Revisiting Post-Laminectomy Kyphosis and Challenges in Its Management: A Case Report.

The posterior ligamentous complex plays a pivotal role in spinal stability during complex movements, especially at the cervical vertebral level. Its disruption leads to the development of post-laminectomy kyphosis. The present case emphasizes the challenges in managing post-laminectomy kyphosis, restoring spinal alignment, and the importance of the posterior tension band as a spine stabilizer. A 19-year-old male underwent C2-C5 laminectomy for cervical C3 neurofibroma at an outside hospital. The patient remained stable for five months and then developed cervical kyphosis, leading to myelopathy. Clinical examination revealed significant neurological deficits, including spasticity, clonus, loss of hand dexterity, and sensory abnormalities. Imaging revealed C3 retrolisthesis with severe cervical kyphosis, cord compression, and myelomalacia. The management involved cervical traction with gradual increments in the weight and correction of the cervical sagittal balance. Principles of kyphotic deformity correction were applied, and C2 pedicle with C3-C5 lateral mass fixation was performed. The patient's modified Japanese Orthopaedic Association score improved from 10 to 16 at six months' follow-up. Post-laminectomy, the disruption of the posterior ligamentous complex increases the range of motion, particularly in the cervical spine, leading to instability and kyphosis. Surgical interventions such as laminoplasty, laminotomy, and laminectomy with posterior cervical fusion aim to mitigate the risk of kyphosis, with techniques such as bone-to-bone ligament-preserving laminoplasty and ultrasonic bone scalpel showing promise in further reducing the risk of kyphosis. The key determinant for the prevention of kyphosis is the integrity of the posterior ligamentous complex. The management of cervical kyphosis includes appropriate pre-operative planning, which includes the evaluation of cervical and spinopelvic parameters. For a posterior spinal approach, one may choose to consider laminotomy, laminoplasty, or laminectomy along with posterior cervical fusion.

Mediating role of social disengagement and loneliness in the nexus between functional health and mental well-being in older individuals.

Few studies have focused sufficiently on the intricate link between functional health and depression among older people aged 60 and above in India. Therefore, the current study investigates the association between functional health and depression among older Indian adults through the mediating role of social disengagement and loneliness and the moderating role of living arrangements using recent data from the Longitudinal Aging Study in India (LASI: 2017-2018). Composite International Diagnostic Interview-Short Form (CIDI-SF) for depression, the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) for functional health, and the indoor/outdoor activities, visits, and religious events for social disengagement were used. The feelings of loneliness and living arrangements were measured using single-item questions and surveys/interviews of household members. Bivariate analysis, logistic regression, and a Partial Least Squares-Structural Equation Model were adopted. The results show that older persons with functional health had 1.85 times higher odds of depression; similarly, those not engaging in social activities and experiencing loneliness were more likely to feel depressed. Living with someone was negatively linked to depression. A significant moderation by living arrangements in the functional health-depression relationship was also observed. The results also indicate significant mediating roles of social disengagement and loneliness, with 22.0% and 3.08% mediation effects, respectively. Therefore, this study recommends the provision of housing and social interaction among older people.

Precision Nanomedicine with Bio-Inspired Nanosystems: Recent Trends and Challenges in Mesenchymal Stem Cells Membrane-Coated Bioengineered Nanocarriers in Targeted Nanotherapeutics.

