Unlocking new avenues for neuropsychiatric disease therapy: the emerging potential of Peroxisome proliferator-activated receptors as promising therapeutic targets.

RATIONALE: Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate various physiological processes such as inflammation, lipid metabolism, and glucose homeostasis. Recent studies suggest that targeting PPARs could be beneficial in treating neuropsychiatric disorders by modulating neuronal function and signaling pathways in the brain. PPAR-α, PPAR-δ, and PPAR-γ have been found to play important roles in cognitive function, neuroinflammation, and neuroprotection. Dysregulation of PPARs has been associated with neuropsychiatric disorders like bipolar disorder, schizophrenia, major depression disorder, and autism spectrum disorder. The limitations and side effects of current treatments have prompted research to target PPARs as a promising novel therapeutic strategy. Preclinical and clinical studies have shown the potential of PPAR agonists and antagonists to improve symptoms associated with these disorders. OBJECTIVE: This review aims to provide an overview of the current understanding of PPARs in neuropsychiatric disorders, their potential as therapeutic targets, and the challenges and future directions for developing PPAR-based therapies. METHODS: An extensive literature review of various search engines like PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out with the keywords "PPAR, Neuropsychiatric disorders, Oxidative stress, Inflammation, Bipolar Disorder, Schizophrenia, Major depression disorder, Autism spectrum disorder, molecular pathway". RESULT & CONCLUSION: Although PPARs present a hopeful direction for innovative therapeutic approaches in neuropsychiatric conditions, additional research is required to address obstacles and convert this potential into clinically viable and individualized treatments.

Fabrication and Synthesis of Thiococlchicoside loaded Matrix type Transdermal Patch.

BACKGROUND: The goal of this work was to synthesize and fabricate matrix type transdermal patches based on a combination of polymers (Eudragit L100, HPMC and PVP K30), plasticizer and crosslinking agents (propylene glycol and triethyl citrate) and adhesives (Dura Tak 87-6908) to increase Thiocolchicoside (THC) absorption via topical route. This method allows avoidance of first-pass metabolism along with a consistent and extended duration of therapeutic activity. METHODS: Fabrication and casting of polymeric solutions containing THC was done either in petri plates or through lab coater to get transdermal patches. Finally, the formulated patches were studied for their physicochemical and biological evaluation using scanning electron microscopy, FTIR, DSC, XRD and ex-vivo permeation studies using pig ear skin. RESULTS: FTIR studies confirm that the THC characteristics peaks (carbonyl (Amide I) at 1525.5 cm-1, C=O stretching (tropane ring) at 1664.4 cm-1, Amide II band (N-H stretching) at 3325.9cm-1, thioether band at 2360.7cm-1, and OH group stretching band at 3400.2 cm-1) are still present in the polymer mixture even after formulation as a transdermal patch, indicating compatibility among all excipients. While on the other hand, DSC studies confirm endothermic peaks for all the polymers along with THC with the highest enthalpy of 65.979 J/g, which is an indicator of sharp endothermic peak at 198℃, leading to the melting of THC. The percentage drug content and percentage moisture uptake of all the formulation was found in the range of 96±2.04 to 98.56±1.34% and 4.13±1.16 to 8.23±0.90%, respectively. Drug release and release kinetics studies confirm that it is dependent on the composition of individual formulation. CONCLUSION: All these findings support the possibility of using suitable polymeric composition, as well as proper formulation and manufacturing circumstances, to create a one-of-a-kind technology platform for transdermal drug administration.

miRNA-encapsulated abiotic materials and biovectors for cutaneous and oral wound healing: Biogenesis, mechanisms, and delivery nanocarriers.

MicroRNAs (miRNAs) as therapeutic agents have attracted increasing interest in the past decade owing to their significant effectiveness in treating a wide array of ailments. These polymerases II-derived noncoding RNAs act through post-transcriptional controlling of different proteins and their allied pathways. Like other areas of medicine, researchers have utilized miRNAs for managing acute and chronic wounds. The increase in the number of patients suffering from either under-healing or over-healing wound demonstrates the limited efficacy of the current wound healing strategies and dictates the demands for simpler approaches with greater efficacy. Various miRNA can be designed to induce pathway beneficial for wound healing. However, the proper design of miRNA and its delivery system for wound healing applications are still challenging due to their limited stability and intracellular delivery. Therefore, new miRNAs are required to be identified and their delivery strategy needs to be optimized. In this review, we discuss the diverse roles of miRNAs in various stages of wound healing and provide an insight on the most recent findings in the nanotechnology and biomaterials field, which might offer opportunities for the development of new strategies for this chronic condition. We also highlight the advances in biomaterials and delivery systems, emphasizing their challenges and resolutions for miRNA-based wound healing. We further review various biovectors (e.g., adenovirus and lentivirus) and abiotic materials such as organic and inorganic nanomaterials, along with dendrimers and scaffolds, as the delivery systems for miRNA-based wound healing. Finally, challenges and opportunities for translation of miRNA-based strategies into clinical applications are discussed.

