Targeted Redox Balancing through Pulmonary Nanomedicine Delivery Reverses Oxidative Stress Induced Lung Inflammation.

Non-invasive delivery of drugs is important for the reversal of respiratory diseases essentially by-passing metabolic pathways and targeting large surface area of drug absorption. Here, we study the inhalation of a redox nano medicine namely citrate functionalized Mn3O4 (C-Mn3O4) duly encapsulated in droplet evaporated aerosols for the balancing of oxidative stress generated by the exposure of Chromium (VI) ion, a potential lung carcinogenic agent. Our optical spectroscopic in-vitro experiments demonstrates the efficacy of redox balancing of the encapsulated nanoparticles (NP) for the maintenance of a homeostatic condition. The formation of Cr-NP complex as an excretion of the heavy metal is also demonstrated through optical spectroscopic and high resolution transmission optical microscopy (HRTEM). Our studies confirm the oxidative stress mitigation activity of the Cr-NP complex. A detailed immunological assay followed by histopathological studies and assessment of mitochondrial parameters in pre-clinical mice model with chromium (Cr) induced lung inflammation establishes the mechanism of drug action to be redox-buffering. Thus, localised delivery of C-Mn3O4 NPs in the respiratory tract via aerosols can act as an effective nanotherapeutic agent against oxidative stress induced lung inflammation.

A study of scarless wound healing through programmed inflammation, proliferation and maturation using a redox balancing nanogel.

In the study, we have shown the efficacy of an indigenously developed redox balancing chitosan gel with impregnated citrate capped Mn3O4 nanoparticles (nanogel). Application of the nanogel on a wound of preclinical mice model shows role of various signaling molecules and growth factors, and involvement of reactive oxygen species (ROS) at every stage, namely hemostasis, inflammation, and proliferation leading to complete maturation for the scarless wound healing. While in vitro characterization of nanogel using SEM, EDAX, and optical spectroscopy reveals pH regulated redox buffering capacity, in vivo preclinical studies on Swiss albino involving IL-12, IFN-γ, and α-SMA signaling molecules and detailed histopathological investigation and angiogenesis on every stage elucidate role of redox buffering for the complete wound healing process.

Surgical management of stricture urethra in patients with chronic renal failure: Ten years' experience at a tertiary center.

Introduction: Patients suffering from stricture urethra and deranged renal function have poor quality of life. The incidence of urethral stricture co-existing with renal failure is comparatively small and cause may be multifactorial. There is paucity of literature on management of urethral stricture associated with deranged renal function. We present our experience of managing stricture urethra associated with chronic renal failure. Materials and Methods: This was a retrospective study conducted from 2010 to 2019. Patients with stricture urethra and deranged renal function (serum creatinine >1.5 mg/dl) who underwent urethroplasty or perineal urethrostomy were included in our study. A total of 47 patients met the inclusion criteria and were included in this study. Patients were followed every 3 months in their 1st year of surgery and 6 monthly thereafter. Statistical analysis was done using SPSS version 16. Results: There was a significant increase in the mean postopérative maximum and average urinary flow rates when compared to the preoperative values. The overall success rate was 76.59%. Out of 47 patients, 10 had wound infection and delayed wound healing, 2 patients developed ventricular arrhythmias, 6 patients developed fluid and electrolyte imbalance, 2 patients developed seizures, and 1 patient developed septicemia in the postoperative period. Conclusion: Prevalence of patients with chronic renal failure associated with stricture urethra was 4.58% and features suggestive of deranged renal function at presentation were present in 1.81% patients. In the present study, complications related with chronic renal failure occurred in 17 (36.17%) patients. Multidisciplinary care of the patient along with appropriate surgical management is a viable option in this sub-group of patients.

Chemoprevention of bilirubin encephalopathy with a nanoceutical agent.