In the recent past, the formulation and development of nanocarriers has been elaborated into the broader fields and opened various avenues in their preclinical and clinical applications. In particular, the cellular membrane-based nanoformulations have been formulated to surpass and surmount the limitations and restrictions associated with naïve or free forms of therapeutic compounds and circumvent various physicochemical and immunological barriers including but not limited to systemic barriers, microenvironmental roadblocks, and other cellular or subcellular hinderances-which are quite heterogeneous throughout the diseases and patient cohorts. These limitations in drug delivery have been overcome through mesenchymal cells membrane-based precision therapeutics, where these interventions have led to the significant enhancements in therapeutic efficacies. However, the formulation and development of nanocarriers still focuses on optimization of drug delivery paradigms with a one-size-fits-all resolutions. As mesenchymal stem cell membrane-based nanocarriers have been engineered in highly diversified fashions, these are being optimized for delivering the drug payloads in more and better personalized modes, entering the arena of precision as well as personalized nanomedicine. In this Review, we have included some of the advanced nanocarriers which have been designed and been utilized in both the non-personalized as well as precision applicability which can be employed for the improvements in precision nanotherapeutics. In the present report, authors have focused on various other aspects of the advancements in stem cells membrane-based nanoparticle conceptions which can surmount several roadblocks and barriers in drug delivery and nanomedicine. It has been suggested that well-informed designing of these nanocarriers will lead to appreciable improvements in the therapeutic efficacy in therapeutic payload delivery applications. These approaches will also enable the tailored and customized designs of MSC-based nanocarriers for personalized therapeutic applications, and finally amending the patient outcomes.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY): Scoping Review of Case Reports and Case Series.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is considered one of the low-grade neuroepithelial tumors, as per the World Health Organization 2021 classification of brain tumors. First described in 2016, these morphologically variable tumors are characterized by oligodendroglioma-like cellular components, infiltrative growth patterns, and cluster of differentiation 34 immunopositivity. A literature search of the PubMed/MEDLINE, SCOPUS, ScienceDirect, and COCHRANE databases (from inception to 20th June 2022) was carried out to identify relevant studies. To identify additional studies, we performed a recursive search of the bibliographies of the selected articles and published systematic reviews on this topic. The search yielded a total of 64 results. After removing duplicates, 26 articles were eligible for the review. The diagnostic criteria for these glioneuronal variants, representing a broad neuropathological spectrum, are not distinct and hence impede proper diagnosis and prognosis. Frequent genetic abnormalities involving mitogen-activated protein kinase pathway constituents, such as B-Raf proto-oncogene or fibroblast growth receptor 2/3, are harbored by PLNTYs. Recent advances in molecular diagnostics have resulted in more accurate tumor classification systems, based on gene expression profiles and DNA methylation patterns. Gross total resection seems curative, with a low recurrence rate. Malignant transformation is rare; however, adjuvant radiation therapy and chemotherapy may be beneficial in selected cases.

Exploring the synergy between copper electrolytes and molecularly engineered thiocyanate-free cyclometalated ruthenium sensitizers for dye-sensitized solar cells.

Two novel cyclometalated ruthenium complexes, RC-4 and RC-5, featuring 1-phenylisoquinoline and phenyl quinazoline as ancillary ligands, respectively, were synthesized to investigate their viability with the environmentally friendly copper (Cu) redox mediator, [Cu(bpye)2]2+/+. The modification of the ligand environment resulted in variations in the energetics, photophysical properties, and photovoltaic performance of RC-4 and RC-5 sensitizers. Despite RC-5 sensitizer possessing a more positive ground state potential of 1.19 V versus the NHE, the RC-4 sensitizer, with a lower HOMO level of 0.72 V versus NHE, exhibited superior photovoltaic performance along with the Cu electrolyte, attributed to its enhanced light harvesting ability, improved lifetime and reduced back electron transfer, contributing to higher Jsc, Voc, and PCE.

Disappearance of "Elongated Pony Tail Sign" Following Chemoradiotherapy in a Case of Primary Cerebellopontine Angle Ependymoma With Spinal Drop Metastasis: 18 F-FDG PET/CT Scan Findings.

ABSTRACT: Ependymomas are rare glial tumors that commonly arise from the lining cells of ventricular system and constitute ~10% of intracranial pediatric malignancies. The incidence of ependymoma in adults is rare. Due to close approximation with the ventricular system, subtentorial ependymomas are more prone to show cerebrospinal fluid metastasis compared with supratentorial ependymomas. We present a case of subtentorial cerebellopontine angle ependymoma with diffuse spinal drop metastases showing "elongated pony tail appearance" in a 69-year-old man with complete metabolic response on 18 F-FDG PET/CT imaging following chemoradiotherapy.