Polyisobutylene-based glycopolymers as potent inhibitors for in vitro insulin aggregation.

A family of amphiphilic diblock copolymers containing a hydrophobic polyisobutylene (PIB, Mn = 1000 g mol-1) segment and a hydrophilic block with sugar pendants has been synthesized by combining living cationic and reversible addition-fragmentation chain transfer (RAFT) polymerization techniques; to explore their potential in insulin fibrillation inhibition. The glucose content in the hydrophilic segment has been tailor-made from 20 to 57 units to prepare block copolymers. The removal of the acetates from the pendent glucose units resulted in amphiphilic block copolymers that generated micellar aggregates in aqueous media. The treatment of insulin with these block copolymers affected the fibril formation process which was demonstrated using an array of biophysical techniques, namely, thioflavin T (ThT) fluorescence, tyrosine (Tyr) fluorescence, Nile red (NR) fluorescence, isothermal titration calorimetry (ITC), etc. The Tyr fluorescence assay and NR fluorescence study revealed the crucial role of hydrophobic interaction in the inhibition process, whereas ITC measurements confirmed the importance of polar interaction. Thus, the block copolymers exhibit potent inhibition of insulin fibrillation owing to hydrophobic (from PIB segment) and glycosidic cluster effect (from sugar pendant block).

Nucleic acid-based therapeutics for dermal wound healing.

Non-healing wounds have long been the subject of scientific and clinical investigations. Despite breakthroughs in understanding the biology of delayed wound healing, only limited advances have been made in properly treating wounds. Recently, research into nucleic acids (NAs) such as small-interfering RNA (siRNA), microRNA (miRNA), plasmid DNA (pDNA), aptamers, and antisense oligonucleotides (ASOs) has resulted in the development of a latest therapeutic strategy for wound healing. In this regard, dendrimers, scaffolds, lipid nanoparticles, polymeric nanoparticles, hydrogels, and metal nanoparticles have all been explored as NA delivery techniques. However, the translational possibility of NA remains a substantial barrier. As a result, different NAs must be identified, and their distribution method must be optimized. This review explores the role of NA-based therapeutics in various stages of wound healing and provides an update on the most recent findings in the development of NA-based nanomedicine and biomaterials, which may offer the potential for the invention of novel therapies for this long-term condition. Further, the challenges and potential for miRNA-based techniques to be translated into clinical applications are also highlighted.

Cellular Therapeutics for Chronic Wound Healing: Future for Regenerative Medicine.

Chronic wounds are associated with significant morbidity and mortality, which demand long-term effective treatment and represent a tremendous financial strain on the global healthcare systems. Regenerative medicines using stem cells have recently become apparent as a promising approach and are an active zone of investigation. They hold the potential to differentiate into specific types of cells and thus possess self-renewable, regenerative, and immune-modulatory effects. Furthermore, with the rise of technology, various cell therapies and cell types such as Bone Marrow and Adipose-derived Mesenchymal Cell (ADMSC), Endothelial Progenitor Cells (EPCs), Embryonic Stem Cells (ESCs), Mesenchymal Stem Cell (MSCs), and Pluripotent Stem Cells (PSCs) are studied for their therapeutic impact on reparative processes and tissue regeneration. Cell therapy has proven to have substantial control over enhancing the quality and rate of skin regeneration and wound restoration. The literature review brings to light the mechanics of wound healing, abnormalities resulting in chronic wounds, and the obstacles wound care researchers face, thus exploring the multitude of opportunities for potential improvement. Also, the review is focused on providing particulars on the possible cell-derived therapeutic choices and their associated challenges in healing, in the context of clinical trials, as solutions to these challenges will provide fresh and better future opportunities for improved study design and therefore yield a substantial amount of data for the development of more specialized treatments.