BACKGROUND: Targeted rapid degradation of bilirubin has the potential to thwart incipient bilirubin encephalopathy. We investigated a novel spinel-structured citrate-functionalized trimanganese tetroxide nanoparticle (C-Mn3O4 NP, the nanodrug) to degrade both systemic and neural bilirubin loads. METHOD: Severe neonatal unconjugated hyperbilirubinemia (SNH) was induced in neonatal C57BL/6j mice model with phenylhydrazine (PHz) intoxication. Efficiency of the nanodrug on both in vivo bilirubin degradation and amelioration of bilirubin encephalopathy and associated neurobehavioral sequelae were evaluated. RESULTS: Single oral dose (0.25 mg kg-1 bodyweight) of the nanodrug reduced both total serum bilirubin (TSB) and unconjugated bilirubin (UCB) in SNH rodents. Significant (p < 0.0001) UCB and TSB-degradation rates were reported within 4-8 h at 1.84 ± 0.26 and 2.19 ± 0.31 mg dL-1 h-1, respectively. Neural bilirubin load was decreased by 5.6 nmol g-1 (p = 0.0002) along with improved measures of neurobehavior, neuromotor movements, learning, and memory. Histopathological studies confirm that the nanodrug prevented neural cell reduction in Purkinje and substantia nigra regions, eosinophilic neurons, spongiosis, and cell shrinkage in SNH brain parenchyma. Brain oxidative status was maintained in nanodrug-treated SNH cohort. Pharmacokinetic data corroborated the bilirubin degradation rate with plasma nanodrug concentrations. CONCLUSION: This study demonstrates the in vivo capacity of this novel nanodrug to reduce systemic and neural bilirubin load and reverse bilirubin-induced neurotoxicity. Further compilation of a drug-safety-dossier is warranted to translate this novel therapeutic chemopreventive approach to clinical settings. IMPACT: None of the current pharmacotherapeutics treat severe neonatal hyperbilirubinemia (SNH) to prevent risks of neurotoxicity. In this preclinical study, a newly investigated nano-formulation, citrate-functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), exhibits bilirubin reduction properties in rodents. Chemopreventive properties of this nano-formulation demonstrate an efficacious, efficient agent that appears to be safe in these early studies. Translation of C-Mn3O4 NPs to prospective preclinical and clinical trials in appropriate in vivo models should be explored as a potential novel pharmacotherapy for SNH.

Antimony resistance mechanism in genetically different clinical isolates of Indian Kala-azar patients.

The central theme of this enterprise is to find common features, if any, displayed by genetically different antimony (Sb)-resistant viscerotropic Leishmania parasites to impart Sb resistance. In a limited number of clinical isolates (n = 3), we studied the breadth of variation in the following dimensions: (a) intracellular thiol content, (b) cell surface expression of glycan having N-acetyl-D-galactosaminyl residue as the terminal sugar, and (c) gene expression of thiol-synthesizing enzymes (CBS, MST, gamma-GCS, ODC, and TR), antimony-reducing enzymes (TDR and ACR2), and antimonial transporter genes (AQP1, MRPA, and PRP1). One of the isolates, T5, that was genotypically characterized as Leishmania tropica, caused Indian Kala-azar and was phenotypically Sb resistant (T5-LT-SSG-R), while the other two were Leishmania donovani, out of which one isolate, AG83, is antimony sensitive (AG83-LD-SSG-S) and the other isolate, T8, is Sb resistant (T8-LD-SSG-R). Our study showed that the Sb-resistant parasites, regardless of their genotype, showed significantly higher intracellular thiol compared with Sb-sensitive AG83-LD-SSG-S. Seemingly, T5-LT-SSG-R showed about 1.9-fold higher thiol content compared with T8-LD-SSG-R which essentially mirrored cell surface N-acetyl-D-galactosaminyl expression. Except TR, the expression of the remaining thiol-synthesizing genes was significantly higher in T8-LD-SSG-R and T5-LT-SSG-R than the sensitive one, and between the Sb-resistant parasites, the latter showed a significantly higher expression. Furthermore, the genes for Sb-reducing enzymes increased significantly in resistant parasites regardless of genotype compared with the sensitive one, and between two resistant parasites, there was hardly any difference in expression. Out of three antimony transporters, AQP1 was decreased with the concurrent increase in MRPA and PRP1 in resistant isolates when compared with the sensitive counterpart. Interestingly, no difference in expression of the above-mentioned transporters was noted between two Sb-resistant isolates. The enduring image that resonated from our study is that the genetically diverse Sb-resistant parasites showed enhanced thiol-synthesizing and antimony transporter gene expression than the sensitive counterpart to confer a resistant phenotype.

