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.

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.

Chitosan functionalized Mn3O4 nanoparticles counteracts ulcerative colitis in mice through modulation of cellular redox state.

Recent findings suggest a key role for reactive oxygen species (ROS) in the pathogenesis and progression of ulcerative colitis (UC). Several studies have also highlighted the efficacy of citrate functionalized Mn3O4 nanoparticles as redox medicine against a number of ROS-mediated disorders. Here we show that synthesized nanoparticles consisting of chitosan functionalized tri-manganese tetroxide (Mn3O4) can restore redox balance in a mouse model of UC induced by dextran sulfate sodium (DSS). Our in-vitro characterization of the developed nanoparticle confirms critical electronic transitions in the nanoparticle to be important for the redox buffering activity in the animal model. A careful administration of the developed nanoparticle not only reduces inflammatory markers in the animals, but also reduces the mortality rate from the induced disease. This study provides a proof of concept for the use of nanomaterial with synergistic anti-inflammatory and redox buffering capacity to prevent and treat ulcerative colitis.

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.

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.

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: .

Lower oesophageal peptic stricture after laparoscopic sleeve gastrectomy: World's first case report.

Laparoscopic sleeve gastrectomy (LSG) is the most commonly performed bariatric surgery worldwide. De novo gastroesophageal reflux disease after LSG has been reported in the range of 0%-34.9%. Benign lower oesophageal peptic stricture is rare and has not been reported till date. We present the first case report of benign oesophageal peptic stricture post-sleeve gastrectomy and its management. The management modalities for peptic stricture post-LSG include proton pump inhibitors, endoscopic dilatation and surgical management. Revisional Roux-en-Y gastric bypass along with optimal usage of serial dilatation and medical treatment has been shown to be an effective treatment for the same.

A Smart Nanotherapeutic Agent for in†vitro and in†vivo Reversal of Heavy-Metal-Induced Causality: Key Information from Optical Spectroscopy.

Human exposure to heavy metals can cause a variety of life-threatening disorders, affecting almost every organ of the body, including the nervous, circulatory, cardiac, excretory, and hepatic systems. The presence of heavy metal (cause) and induced oxidative stress (effect) are both responsible for the observed toxic effects. The conventional and effective way to combat heavy metal overload diseases is through use of metal chelators. However, they possess several side effects and most importantly they fail to manage the entire causality. In this study, we introduce citrate-functionalized Mn3 O4 nanoparticles (C-Mn3 O4 NPs) as an efficient chelating agent for treatment of heavy metal overload diseases. By means of UV/Vis absorbance and steady-state fluorescence spectroscopic techniques we investigated the efficacy of the NPs in chelation of a model heavy metal, lead (Pb). We also explored the retention of antioxidant properties of the Pb-chelated C-Mn3 O4 NPs using a UV/Vis-assisted DPPH assay. Through CD spectroscopic studies we established that the NPs can reverse the Pb-induced structural modifications of biological macromolecules. We also studied the in vivo efficacy of NPs in Pb-intoxicated C57BL/6j mice. The NPs were not only able to mobilize the Pb from various organs through chelation, but also saved the organs from oxidative damage. Thus, the C-Mn3 O4 NPs could be an effective nanotherapeutic agent for complete reversal of heavy-metal-induced toxicity through chelation of the heavy metal and healing of the associated oxidative stress.

Rationalization of a traditional liver medicine using systems biology approach and its evaluation in preclinical trial.

'Bottom-up', i.e., molecule to medicine strategy for the discovery of new drugs takes enormous time and cost. In most of the cases, inherent toxicity and undesired side effects of the developed drug hinder its way beyond the early stages of development. In this regard, the systems pharmacology can play an excellent role by reducing the cost and time of drug development through rationalization and/or repurposing of traditional drugs with known side effects. In the present study, our aim was to develop an integrated systems biology method for the prediction of active ingredients of a traditional medicine and their potential targets inside the body. Further, we evaluated the predictive capacity of the developed method in a preclinical animal model. Here, we have prepared a formulation (SKP17LIV01) from an extract of eight medicinal plants traditionally used as liver medicine and identified the constituents using UHPLC-MS technique. Using systems biology approach, we have rationalized the components of the formulation for potential use in the treatment of heavy metal-induced hepatotoxicity. The active ingredients and potential therapeutic targets were also predicted. A detailed biochemical, histopathological and molecular study on the mice model of lead toxicity confirms the efficacy of the formulation as per prediction by the systems pharmacology approach. The study may open a new frontier for re-discovery of drugs that are already used in traditional medicine.