Dendrimers as nanoscale vectors: Unlocking the bars of cancer therapy.

Chemotherapy is the first choice in the treatment of cancer and is always preferred to other approaches such as radiation and surgery, but it has never met the need of patients for a safe and effective drug. Therefore, new advances in cancer treatment are now needed to reduce the side effects and burdens associated with chemotherapy for cancer patients. Targeted treatment using nanotechnology are now being actively explored as they could effectively deliver therapeutic agents to tumor cells without affecting normal cells. Dendrimers are promising nanocarriers with distinct physiochemical properties that have received considerable attention in cancer therapy studies, which is partly due to the numerous functional groups on their surface. In this review, we discuss the progress of different types of dendrimers as delivery systems in cancer therapy, focusing on the challenges, opportunities, and functionalities of the polymeric molecules. The paper also reviews the various role of dendrimers in their entry into cells via endocytosis, as well as the molecular and inflammatory pathways in cancer. In addition, various dendrimers-based drug delivery (e.g., pH-responsive, enzyme-responsive, redox-responsive, thermo-responsive, etc.) and lipid-, amino acid-, polymer- and nanoparticle-based modifications for gene delivery, as well as co-delivery of drugs and genes in cancer therapy with dendrimers, are presented. Finally, biosafety concerns and issues hindering the transition of dendrimers from research to the clinic are discussed to shed light on their clinical applications.

Block Copolymer Synthesis by the Combination of Living Cationic Polymerization and Other Polymerization Methods.

The foremost limitation of block copolymer synthesis is to polymerize two or more different types of monomers with different reactivity profiles using a single polymerization technique. Controlled living polymerization techniques play a vital role in the preparation of wide range of block copolymers, thus are revolutionary techniques for polymer industry. Polymers with good control over molecular weight, molecular weight distribution, chain-end functionality and architectures can be prepared by these processes. In order to improve the existing applications and create new opportunities to design a new block copolymer system with improved physical and chemical properties, the combination of two different polymerization techniques have tremendous scope. Such kinds of macromolecules may be attended by combination of homopolymerization of different monomers by post-modification techniques using a macroinitiator or by using a dual initiator which allows the combination of two mechanistically distinct techniques. This review focuses on recent advances in synthesis of block copolymers by combination of living cationic polymerization with other polymerization techniques and click chemistry.

Interactions and Dynamics in Aqueous Solutions of pH-Responsive Polymers: A Combined Fluorescence and Dielectric Relaxation Study.

Interaction and dynamics of aqueous solutions of pH-responsive smart polymers are investigated via steady-state, time-resolved fluorescence emission spectroscopy with the help of external local reporter coumarin 153 (C153), while MHz to GHz dielectric relaxation spectroscopic (DRS) measurement reports the intrinsic medium relaxation features. A series of pH-responsive random copolymers (DPL-DP60) comprising of a pH-responsive moiety 2-((leucinyl)oxy)ethyl methacrylate (l-Leu-HEMA) and hydrophobic methyl methacrylate (MMA) are synthesized and characterized. A balance between the pH-responsive (l-Leu-HEMA) and the hydrophobic (MMA) content dictates the phase transition pH, which is found to be ∼5-7 for these aqueous copolymer solutions (1 mg/mL). Dynamic light scattering measurements in aqueous solutions of these polymers reflect a small particle size (∼2-8 nm) at solution pH below their individual phase transition pH, while a large particle size (∼140-340 nm) forms beyond their phase transition pH. No signature of a phase transition pH-driven abrupt change in static and dynamic properties of aqueous polymer solutions has been registered from pH-dependent dielectric relaxation as well as solute (C153)-centric fluorescence measurements. A significant impact of varying the l-Leu-HEMA/MMA segment ratio on steady-state fluorescence emission and rotational anisotropy decay of the fluorophore solute (C153) has been observed. MHz to GHz DRS in aqueous solutions of these pH-responsive polymers reflects bulk water-like dielectric features.

Stem cells and growth factors-based delivery approaches for chronic wound repair and regeneration: A promise to heal from within.