A Targetable Self-association Surface of the Huntingtin exon1 Helical Tetramer Required for Assembly of Amyloid Pre-nucleation Oligomers.

Polyglutamine (polyQ) sequences undergo repeat-length dependent formation of disease-associated, amyloid-like cross-ß core structures with kinetics and aggregate morphologies often influenced by the flanking sequences. In Huntington's disease (HD), the httNT segment on the polyQ's N-terminal flank enhances aggregation rates by changing amyloid nucleation from a classical homogeneous mechanism to a two-step process requiring an ɑ-helix-rich oligomeric intermediate. A folded, helix-rich httNT tetrameric structure suggested to be this critical intermediate was recently reported. Here we employ single alanine replacements along the httNT sequence to assess this proposed structure and refine the mechanistic model. We find that Ala replacement of hydrophobic residues within simple httNT peptides greatly suppresses helicity, supporting the tetramer model. These same helix-disruptive replacements in the httNT segment of an exon-1 analog greatly reduce aggregation kinetics, suggesting that an ɑ-helix rich multimer - either the tetramer or a larger multimer - plays an on-pathway role in nucleation. Surprisingly, several other Ala replacements actually enhance helicity and/or amyloid aggregation. The spatial localization of these residues on the tetramer surface suggests a self-association interface responsible for formation of the octomers and higher-order multimers most likely required for polyQ amyloid nucleation. Multimer docking of the tetramer, using the protein-protein docking algorithm ClusPro, predicts this symmetric surface to be a viable tetramer dimerization interface. Intriguingly, octomer formation brings the emerging polyQ chains into closer proximity at this tetramer-tetramer interface. Further supporting the potential importance of tetramer super-assembly, computational docking with a known exon-1 aggregation inhibitor predicts ligand contacts with residues at this interface.

Multigenerational Effect of Heat Stress on the Drosophila melanogaster Sperm Proteome.

The effect of the parental environment on offspring through non-DNA sequence-based mechanisms, such as DNA methylation, chromatin modifications, noncoding RNAs, and proteins, could only be established after the conception of "epigenetics". These effects are now broadly referred to as multigenerational epigenetic effects. Despite accumulating evidence of male gamete-mediated multigenerational epigenetic inheritance, little is known about the factors that underlie heat stress-induced multigenerational epigenetic inheritance via the male germline in Drosophila. In this study, we address this gap by utilizing an established heat stress paradigm in Drosophila and investigating its multigenerational effect on the sperm proteome. Our findings indicate that multigenerational heat stress during the early embryonic stage significantly influences proteins in the sperm associated with translation, chromatin organization, microtubule-based processes, and the generation of metabolites and energy. Assessment of life-history traits revealed that reproductive fitness and stress tolerance remained unaffected by multigenerational heat stress. Our study offers initial insights into the chromatin-based epigenetic mechanisms as a plausible means of transmitting heat stress memory through the male germline in Drosophila. Furthermore, it sheds light on the repercussions of early embryonic heat stress on male reproductive potential. The data sets from this study are available at the ProteomeXchange Consortium under the identifier PXD037488.

Exploring the Potential of Artificial Intelligence as a Facilitating Tool for Formulation Development in Fluidized Bed Processor: a Comprehensive Review.