Impact of Bariatric Surgery on Female Reproductive Health and Maternal Outcomes.

INTRODUCTION: Obesity has a derogatory effect on female reproductive health. Obesity contributes to difficulty in natural conception, increased risk of pregnancy-associated complications, miscarriages, congenital anomalies, and also the long-term negative impact on both mother and the child. OBJECTIVES: Our study aimed to analyze and assess the reproductive health-associated outcomes of females who underwent bariatric surgery. METHODS: We performed a retrospective analysis from a prospectively collected database from June 2013 to June2016. Out of 71 females studied, 45 patients (63.5%) had completed 3 years of follow-up. The data were collected from inpatient and outpatient records. Patients were studied under three groups (A, patients with polycystic ovarian disease (PCOD) symptoms; B, patients with primary infertility; and C, patients who conceived after bariatric surgery that were included in groups A and B). RESULTS: Out of 45 patients studied, 40 patients underwent laparoscopic sleeve gastrectomy (LSG), four patients underwent laparoscopic Roux-en-Y gastric bypass (RYGB), and one patient underwent laparoscopic adjustable gastric banding (LAGB). The mean BMI of the patients was 43.64 ± 6.8 kg/m2. PCOD symptoms improved symptomatically (p = 0.001) after surgery in the group. Seven (43.75%) primary infertility patients conceived after surgery. Three (42.9%) patients conceived naturally while 4 (57.1%) conceived with ART in group B. Out of total population of 45 in group C, percentages of patients who delivered baby with short gestational age (SGA), low birth weight (LBW), normal vaginal deliveries (NVD), and maternal anemia were 63.15%,47.3%,73.4%, and26.3%, respectively. CONCLUSION: Obesity is closely associated with primary infertility and PCOD. Menstrual abnormalities associated with PCOD significantly improve after bariatric surgery with significant improvement in fertility along with maternal outcomes.

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.

Long-term outcomes of laparoscopic sleeve gastrectomy from the Indian subcontinent.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is the most commonly performed metabolic surgery worldwide. There are few mid- to long-term studies for LSG, especially from the Indian subcontinent. OBJECTIVE: The primary outcome of the study was percent total weight loss (%TWL), and secondary outcomes included type 2 diabetes mellitus remission (T2DM) rates, comorbidity resolution rates, revisional surgeries, and complications related to LSG, 3 and 5 years after surgery. METHOD: The study was a single-center, retrospective analysis from patients who underwent primary as well as revisional LSG between January 2012 and December 2013 from a tertiary care center in India. We included patients who completed a minimum follow-up of 5 years. Details of the patients were collected from outpatient and inpatient case sheet records, during their follow-up. RESULTS: Out of a total of 284 patients, 57% were females. Mean baseline body mass index (BMI) was 44.9 ± 7.9 kg/m2. The diabetic population comprised 14.8% of the total patients. Mean %TWL at 5 years was 26.0 ± 9.9%. T2DM remission at 1, 3, and 5 years were 78.5%, 71.4%, and 66.6%, respectively. Preoperative BMI (p = 0.02), glycosylated hemoglobin (HbA1c) (p = 0.04), duration of diabetes in years (p = 0.04), and preoperative insulin usage (p = 0.04) were the preoperative predictors for T2DM remission. Early (< 30 days) and late (> 30 days) complications were seen in 4.5% and 0.7% of the population, respectively. CONCLUSION: Weight loss after LSG was maintained in the majority of the patients, while a small proportion has significant weight regain at 5 years. T2DM resolution and other comorbidity resolutions were well supported after LSG.

Gastroesophageal reflux-related physiologic changes after sleeve gastrectomy and Roux-en-Y gastric bypass: a prospective comparative study.