The sophisticated chain of cellular and molecular episodes during wound healing includes cell migration, cell proliferation, deposition of extracellular matrix, and remodelling and are onerous to replicate. Encapsulation of growth factors (GFs) and Stem cell-based (SCs) has been proclaimed to accelerate healing by transforming every phase associated with wound healing to enhance skin regeneration. Therapeutic application of mesenchymal stem cells (MSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (PSCs) provides aid in wound fixing, tissue integrity restoration and function of impaired tissue. Several scientific studies have established the essential role GFs in wound healing and their reduced degree in the chronic wound. The overall limitation includes half-life, unfriendly microhabitat abundant with protease, and inadequate delivery approaches results in decreased delivery of effective amounts in a suitable time-based fashion. Advancements in the area of reformative medicine as well as tissue engineering have offered techniques competent of dispensing SCs and GFs in site-oriented manner. The progress in nanotechnology-based approaches attracts researcher to study and evaluate the potential of this SCs and GFs based therapy in chronic wounds. These techniques embrace the polymeric regime viz., nano-formulations, hydrogels, liposomes, scaffolds, nanofibers, metallic nanoparticles, lipid-based nanoparticles and dendrimers that have established better retort through targeting tissues when GFs and SCs are transported via these humans made devices. Assumed the current problems, improvements in delivery approaches and difficulties offered by chronic wounds, we hope to show that encapsulation of SCs and GFs loaded nanoformulations therapies is the rational next step in improving wound care.

Prevalence and Genetic Characterization of Cryptosporidium and Microsporidia Infecting Hematological Malignancy Patients.

PURPOSE: To evaluate the prevalence of Cryptosporidium and Microsporidia, associated risk factors and species identification in patients with haematological malignancies (HM). METHODS: A total of 148 consecutive patients with HM and 101 healthy subjects were evaluated for Cryptosporidium and Microsporidia using modified Kinyoun and modified Trichrome staining. Clinical, demographic and laboratory parameters were studied. The species of Cryptosporidium and Microsporidia were studied using PCR-RFLP. RESULTS: Of 148 HM patients initially screened, 47 were excluded from the final analysis due to inadequate clinical records. Patients with HM [n = 101, 63 (62.4%) male] more often had Cryptosporidium than healthy subjects [n = 101, 65 (74.4%) male] [3/101 (3%) vs. 0/101 (0%), p = 0.02]. Two of 101 (2%) HM patients and none of the healthy subjects had Microsporidia (p = 0.155). Diarrhea was more prevalent in HM patients with Cryptosporidium than those without [3, 100% vs. 39/96, 40.62%; p = 0.04). Both patients infected with Microsporidia presented with persistent diarrhea and fever. Cryptosporidium hominis was identified in all the three HM patients. Enterocytozoon bieneusi was identified in one HM patient infected with Microsporidia, which was classified as genotype Ind2. CONCLUSION: Cryptosporidium and Microsporidia may infect HM patients leading to overwhelming diarrhea. The commonest species of Cryptosporidium and Microsporidia found to infect HM patients are C. hominis and E. bieneusi.

Exploring the multifocal therapeutic approaches in COVID-19: A ray of hope.

The ongoing global pandemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is marked as one of the most challenging infectious diseases in the history of mankind with affliction of ~29,737,453 confirmed cases globally. Looking at the present scenario where there is a parallel increment in curve with time, there is an utmost emergency to discover a perennial solution to this life-threatening virus which has led the Human race in an unusual state of affair. The entire health care fraternity is engaged in endeavouring an ultimate way out to hit this pandemic but no such research made till now has been approved yet, to have the potential to bring an end to this fatal situation. Although a few possible treatment choices exist at the moment yet the requirement to search for a still better therapeutic option remains persistent. Global laboratories are working day and night in search for an effective vaccine, many are undergoing clinical trials but their commercialization is no less than a year away. The present review highlights the current potential therapies viz., vaccines, immunotherapies, convulsant plasma therapies, corticosteroids, antithrombotic, intravenous immunoglobulins, nocturnal oxygen therapy etc. that may prove beneficial in attenuating the pandemic situation. However, comparison and presentation of collective data on the therapeutic advancements in mitigating the pandemic situation needs further clinical investigations in order to prove boon to mankind.

Intestinal cryptosporidiosis in renal transplant recipients: Prevalence, species detection and comparative evaluation of SSU rRNA and Cryptosporidium oocyst wall protein genes.