This in-depth study looks into how artificial intelligence (AI) could be used to make formulation development easier in fluidized bed processes (FBP). FBP is complex and involves numerous variables, making optimization challenging. Various AI techniques have addressed this challenge, including machine learning, neural networks, genetic algorithms, and fuzzy logic. By integrating AI with experimental design, process modeling, and optimization strategies, intelligent systems for FBP can be developed. The advantages of AI in this context include improved process understanding, reduced time and cost, enhanced product quality, and robust formulation optimization. However, data availability, model interpretability, and regulatory compliance challenges must be addressed. Case studies demonstrate successful applications of AI in decision-making, process outcome prediction, and scale-up. AI can improve efficiency, quality, and cost-effectiveness in significant ways. Still, it is important to think carefully about data quality, how easy it is to understand, and how to follow the rules. Future research should focus on fully harnessing the potential of AI to advance formulation development in FBP.

Microalgae derived honeycomb structured mesoporous diatom biosilica for adsorption of malachite green: Process optimization and modeling.

The present study investigated the removal of malachite green dye from aquifers by means of microalgae-derived mesoporous diatom biosilica. The various process variables (dye concentration, pH, and adsorbent dose) influencing the removal of the dye were optimized and their interactive effects on the removal efficiency were explored by response surface methodology. The pH of the solution (pH = 5.26) was found to be the most dominating among other tested variables. The Langmuir isotherm (R2 = 0.995) best fitted the equilibrium adsorption data with an adsorption capacity of 40.7 mg/g at 323 K and pseudo-second-order model (R2 = 0.983) best elucidated the rate of dye removal (10.6 mg/g). The underlying mechanism of adsorption was investigated by Weber-Morris and Boyd models and results revealed that the film diffusion governed the overall adsorption process. The theoretical investigations on the dye structure using DFT-based chemical reactivity descriptors indicated that malachite green cations are electrophilic, reactive and possess the ability to accept electrons, and are strongly adsorbed on the surface of diatom biosilica. Also, the Fukui function analysis proposed the favorable adsorption sites available on the adsorbent surface.

Systematic review and meta-analysis of studies comparing baseline D-dimer level in stroke patients with or without cancer: Strength of current evidence.

Objectives: D-dimer levels are increased in stroke and cancer. Cancer patients are at a higher risk of stroke. However, the evidence is unclear if high D-dimer in stroke patients can suggest the diagnosis of concomitant cancer or the development of stroke in a cancer patient. The objective is to assess the evidence available on the baseline D-dimer level in stroke patients with and without cancer. Materials and Methods: We conducted the systematic review and meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. We searched PUBMED, Cochrane, ScienceDirect, and Scopus for potentially eligible articles published till June 2023. All the review steps were iterative and done independently by two reviewers. The Newcastle-Ottawa scale tool was used to assess the quality of included studies for case control and cohort studies and the Agency for Healthcare Research and Quality tool for cross-sectional studies. The qualitative synthesis is presented narratively, and quantitative synthesis is shown in the forest plot using the random effects model. I2 of more than 60% was considered as high heterogeneity. Results: The searches from all the databases yielded 495 articles. After the study selection process, six papers were found eligible for inclusion in the qualitative and quantitative synthesis. In the present systematic review, 2651 patients with ischemic infarcts are included of which 404 (13.97%) patients had active cancer while 2247 (86.02%) did not. The studies included were of high quality and low risk of bias. There were significantly higher baseline D-dimer levels in stroke patients with cancer than in non-cancer patients with a mean difference of 4.84 (3.07-6.60) P < 0.00001. Conclusion: D-dimer is a simple and relatively non-expensive biomarker that is increased to significant levels in stroke patients, who have cancer and therefore may be a tool to predict through screening for active or occult cancer in stroke patients.

Spontaneous Curvature Induction in an Artificial Bilayer Membrane.