Headway and the remaining hurdles of mesenchymal stem cells therapy for bronchopulmonary dysplasia.

OBJECTIVE: Preterm infants are at a high risk of developing BPD. Although progression in neonatal care has improved, BPD still causes significant morbidity and mortality, which can be attributed to the limited therapeutic choices for BPD. This review discusses the potential of MSC in treating BPD as well as their hurdles and possible solutions. DATA SOURCES: The search for data was not limited to any sites but was mostly performed on all clinical trials available in ClinicalTrials.gov as well as on PubMed by applying the following keywords: lung injury, preterm, inflammation, neonatal, bronchopulmonary dysplasia and mesenchymal stem cells. STUDY SELECTIONS: The articles chosen for this review were collectively determined to be relevant and appropriate in discussing MSC not only as a potential treatment strategy for curbing the incidence of BPD but also including insights on problems regarding MSC treatment for BPD. RESULTS: Clinical trials regarding the use of MSC for BPD had good results but also illustrated insights on problems to be addressed in the future regarding the treatment strategy. Despite that, the clinical trials had mostly favourable reviews. CONCLUSION: With BPD existing as a constant threat and there being no permanent solutions, the idea of regenerative medicine such as MSC may prove to be a breakthrough strategy when it comes to treating BPD. The success in clinical trials led to the formulation of prospective MSC-derived products such as PNEUMOSTEM®, and there is the possibility of a stem cell medication and permanent treatment for BPD in the near future.

A nano erythropoiesis stimulating agent for the treatment of anemia and associated disorders.

The usual treatment for anemia and especially for anemia of inflammation (also called anemia of chronic disease) is supportive care with the target of improving the lifestyle of the patients. There is no effective medication to date for proper management. As the inflammation, erythropoiesis, and oxidative stress are the major concerns in this case, it inspired us to use a nano-erythropoietin stimulating agent (nano-ESA) made up of a nano-complex of manganese and citrate (Mn-citrate nano-complex), which has been hypothesized to have excellent antioxidant and anti-inflammatory mechanisms. Single oral dose of the nano-ESA efficiently prevented the onset of anemia as well as led to recovery from anemia in our phenylhydrazine (PHz)-intoxicated C57BL/6J mice model of anemia without any toxicological side effects. These preliminary findings may pave the way for an affordable and safe clinical use of the nano-ESA as a rapid recovery medication of anemia, especially anemia of inflammation.

Mesenchymal Stem Cell-Derived Extracellular Vesicles: Progress and Remaining Hurdles in Developing Regulatory Compliant Quality Control Assays.

Regenerative medicine is shaping into a new paradigm and could be the future medicine driven by the therapeutic capabilities shown by mesenchymal stem cell-derived extracellular vesicles (MSC-EVs). Despite the advantages and promises, the therapeutic effectiveness of MSC-EVs in some clinical applications is restricted due to inconsistent manufacturing process and the lack of stringent quality control (QC) measurement. In particular, QC assays which are crucial to confirm the safety, efficacy, and quality of MSC-EVs available for end use are poorly designed. Hence, in this review, characterization of MSC-EVs and quality control guidelines for biologics are presented, with special attention given to the description of technical know-how in developing QC assays for MSC-EVs adhering to regulatory guidelines. The remaining challenges surrounding the development of potency and stability of QC assays are also addressed.

An Affordable Approach of Mesenchymal Stem Cell Therapy in Treating Perianal Fistula Treatment.

The application of stem cells to treat perianal fistula due to Crohn's disease has attracted a lot of interest in recent decades. Though still a popular procedure, the existing surgical methods may be an ideal form of therapy since the recurrence rate is high, which affects the quality of life badly. Stem cell therapy offers to be a better solution in treating PF, but the utilisation is often restricted because of the manufacturing cost. Hence in this review, the selection of suitable cell sources, the use of bioreactors and preconditioning MSCs as well as modified stem cells will be discussed for a more affordable as compared with the current MSC therapy towards PF. We anticipate that exploring these approaches may give a complete picture in understanding stem cells in order to make them effective and affordable for long-term therapeutic applications.