Context: Cryptosporidiosis is intestinal opportunistic infection commonly occurring in immunocompromised patients including renal transplant (RT) recipients receiving continuous immunosuppressive therapy. Knowledge about species of Cryptosporidium-infecting RT recipients is necessary to know about mode of its transmission (anthroponotic or zoonotic). Various genes such as small subunit rRNA (SSU rRNA) and Cryptosporidium oocyst wall protein (COWP) genes may help in species identification though their sensitivity and specificity are highly variable. Subjects and Methods: A total of 993 and 575 stool samples were examined for Cryptosporidium by microscopy from 358 RT recipients and 200 healthy controls, respectively. Stool samples of RT recipients and healthy controls were subjected to polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) for species identification. Results: Cryptosporidium was more commonly detected amongst RT recipients than healthy controls (30/358, 8.4% vs. 0/200, respectively; P < 0.001). The infection was more common amongst patients with diarrhoea than those without (26/162, 16.1% vs. 4/145, 2.8%; P < 0.001). Cryptosporidium parvum was identified in 10/30 (33.3%) and Cryptosporidium hominis in 20/30 (66.7%) samples. SSU gene PCR-RFLP proved to be more sensitive (100%) than COWP (90%); however, specificity of both was same (100%). Conclusions: Cryptosporidiosis is common amongst RT recipients, particularly those with diarrhoea. C. hominis is the most common species in the studied population. SSU rRNA PCR was more sensitive molecular method for the differentiation of Cryptosporidium species.

Evaluation of enzyme linked immunosorbent assay for stool antigen detection for the diagnosis of cryptosporidiosis among HIV negative immunocompromised patients in a tertiary care hospital of northern India.

The diagnosis of cryptosporidiosis among HIV positive patients has been the focus of many studies worldwide. However, there is a paucity of data on HIV negative immunocompromised patients like post-renal transplant recipients and those with haematological malignancies. Stool microscopy, the conventional method of diagnosis, is fraught with difficulties like cumbersome sample processing and subjective interpretation. Enzyme linked immunosorbent assay (ELISA), on the other hand, is quicker and easier. The present study was conducted in a tertiary care and super speciality hospital of north India. Stool specimens from HIV negative immunocompromised patients were subjected to both modified acid fast staining for oocysts of Cryptosporidium and ELISA for detection of Cryptosporidium copro-antigen, over a period of six years. Of the 637 specimens evaluated, 97 (15.23%) samples were positive for Cryptosporidium by both techniques; 25 (3.92%) specimens were positive by ELISA and negative by microscopy, 14 (2.20%) specimens were positive by microscopy but negative by ELISA, while 501 (78.65%) specimens were negative for Cryptosporidium by both techniques. Significant correlation was observed as a measure of agreement (Kappa test value 0.795) between modified ZN stained microscopy and ELISA for the detection of Cryptosporidium oocysts. The sensitivity, specificity, positive and negative predictive value of ELISA, keeping stool microscopy as gold standard were 87.38%, 95.25%, 87.39% and 97.28% respectively. We conclude that ELISA may be used as a reliable substitute for microscopy in setups where the case load is higher or expertise in special staining techniques is not available. The cost of the kit can be justified if the sample load is sufficiently high or if immunocompromised patients form a significant patient population.

Genotyping of Cryptosporidium Species and Their Clinical Manifestations in Patients with Renal Transplantation and Human Immunodeficiency Virus Infection.

In the present study we aimed to determine (i) frequency of Cryptosporidium species among patients with renal transplantation (RT) and human immunodeficiency virus (HIV) infection and (ii) relationship of the nature, severity, and duration of symptoms with different species and load of Cryptosporidium. Stool samples from 70 (42 RT and 28 HIV) and 140 immunocompromised patients with and without cryptosporidiosis by modified Kinyoun's staining were subjected to qPCR-melting curve analysis for identification of parasite species. qPCR detected one microscopically negative sample to be positive for cryptosporidiosis. C. hominis, C. parvum, and mixed infection were detected in 50/71 (70.4%), 19/71 (26.8%), and 2/71 (2.8%) patients, respectively. Patients with cryptosporidiosis had higher stool frequency (median, IQR: 4, 3-6/d versus 3, 2-4/d; P = 0.017) and watery stool (52/71 [73%] versus 64/139 [46%]; P = 0.003). Parasite load (median, IQR: Log10 6.37 (5.65-7.12), Log10 5.81 (4.26-6.65); P = 0.046) and nausea/vomiting (29/50 [58%] versus 5/19 [26%]; P = 0.032) were more frequent with C. hominis than with C. parvum infection. Thus, Cryptosporidium spp. (mainly C. hominis) is a common cause of diarrhoea in RT and HIV patients.