Maintaining lipid asymmetry across membrane leaflets is critical for functions like vesicular traffic and organelle homeostasis. However, a lack of molecular-level understanding of the mechanisms underlying membrane fission and fusion processes in synthetic systems precludes their development as artificial analogs. Here, we report asymmetry induction of a bilayer membrane formed by an extended π-conjugated molecule with oxyalkylene side chains bearing terminal tertiary amine moieties (BA1) in water. Autogenous protonation of the tertiary amines in the periphery of the bilayer by water induces anisotropic curvature, resulting in membrane fission to form vesicles and can be monitored using time-dependent spectroscopy and microscopy. Interestingly, upon loss of the induced asymmetry by extensive protonation using an organic acid restored bilayer membrane. The mechanism leading to the compositional asymmetry in the leaflet and curvature induction in the membrane is validated by density functional theory (DFT) calculations. Studies extended to control molecules having changes in hydrophilic (BA2) and hydrophobic (BA3) segments provide insight into the delicate nature of molecular scale interactions in the dynamic transformation of supramolecular structures. The synergic effect of hydrophobic interaction and the hydrated state of BA1 aggregates provide dynamicity and unusual stability. Our study unveils mechanistic insight into the dynamic transformation of bilayer membranes into vesicles.

Antimicrobial resistance landscape in a metropolitan city context using open drain wastewater-based metagenomic analysis.

One Health concept recognizes the inextricable interactions of diverse ecosystems and their subsequent effect on human, animal and plant health. Antimicrobial resistance (AMR) is a major One Health concern and is predicted to cause catastrophes if appropriate measures are not implemented. To understand the AMR landscape in a south Indian metropolitan city, metagenomic analysis of open drains was performed. The data suggests that in January 2022, macrolide class of antibiotics contributed the highest resistance of 40.1% in the city, followed by aminoglycoside- 24.4%, tetracycline- 11.3% and lincosamide- 6.7%. The 'mutations in the 23S rRNA gene conferring resistance to macrolide antibiotics' were the major contributor of resistance with a prevalence of 39.7%, followed by '16s rRNA with mutation conferring resistance to aminoglycoside antibiotics'- 22.2%, '16S rRNA with mutation conferring resistance to tetracycline derivatives'- 9.2%, and '23S rRNA with mutation conferring resistance to lincosamide antibiotics'- 6.7%. The most prevalent antimicrobial resistance gene (ARG) 'mutations in the 23S rRNA gene conferring resistance to macrolide antibiotics' was present in multiple pathogens including Escherichia coli, Campylobacter jejuni, Acinetobacter baumannii, Streptococcus pneumoniae, Pseudomonas aeruginosa, Neisseria gonorrhoeae, Klebsiella pneumoniae and Helicobacter pylori. Most of the geographical locations in the city showed a similar landscape for AMR. Considering human mobility and anthropogenic activities, such an AMR landscape could be common across other regions too. The data indicates that pathogens are evolving and acquiring antibiotic resistance genes to evade antibiotics of multiple major drug classes in diverse hosts. The outcomes of the study are relevant not only in understanding the resistance landscape at a broader level but are also important for identifying the resistant drug classes, the mechanisms of gaining resistance and for developing new drugs that target specific pathways. This kind of surveillance protocol can be extended to regions in other developing countries to assess and combat the problem of antimicrobial resistance.

DNMT3L interacts with Piwi and modulates the expression of piRNAs in transgenic Drosophila.

Aim: To explore the role of Piwi protein and piRNAs in DNMT3L-mediated epigenetic inheritance. Materials & methods: Transgenic Drosophila were used to examine the effect of ectopically expressed DNMT3L on the profile of piRNAs by sequencing of small RNAs. Results & conclusion: Our previous work showed accumulation and inheritance of epimutations across multiple generations in transgenic DNMT3L Drosophila. Here, we show interaction of DNMT3L with Piwi and a significant alteration in the piRNA profile across multiple generations in transgenic Drosophila. In the light of its interaction with histone H1, we propose that in addition to its role of modulating core histone modifications, DNMT3L allows for inheritance of epigenetic information through its collaboration with Piwi, piRNAs and histone H1.

mRNA biotherapeutics landscape for rare genetic disorders.

