widened DNA minor groove, SRY and related Sox factors induce sharp bends at specific DNA target sites. Here, we present the crystal structure of the SRY HMG domain bound to a DNA site containing consensus element 5’-ATTGTT. The structure contains three complexes in the asymmetric unit; in each complex, SRY forms 10 hydrogen bonds with minor-groove base atoms in 5’-CATTGT/ACAATG-3’, shifting the recognition sequence by one base pair (italics). These nucleobase interactions involve conserved residues Arg7, Asn10, and Tyr74 on one side of intercalated Ile13 (the cantilever side chain), and Arg20, Asn32 and Ser36 on the other. Unlike the less-bent NMR structure, DNA bend angles of the distinct box-DNA complexes range from 69-84°, similar to those observed in homologous Sox domain-DNA structures. Electrophoretic studies indicate that respective substitutions of Asn32, Ser36 or Tyr74 by Ala exhibit slightly attenuated specific DNA-binding affinity and bend angles (70-73°) relative to WT (79°). By contrast, respective substitutions of Arg7, Asn10 or Arg20 by Ala markedly impaired DNA-binding affinity in association with much smaller DNA bend angles (53-65°). In a rodent cell-based model of the embryonic gonadal ridge, full-length SRY variants bearing these respective, Ala substitutions exhibited significantly decreased transcriptional activation of SRY’s principal target gene (Sox9). Together, our findings suggest that nucleobase-specific hydrogen bonds by SRY are critical for specific DNA binding, bending, and transcriptional activation.

Nano-based formulations of thymoquinone are new approaches for psoriasis treatment: a literature review.

Psoriasis, a persistent immune-mediated inflammatory skin condition, affects approximately 2-3% of the global population. Current treatments for psoriasis are fraught with limitations, including adverse effects, high costs, and diminishing efficacy over time. Thymoquinone (TQ), derived from Nigella sativa seeds, exhibits promising anti-inflammatory, antioxidant, and immunomodulatory properties that could prove beneficial in managing psoriasis. However, TQ's hydrophobic nature and poor bioavailability have hindered its usefulness as a therapeutic agent. Recent research has strategically addressed these challenges by developing nano-thymoquinone (nano-TQ) formulations to enhance delivery and efficacy in treating psoriasis. Preclinical studies employing mouse models have demonstrated that nano-TQ effectively mitigates inflammation, erythema, scaling, epidermal thickness, and cytokine levels in psoriatic lesions. Various nano-TQ formulations, including nanoemulsions, lipid vesicles, nanostructured lipid carriers, and ethosomes, have been explored to improve solubility, facilitate skin penetration, ensure sustained release, and achieve site-specific targeting. Although clinical trials are currently scarce, the outcomes from in vitro and animal models are promising. The potential co-delivery of nano-TQ with other anti-psoriatic agents also presents avenues for further investigation.

Comprehensive analysis of malabar tamarind fruit rind total extract: HPTLC fingerprinting, in-silico exploration of its metabolites for SARS-cov-2 omicron spike protein, antibacterial and antidiabetic potentials with in vitro evaluation of antidiabetic and antioxidant activities

Malabar tamarind tropical fruit, scientifically known as Garcinia gummi-gutta, is indigenous to Southeast Asia. In this work, the total methanolic extract of the Malabar fruit rind was examined by HPTLC fingerprinting, with quantitative evaluation of the total phenolics and flavonoids. Library of previously reported natural metabolites was utilized to demonstrate their affinity for specific target sites, they were evaluated against Omicron SARS-CoV-2 mainly it's Spike Protein, bacterial tyrosinase, and antidiabetic targets such α-glucosidase, pancreatic lipase and also α-amylase enzymes. The molecular docking revealed that the Guttiferone R possessed the highest binding affinity toward the Omicron Spike Protein with a stable binding mode, −8.67 kcal/mol binding energy and a 1.07 Å RMSD value compared to reference, Azithromycin, which has −8.90 kcal/mol binding affinity and a 1.20 Å RMSD value. On the other hand, the identified polyphenolic compounds; Vitexin, Prunin, Naringin, Hinokiflavone, Kaempherol-3-O-rutinoside, Gallic acid, Naringenin, and Catechin, showed remarkable antidiabetic activity by strong inhibitory activity against α-glucosidase and notable activity against α-amylase compared with acarbose as reference. According to antibacterial activity, the identified compounds showed low affinity with weak activity against screened bacterial strains. In-vitro evaluation of Tamarind antioxidant and antidiabetic potentials, it exhibited a free radical-scavenging potential with 71.75 % retardation and α-glucosidase, α-amylase and pancreatic lipase inhibitor activities with an IC50 of 391.3 ± 26.27, 95.03 ± 0.03 and 0.01043 ± 0.0004 μg/mL, respectively that emphasize the molecular docking study. The findings imply that Malabar tamarind fruit rind possess antioxidant, antidiabetic, antibacterial and antiviral activities.