Wnt5A Signaling Blocks Progression of Experimental Visceral Leishmaniasis.

Visceral leishmaniasis, caused by L. donovani infection is fatal if left untreated. The intrinsic complexity of visceral leishmaniasis complicated further by the increasing emergence of drug resistant L. donovani strains warrants fresh investigations into host defense schemes that counter infections. Accordingly, in a mouse model of experimental visceral leishmaniasis we explored the utility of host Wnt5A in restraining L. donovani infection, using both antimony sensitive and antimony resistant L. donovani strains. We found that Wnt5A heterozygous (Wnt5A +/-) mice are more susceptible to L. donovani infection than their wild type (Wnt5A +/+) counterparts as depicted by the respective Leishman Donovan Units (LDU) enumerated from the liver and spleen harvested from infected mice. Higher LDU in Wnt5A +/- mice correlated with increased plasma gammaglobulin level, incidence of liver granuloma, and disorganization of splenic white pulp. Progression of infection in mice by both antimony sensitive and antimony resistant strains of L. donovani could be prevented by activation of Wnt5A signaling through intravenous administration of rWnt5A prior to L. donovani infection. Wnt5A mediated blockade of L. donovani infection correlated with the preservation of splenic macrophages and activated T cells, and a proinflammatory cytokine bias. Taken together our results indicate that while depletion of Wnt5A promotes susceptibility to visceral leishmaniasis, revamping Wnt5A signaling in the host is able to curb L. donovani infection irrespective of antimony sensitivity or resistance and mitigate the progression of disease.

Genetic Modification as a New Approach to Ameliorate the Therapeutic Efficacy of Stem Cells in Diabetic Retinopathy.

Over the last decades, the strategy of using stem cells has gained a lot of attention in treating many diseases. Recently, DR was identified as one of the common complications experienced by diabetic patients around the world. The current treatment strategy needs to be addressed since the active progression of DR may lead to permanent blindness. Interestingly, varieties of stem cells have emerged to optimize the therapeutic effects. It is also known that stem cells possess multilineage properties and are capable of differentiating, expanding in vitro and undergoing genetic modification. Moreover, modified stem cells have shown to be an ideal resource to prevent the degenerative disease and exhibit promising effects in conferring the migratory, anti-apoptotic, anti-inflammatory and provide better homing for cells into the damaged tissue or organ as well promoting healing properties. Therefore, the understanding of the functional properties of the stem cells may provide the comprehensive guidance to understand the manipulation of stem cells making them useful for long-term therapeutic applications. Hence in this review the potential use and current challenges of genetically modified stem cells to treat DR will be discussed along with its future perspectives.

Genome wide comparison of Leishmania donovani strains from Indian visceral leishmaniasis and para-kala-azar dermal leishmaniasis patients.

Visceral leishmaniasis (VL) or Kala-azar, primarily caused by Leishmania donovani, is a major health concern in many countries including India. Growing unresponsiveness among the parasites toward the available drugs is alarming, and so, it is necessary to decipher the underlying mechanism of such development for designing new therapeutics. Moreover, even after successful treatment, some VL patients develop apparently harmless skin lesions known as post-kala-azar dermal leishmaniasis (PKDL) which may serve as a reservoir of the parasite in the transmission cycle. Furthermore, recent reports of para-kala-azar dermal leishmaniasis (para-KDL) cases having PKDL manifestation with concomitant VL, emphasize the necessity of more attention to address complex nature of the parasite for eradicating the disease effectively. In the present study, whole genome sequencing is performed with sodium stibogluconate (SSG) sensitive and resistant L. donovani strains along with SSG sensitive para-KDL strains, derived from the clinical isolates of Indian patients to identify the genomic variations among them. Notably, the analyses of chromosome somy values and genome wide mutation profile in the coding regions reveal distinct clustering of the para-KDL strains with 24 genes being mutated uniquely in this group. Such distinguishing genomic changes among the para-KDL strains could be significant for the parasites to become dermatotropic. Overall, the study reveals a possible correlation of the development of SSG resistance and the transition towards the manifestation of PKDL with chromosome aneuploidy and non-synonymous genetic variations in the coding sequences of the L. donovani strains from Indian patients.