The medical emergency of COVID-19 brought to the forefront mRNA vaccine technology where the mRNA vaccine candidates mRNA-1273 and BNT162b2 displayed superlative and more than 90% efficacy in protecting against SARS-CoV2 infections. Rare genetic disorders are rare individually, but collectively they are common and represent a medical emergency. In mRNA biotherapeutic technology, administration of a therapeutic protein-encoding mRNA-nanoparticle formulation allows for in vivo production of therapeutic proteins to functionally complement the protein functions lacking in rare disease patients. The platform nature of mRNA biotherapeutic technology propels rare disease drug discovery and, owing to the scalable and synthetic nature of mRNA manufacturing, empowers parallel product development using a universal production pipeline. This review focuses on the advantages of mRNA biotherapeutic technology over current therapies for rare diseases and provides summaries for the proof-of-concept preclinical studies performed to demonstrate the potential of mRNA biotherapeutic technology. Apart from preclinical studies, this review also spotlights the clinical trials currently being conducted for mRNA biotherapeutic candidates. Currently, seven mRNA biotherapeutic candidates have entered clinical trials for rare diseases, and of them, 3 candidates entered in the year 2023 alone. The rapid pace of clinical development promises a future where, as with mRNA vaccines for COVID-19, mRNA biotherapeutic technology would combat an emergency of rare genetic disorders.

Current status of research in rare genetic disorders and drug discovery in India.

The major health agenda of India so far has prioritized infectious diseases and public health. Given the socioeconomic conditions and poverty, a large fraction of the Indian population is exposed to infections from different pathogens, most notably enteric, parasitic, mycobacterial, and viral. In recent years, however, there has been a decline in the spread of these diseases with better surveillance, availability of therapy, improvement of socioeconomic conditions, and education. It is now being realized that non-communicable diseases are reaching epidemic proportions in India and there is a greater emphasis on the diagnosis and management of these diseases. The proportion of deaths due to non-communicable diseases has gone up substantially and was found to be about 61.8% of all deaths in 2016 (https://www.wbhealth.gov.in/NCD/).

A comprehensive review of dengue with a focus on emerging solutions for precision and timely detection.

Dengue is a global health problem, caused by the dengue virus (DENV), which belongs to the Flaviviridae family of viruses. The transmission of DENV occurs through vectors, Ae. aegypti and Ae. Albopictus mosquitoes, to the human host, classifying it as a vector-borne disease. The disease incidence is increasing at an alarming rate and needs to be tackled to reduce the morbidity and mortality caused by the disease. Environmental and clinical surveillance, detection of the virus, and diagnostics are critical tools to address this issue. In this comprehensive review, we explore various diagnostic techniques and the associated challenges within the context of dengue. While we briefly touch upon dengue's epidemiology, serotypes, and pathogenesis, our primary emphasis remains on diagnostics. We delve into the intricacies of these diagnostic methods, considering both the challenges they entail and the potential they hold in terms of accuracy and accessibility. It's important to note that the review does not extensively cover clinical aspects or regional variations of the disease.

Analysis of traumatic intracranial hemorrhage and delayed traumatic intracranial hemorrhage in patients with isolated head injury on anticoagulation and antiplatelet therapy.

Objectives: Anticoagulants and antiplatelet (ACAP) agents are increasingly and frequently used, especially in the elderly. The present study was carried out to assess the prevalence of delayed traumatic intracranial hemorrhage (dtICH) after a normal result on an initial head computed tomography (CT) in adults who were taking ACAP medication. Materials and Methods: The present retrospective included all adult patients who arrived in the emergency department between January 2017 and January 2021 with a history of fall from the patient's own height, while being on ACAP medication with an isolated head injury. The Institutional Review Board approved the study with a waiver of consent. The primary outcome measures were prevalence of dtICH in patients who had initial normal CT scan brain and were on ACAP medication. Results: There were 2137 patients on ACAP medication, of which 1062 were male, and 1075 were of the female gender. The mean age of the patients was 82.1 years. About 8.2% had positive first CT scans (176/2137), while 0.023 (27/1149) had dtICH. The most common positive finding on the CT scan was subarachnoid hemorrhage followed by subdural hemorrhage. Male gender positively correlated with increased risk for first CT being positive (P = 0.033). Patient's with comorbidity of cirrhosis and chemotherapy had higher risk of dtICH (P = 0.47, 0.011). Conclusion: There was a very low (0.023%) prevalence of dtICH. Dual therapy or Coumadin therapy made up the majority of tICH. Cirrhosis and chemotherapy were associated with the risk of a repeat CT scan being positive with an initial CT scan negative.