Poly(2-(dimethylamino) ethyl methacrylate)-b-poly (hydroxy propyl methacrylate) nanoparticles for guided delivery of MCL-1 CRISPR-Cas9 plasmid and doxorubicin to non-small cell lung cancer

Combining gene therapy with other therapeutic methods, such as chemotherapy, using nanocarriers can lead to higher therapeutic effects through different mechanisms. In the current study, poly(2-(dimethylamino) ethyl methacrylate)-b-poly (hydroxy propyl methacrylate) (PDMAEMA-b-PHPMA) copolymer was synthesized in order to encapsulate either doxorubicin (DOX) or MCL-1 CRISPR.Cas9 plasmid (NP/DOX and NP/CRISPR.Cas9 plasmid). Then, for site-specific targeting against non-small cell lung cancer (SKMES-1 and A549 cell lines) overexpressing nucleolin receptors, AS1411 aptamer was attached to the surface of the prepared platforms through electrostatic interactions. The developed system was extensively evaluated for its transfection efficiency, cellular toxicity, and effectiveness in treating SKMES-1 tumor-bearing C57BL/6 nude mice. The results indicated that the targeted NP/DOX+NP/CRISPR.Cas9 plasmid complex enhanced cellular uptake into target cells, SKMES-1 and A549, through receptor- mediated endocytosis. Furthermore, comparative in vitro cytotoxicity results showed that the cells were exposed to the combination of NP/DOX and NP/CRISPR.Cas9 plasmid complex caused significantly enhanced cytotoxicity compared to treatment with each of them alone. In vivo study revealed that the AS1411-tagged nanoparticles (Apt-NP/DOX+Apt-NP/CRISPR.Cas9 plasmid) had a more pronounced inhibitory effect on tumor growth compared to non-targeted nanoparticles (NP/DOX+NP/CRISPR.Cas9 plasmid), moreover, co-treatment with MCL-1 sgRNA CRISPR.Cas9 plasmid and DOX increased the drug sensitivity of SKMES-1 cells towards DOX, which enhanced the therapeutic effects in mice receiving treatment with Apt-NP/DOX in combination with Apt-CRISPR.Cas9 plasmid nanocomplex. In conclusion, the findings indicated that the combination of common chemotherapy such as DOX and genome editing for MCL-1 through CRISPR.Cas9 system would provide a potential and safe method for treating non-small cell lung cancer which has excellent capacity for the clinical translation.

Breaking the Cycle: Matrix Metalloproteinase Inhibitors as an Alternative Approach in Managing Tuberculosis Pathogenesis and Progression.

Mycobacterium tuberculosis (Mtb) has long posed a significant challenge to global public health, resulting in approximately 1.6 million deaths annually. Pulmonary tuberculosis (TB) instigated by Mtb is characterized by extensive lung tissue damage, leading to lesions and dissemination within the tissue matrix. Matrix metalloproteinases (MMPs) exhibit endopeptidase activity, contributing to inflammatory tissue damage and, consequently, morbidity and mortality in TB patients. MMP activities in TB are intricately regulated by various components, including cytokines, chemokines, cell receptors, and growth factors, through intracellular signaling pathways. Primarily, Mtb-infected macrophages induce MMP expression, disrupting the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thereby impairing extracellular matrix (ECM) deposition in the lungs. Recent research underscores the significance of immunomodulatory factors in MMP secretion and granuloma formation during Mtb pathogenesis. Several studies have investigated both the activation and inhibition of MMPs using endogenous MMP inhibitors (i.e., TIMPs) and synthetic inhibitors. However, despite their promising pharmacological potential, few MMP inhibitors have been explored for TB treatment as host-directed therapy. Scientists are exploring novel strategies to enhance TB therapeutic regimens by suppressing MMP activity to mitigate Mtb-associated matrix destruction and reduce TB induced lung inflammation. These strategies include the use of MMP inhibitor molecules alone or in combination with anti-TB drugs. Additionally, there is growing interest in developing novel formulations containing MMP inhibitors or MMP-responsive drug delivery systems to suppress MMPs and release drugs at specific target sites. This review summarizes MMPs' expression and regulation in TB, their role in immune response, and the potential of MMP inhibitors as effective therapeutic targets to alleviate TB immunopathology.