Redox nanomedicine ameliorates chronic kidney disease (CKD) by mitochondrial reconditioning in mice.

Targeting reactive oxygen species (ROS) while maintaining cellular redox signaling is crucial in the development of redox medicine as the origin of several prevailing diseases including chronic kidney disease (CKD) is linked to ROS imbalance and associated mitochondrial dysfunction. Here, we have shown that a potential nanomedicine comprising of Mn3O4 nanoparticles duly functionalized with biocompatible ligand citrate (C-Mn3O4 NPs) can maintain cellular redox balance in an animal model of oxidative injury. We developed a cisplatin-induced CKD model in C57BL/6j mice with severe mitochondrial dysfunction and oxidative distress leading to the pathogenesis. Four weeks of treatment with C-Mn3O4 NPs restored renal function, preserved normal kidney architecture, ameliorated overexpression of pro-inflammatory cytokines, and arrested glomerulosclerosis and interstitial fibrosis. A detailed study involving human embryonic kidney (HEK 293) cells and isolated mitochondria from experimental animals revealed that the molecular mechanism behind the pharmacological action of the nanomedicine involves protection of structural and functional integrity of mitochondria from oxidative damage, subsequent reduction in intracellular ROS, and maintenance of cellular redox homeostasis. To the best of our knowledge, such studies that efficiently treated a multifaceted disease like CKD using a biocompatible redox nanomedicine are sparse in the literature. Successful clinical translation of this nanomedicine may open a new avenue in redox-mediated therapeutics of several other diseases (e.g., diabetic nephropathy, neurodegeneration, and cardiovascular disease) where oxidative distress plays a central role in pathogenesis.

Redox Buffering Capacity of Nanomaterials as an Index of ROS-Based Therapeutics and Toxicity: A Preclinical Animal Study.

Precise control of intracellular redox status, i.e., maintenance of the physiological level of reactive oxygen species (ROS) for mediating normal cellular functions (oxidative eustress) while evading the excess ROS stress (distress), is central to the concept of redox medicine. In this regard, engineered nanoparticles with unique ROS generation, transition, and depletion functions have the potential to be the choice of redox therapeutics. However, it is always challenging to estimate whether ROS-induced intracellular events are beneficial or deleterious to the cell. Here, we propose the concept of redox buffering capacity as a therapeutic index of engineered nanomaterials. As a steady redox state is maintained for normal functioning cells, we hypothesize that the ability of a nanomaterial to preserve this homeostatic condition will dictate its therapeutic efficacy. Additionally, the redox buffering capacity is expected to provide information about the nanoparticle toxicity. Here, using citrate-functionalized trimanganese tetroxide nanoparticles (C-Mn3O4 NPs) as a model nanosystem, we explored its redox buffering capacity in erythrocytes. Furthermore, we went on to study the chronic toxic effect (if any) of this nanomaterial in the animal model to co-relate with the experimentally estimated redox buffering capacity. This study could function as a framework for assessing the capability of a nanomaterial as redox medicine (whether maintains eustress or damages by creating distress), thus orienting its application and safety for clinical use.

Incorporation of a Biocompatible Nanozyme in Cellular Antioxidant Enzyme Cascade Reverses Huntington's Like Disorder in Preclinical Model.

The potentiality of nano-enzymes in therapeutic use has directed contemporary research to develop a substitute for natural enzymes, which are suffering from several disadvantages including low stability, high cost, and difficulty in storage. However, inherent toxicity, inefficiency in the physiological milieu, and incompatibility to function in cellular enzyme networks limit the therapeutic use of nanozymes in living systems. Here, it is shown that citrate functionalized manganese-based biocompatible nanoscale material (C-Mn3 O4 NP) efficiently mimics glutathione peroxidase (GPx) enzyme in the physiological milieu and easily incorporates into the cellular multienzyme cascade for H2 O2 scavenging. A detailed computational study reveals the mechanism of the nanozyme action. The in vivo therapeutic efficacy of C-Mn3 O4 nanozyme is further established in a preclinical animal model of Huntington's disease (HD), a prevalent progressive neurodegenerative disorder, which has no effective medication to date. Management of HD in preclinical animal trial using a biocompatible (non-toxic) nanozyme as a part of the metabolic network may uncover a new paradigm in nanozyme based therapeutic strategy.