BACKGROUND: The development of gastroesophageal reflux disease (GERD) after laparoscopic sleeve gastrectomy (LSG) is a major concern as it affects the quality of life of the patients and potentially exposes them to the complications of GERD. The reported incidence of GERD after LSG is up to 35%. Laparoscopic Roux-en-Y gastric bypass (LRYGB) is considered the procedure of choice for patients with morbid obesity with GERD but objective evidence based on physiologic studies for the same are limited. OBJECTIVE: The objectives of the study were to determine the physiologic changes related to gastroesophageal reflux based on symptoms index, 24-hour pH study, impedance, and manometry after LSG and LRYGB. SETTINGS: Tertiary care teaching hospital, India. METHODS: This registered study (CTRI/2017/06/008834) is a prospective, nonrandomized, open-label clinical trial comparing the incidence of GERD after LSG and LRYGB. In this study, non-GERD patients were evaluated for GERD based on clinical questionnaires, 24-hour pH study, and impedance manometry preoperatively and 6 months postoperatively. RESULTS: Thirty patients underwent LSG, and 16 patients underwent LRYGB. The mean DeMeester score increased from 10.9 ± 11.8 to 40.2 ± 38.6 (P = .006) after LSG. The incidence of GERD after LSG was 66.6%. The increase in DeMeester score from 9.5 ± 4.6 to 12.2 ± 17.2 after LRYGB was not significant (P = .7). There was a significant increase in the nonacid reflux both after LSG and LRYGB. CONCLUSION: The incidence of GERD after LSG is high, making it a contraindication for LSG. LRYGB remains the preferred procedure for patients with GERD. However, more studies are needed to understand the physiologic changes in patients with preexisting GERD.

Morbid obesity with ventral hernia: is concomitant bariatric surgery with laparoscopic ventral hernia mesh repair the best approach? An experience of over 150 cases.

BACKGROUND: Obesity has been consistently associated with a higher incidence of ventral hernia. It is preferable to treat both obesity and hernia in such patients because, with weight loss, the risk of recurrence of hernia is reduced. Bariatric surgery offers the best treatment for obesity and its associated co-morbidities and in combination with intraperitoneal onlay mesh repair (IPOM) provides the best treatment in such patients. The bariatric surgical team often faces the dilemma of whether to offer concomitant bariatric surgery with IPOM or a staged procedure in such patients because the safety of a concomitant procedure still creates doubt. OBJECTIVES: In this study we present our long-term results of the concomitant approach in such patients to analyze its long-term safety and efficacy. SETTING: Tertiary care teaching hospital, India. METHODS: We have performed a retrospective evaluation of all patients who underwent concomitant bariatric surgery with IPOM for primary or recurrent ventral hernia from January 2003 to July 2017 who completed a minimum follow-up of 12 months. RESULTS: A total of 156 patients of underwent concomitant bariatric surgery with IPOM, 120 patients (body mass index : 43.64 ± 6.8) underwent sleeve gastrectomy, and 36 patients (body mass index: 42.49 ± 8.57) underwent Roux-en-Y gastric bypass. One-hundred and seventeen patients were operated for primary hernia and 39 for recurrent hernia. There were no postoperative mesh infections and only 1 patient had recurrence. CONCLUSION: Bariatric surgery with IPOM provides the patient with a 1-stage treatment for both obesity and ventral hernia along with reduced risk of recurrence as a result of weight loss. It is safe to do a combined procedure in high volume centers with adequate expertise.

Novel one pot synthesis and spectroscopic characterization of a folate-Mn3O4 nanohybrid for potential photodynamic therapeutic application.