Exploring Nanohydrogels: Crafting Innovations for Biomedical Advancements

AbstractHere in, we discuss different types of nanohydrogels in the field of biomedicine, highlighting their unique properties such as size, biocompatibility, and tuneable drug release capabilities. Nanohydrogels are considered versatile tools for applications in tissue engineering, drug delivery, and diagnostics, with the ability to target specific sites and release therapeutic agents in a controlled manner. The controlled‐release characteristics of nanohydrogels are particularly emphasized for targeted drug delivery, potentially transforming therapies for conditions like cancer by maximizing treatment efficacy while minimizing damage to healthy tissues. Several research articles published on nanohydrogels has been steadily increasing over the years, indicating growing interest and research activity in this field. This review provides an overview of contemporary methodologies employed in nanohydrogel design, their utilization in biomedical contexts, and their pivotal role in shaping advanced therapeutics. Recent investigations on nanohydrogels are scrutinized for their extensive utility in devising strategies conducive to finely tuned biological applications. Challenges and obstacles associated with the nanohydrogel technology in biomedicine also has been discussed. Cautious handling of the interaction of nanohydrogels with complex biological systems is also emphasized for the successful integration of this technology into medical applications.

Combined Theoretical and Experimental Investigations: Design, Synthesis, Characterization, and In Vitro Cytotoxic Activity Assessment of a Complex of a Novel Ureacellobiose Drug Carrier with the Anticancer Drug Carmustine.

Drug delivery systems (DDSs) are used to transport drugs which are characterized by some pharmaceutical problems to the specific target site, enhancing therapeutic efficacy and reducing off-target accumulation in the body. In this work, one of the recently synthesized molecules, 1,10-N,N'-bis-(β-ᴅ-ureidocellobiosyl)-4,7,13,16-tetraoxa-1,10-diazacyclooctadecane (TN), was tested as a potential drug carrier towards the anticancer drug carmustine. For this purpose, different techniques were used, from synthesis and calculations to cytotoxicity assessment. Our results showed that TN is characterized by a very compact geometry, which significantly impacts its complexation properties. Although it forms a very stable complex with carmustine, it adopts a non-inclusion geometry, as verified by both experimental and theoretical NMR analyses. The cytotoxicity study performed for all analyzed molecules (TN; carmustine; TN:carmustine complex) towards normal and cancer (breast and colon) cells revealed that TN is not toxic and that the formation of complexes with carmustine reduces the toxicity of carmustine to normal cells.

Sterilization of fish through adaptable gRNAs targeting dnd1 using CRISPR-Cas13d system

Sterilizing fish is a valuable technique not only for preventing genetic contamination from escaped aquaculture fish but also for enhancing fish meat quality. The clustered regularly interspaced short palindromic repeats-CRISPR-associated 13d (CRISPR-Cas13d) system is capable of RNA-targeted gene knockdown with reduced off-target effects. Unlike morpholino knockdown, which is limited to specific target sites, the CRISPR-Cas13d system utilizes the entire mRNA as a target site for gRNA. This enables the design of adaptable gRNAs by targeting the conserved sequences across fish species, leading to promising sterilization for a wide variety of aquaculture fish. In this study, we demonstrated that the effectiveness of this system in fish sterilization by the knockdown of dead end1 (dnd1) and nanos3, which are crucial for germ cell development. Initially, we demonstrated that gRNAs designed using the cas13design tool, which was developed based on studies of cultured mammalian cells, effectively induced germ cell-deficient medaka with low-cytotoxicity. Additionally, we identified the nucleotide positions of the gRNA (seed sequence) that are crucial for knockdown in teleost fish. These data will be valuable for designing adaptable gRNA in teleost fish and targeting multiple paralogous genes. To develop an adaptable sterilization technique using the CRISPR-Cas13d system, we aligned 81 dnd1 sequences from 70 fish species and identified a highly conserved region of the gRNA targets. Despite not finding a perfectly matched target region in the dnd1 alignment, we designed 15 adaptable gRNAs that potentially targeting dnd1 in 55 out of 70 fish species, leveraging sequences from representative aquaculture and aquarium fish (salmon, tilapia, puffer fish, amberjack, tuna, guppy and carp) and experimental model fish (medaka, zebrafish, and stickleback. To confirm whether adaptable gRNAs had a knockdown effect, we initially injected the gRNAs into medaka embryos. Adaptable gRNAs with a single-nucleotide mismatch against medaka dnd1 resulted in the complete loss of germ cells with little cytotoxicity, suggesting that mismatches are unlikely to induce off-target effects crucial for embryonic development. Additionally, adaptable gRNAs designed based on the salmon dnd1 sequence, which was 100% identical in the Oncorhynchus, Salvelinus, and Salmo groups, effectively generated germ cell-deficient rainbow trout. These results indicate that the knockdown of dnd1 using the CRISPR-Cas13d system is effective for sterilizing both aquaculture and experimental model fish species. Moreover, the adaptable gRNAs designed in this study can potentially sterilize a diverse range of fish species.