Correction: Manganese neurotoxicity: nano-oxide compensates for ion-damage in mammals.

Correction for 'Manganese neurotoxicity: nano-oxide compensates for ion-damage in mammals' by Aniruddha Adhikari et al., Biomater. Sci., 2019, 7, 4491-4502, DOI: .

The Ethics of the Reuse of Disposable Medical Supplies.

The use of single-use items (SUDs) is now ubiquitous in medical practice. Because of the high costs of these items, the practice of reusing them after sterilisation is also widespread especially in resource-poor economies. However, the ethics of reusing disposable items remain unclear. There are several analogous conditions, which could shed light on the ethics of reuse of disposables. These include the use of restored kidney transplantation and the use of generic drugs etc. The ethical issues include the question of patient safety and the possibility of infection. It is also important to understand the role (or otherwise) of informed consent before reuse of disposables. The widespread practice of reuse may bring down high healthcare costs and also reduce the huge amount of hospital waste that is generated. The reuse of disposables can be justified on various grounds including the safety and the cost effectiveness of this practice.

Manganese neurotoxicity: nano-oxide compensates for ion-damage in mammals.

Here, we have compared the behavioral neurotoxicity of a manganese nanoformulation (citrate functionalized Mn3O4 nanoparticles; C-Mn3O4 NPs) with that of the well-known neurotoxicant, ionic Mn, in an animal model. We found that mice administered with C-Mn3O4 NPs showed no signs of a neurobehavioral disorder, but the NPs instead ameliorated Mn-induced neurotoxicity (Parkinson's-like syndrome) through the chelation of excess Mn ions and subsequent reduction of oxidative damage.

Understanding the multifaceted mechanisms of diabetic wound healing and therapeutic application of stem cells conditioned medium in the healing process.

Mesenchymal stem cells (MSCs) transplantation seems to be a promising new therapy for diabetic wound healing (DWH), and currently, arrays of MSCs from various sources ranging from umbilical, adipose to dental sources are available as a treatment modality for this disease. However, it now appears that only a fraction of transplanted cells actually assimilate and survive in host tissues suggesting that the major mechanism by which stem cells participate in tissue repair are most likely related to their secretome level. These include a wide range of growth factors, cytokines, and chemokines, which can be found from the conditioned medium (CM) used to culture the cells. Basic studies and preclinical work confirm that the therapeutic effect of CMs are comparable with the application of stem cells. This review describes in detail the wound healing process in diabetes and the cellular and biological factors that influence the process. Subsequently, through a comprehensive literature search of studies related to wound healing in diabetics, we aim to provide an overview of scientific merits of using MSCs-CM in the treatment of diabetic wound as well as the significant caveats, which restricts its potential use in clinical set-ups. To our best knowledge, this is one of the first review papers that collect the importance of stem cells as an alternative treatment to the DWH. We anticipate that the success of this treatment will have a significant clinical impact on diabetic wounds.

Monoclonal gammopathy in prostate carcinoma: a case report and review of literature.

BACKGROUND: Monoclonal gammopathy is commonly associated with plasma cell dyscrasia. However, monoclonal gammopathy without bone marrow plasmacytosis in prostate carcinoma has rarely been reported. The association between the two conditions is not clearly established. CASE PRESENTATION: We report a case of metastatic prostate carcinoma in a 65-year-old Indian man with the unusual phenomenon of monoclonal band in gamma globulin region without evidence of bone marrow plasmacytosis. CONCLUSIONS: Monoclonal gammopathy in solid tumor has seldom been reported. This case report highlights the rare association of monoclonal gammopathy with malignant prostatic carcinoma. Therefore, while investigating a case such as this, in an elderly male patient, we should always keep a lookout for any solid tumor foci after excluding multiple myeloma.