Treatment of cancer using nanoparticles made of inorganic and metallic compounds has been increasingly used, owing to their novel intrinsic physical properties and their potential to interact with specific cellular sites, thereby significantly reducing severe secondary effects. In this study, we report a facile strategy for synthesis of folate capped Mn3O4 nanoparticles (FA-Mn3O4 NPs) with high colloidal stability in aqueous media using a hydrothermal method for potential application in photodynamic therapy (PDT) of cancer. The capping of FA to Mn3O4 NPs was confirmed using various spectroscopic techniques. In adenocarcinomic human alveolar basal epithelial cells (A549), the nanohybrid synthesised with a combination of FA and Mn3O4 shows remarkable PDT activity via intracellular ROS generation (singlet oxygen). As established by a DNA fragmentation assay and fluorescence studies, the nanohybrid can cause significant nuclear DNA damage by light induced enhanced ROS generation. In the assessment of Bax, Bcl2 provides strong evidence of apoptotic cellular death. Cumulatively, the outcomes of this study suggest that these newly synthesized FA-Mn3O4 NPs can specifically destroy cells with overexpressed folate receptors, thereby providing a solution in the journey of cancer eradication.

Spectroscopic Studies on Dual Role of Natural Flavonoids in Detoxification of Lead Poisoning: Bench-to-Bedside Preclinical Trial.

Ubiquitousness in the target organs and associated oxidative stress are the most common manifestations of heavy-metal poisoning in living bodies. While chelation of toxic heavy metals is important as therapeutic strategy, scavenging of increased reactive oxygen species, reactive nitrogen species and free radicals are equally important. Here, we have studied the lead (Pb) chelating efficacy of a model flavonoid morin using steady-state and picosecond-resolved optical spectroscopy. The efficacy of morin in presence of other flavonoid (naringin) and polyphenol (ellagic acid) leading to synergistic combination has also been confirmed from the spectroscopic studies. Our studies further reveal that antioxidant activity (2,2-diphenyl-1-picrylhydrazyl assay) of the Pb-morin complex is sustainable compared to that of Pb-free morin. The metal-morin chelate is also found to be significantly soluble compared to that of morin in aqueous media. Heavy-metal chelation and sustainable antioxidant activity of the soluble chelate complex are found to accelerate the Pb-detoxification in the chemical bench (in vitro). Considering the synergistic effect of flavonoids in Pb-detoxification and their omnipresence in medicinal plants, we have prepared a mixture (SKP17LIV01) of flavonoids and polyphenols of plant origin. The mixture has been characterized using high-resolution liquid chromatography assisted mass spectrometry. The mixture (SKP17LIV01) containing 34 flavonoids and 76 other polyphenols have been used to investigate the Pb detoxification in mouse model. The biochemical and histopathological studies on the mouse model confirm the dual action in preclinical studies.

Evolution and Standardisation of Techniques in Single-Incision Laparoscopic Bariatric Surgery.

Bariatric surgery has proven benefits for morbid obesity and its associated comorbidities. Laparoscopic approach is well established for bariatric surgery. Single-incision laparoscopic surgery (SILS) offers even more minimally invasive approach for the same with the added advantage of better cosmesis. We have developed and standardised the SILS approach at our institute. We share our experience and technical "tips" and modifications which we have learnt over the years. Technical details of performing sleeve gastrectomy and Roux-en-Y gastric bypass with special attention to liver retraction, techniques of dissection in difficult areas, creation of anastomoses and suturing have all been described. In our experience and in experience of others, single-incision bariatric surgery is feasible. Use of conventional laparoscopic instruments makes single-incision approach practical for day-to-day practice. Supervised training is essential to learn these techniques.

Concomitant intraperitoneal onlay mesh repair with endoscopic component separation and sleeve gastrectomy.

Bariatric surgery can be safely combined with laparoscopic intraperitoneal onlay mesh (IPOM) repair. In case of large ventral hernias, laparoendoscopic component separation can also be combined to achieve tension-free closure of the defect. Concomitant bariatric surgery and hernia repair also offer the additional benefit of reduction in recurrence of hernias as obesity, one of the risk factors, is treated in the process. We present a case of 60-year-old man with a body mass index of 45.3 kg/m2 with a large recurrent ventral hernia. We performed a lap sleeve gastrectomy with laparoendoscopic anterior component separation with IPOM. The operative steps included hernia contents reduction, conventional sleeve gastrectomy, anterior component separation on either side, intra-corporeal closure of hernia defect and placement of a composite mesh. Patient recovery was uneventful. Concomitant bariatric surgery with laparoendoscopic component separation with IPOM may be safe, but more studies are required.