Biochemical Deconstruction and Reconstruction of Nuclear Matrix Reveals the Layers of Nuclear Organization.

Nuclear matrix (NuMat) is the fraction of the eukaryotic nucleus insoluble to detergents and high-salt extractions that manifests as a pan-nuclear fiber-granule network. NuMat consists of ribonucleoprotein complexes, members of crucial nuclear functional modules, and DNA fragments. Although NuMat captures the organization of nonchromatin nuclear space, very little is known about components organization within NuMat. To understand the organization of NuMat components, we subfractionated it with increasing concentrations of the chaotrope guanidinium hydrochloride (GdnHCl) and analyzed the proteomic makeup of the fractions. We observe that the solubilization of proteins at different concentrations of GdnHCl is finite and independent of the broad biophysical properties of the protein sequences. Looking at the extraction pattern of the nuclear envelope and nuclear pore complex, we surmise that this fractionation represents easily solubilized/loosely bound and difficultly solubilized/tightly bound components of NuMat. Microscopic analyses of the localization of key NuMat proteins across sequential GdnHCl extractions of in situ NuMat further elaborate on the divergent extraction patterns. Furthermore, we solubilized NuMat in 8M GdnHCl and upon removal of GdnHCl through dialysis, en masse renaturation leads to RNA-dependent self-assembly of fibrous structures. The major proteome component of the self-assembled fibers comes from the difficultly solubilized, tightly bound component. This fractionation of the NuMat reveals different organizational levels within it which may reflect the structural and functional organization of nuclear architecture.

Enzyme targeted delivery of sivelestat loaded nanomicelle inhibits arthritic severity in experimental arthritis.

AIMS: Rheumatoid arthritis (RA) is chronic inflammatory disorder mainly affects the lining of articular cartilage of synovial joints characterized by severe inflammation and joint damage. The expression of proteolytic enzymes like MMP-2 and Neutrophil Elastase (NE) worsens the RA condition. To address this concern, we have synthesized dual enzyme targeted chlorotoxin conjugated nanomicelles loaded with sivelestat as broad spectrum treatment for RA. MATERIALS AND METHODS: Conjugation of the chlorotoxin over nanomicelle and incorporation of sivelestat in nanomicelle provide it dual targeting potential. The sivelestat loaded nanomicelle (SLM) evaluated for the drug release and in-vitro cytocompatibility. Further, investigated its in-vivo anti-arthritic potential on collagen-induced arthritis in wistar rats. KEY FINDINGS: The microscopic observation of SLM showed spherical ball like appearance with size ranging from 190 to 230 nm. SLM showed good drug loading and encapsulation efficiency along with no cytotoxicity against healthy cell lines. In-vivo therapeutic assessment on collagen induced arthritis rat model showed potential chondroprotection. The microscopic visualization of articular cartilage by staining showed that it restores the cartilage integrity and lowers the expression of pro-inflammatory enzymes showed by Immunohistochemistry and Immunofluorescence. We observed that, it restrain the mediators of synovial inflammation by simultaneous inhibition of the proteolytic enzymes involved in swelling, cartilage destruction and joint damage which provides strong chondroprotection. SIGNIFICANCE: We report that significant alleviation of inflammation and inhibition of proteolytic enzymes together might provide enhanced potential for the treatment and management of RA.