GSK-3ß: An exuberating neuroinflammatory mediator in Parkinson's disease.

Neuroinflammation is a critical degradative condition affecting neurons in the brain. Progressive neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease (PD) have been strongly linked to neuroinflammation. The trigger point for inflammatory conditions in the cells and body is the physiological immune system. The immune response mediated by glial cells and astrocytes can rectify the physiological alterations occurring in the cell for the time being but prolonged activation leads to pathological progression. The proteins mediating such an inflammatory response, as per the available literature, are undoubtedly GSK-3ß, NLRP3, TNF, PPARγ, and NF-κB, along with a few other mediatory proteins. NLRP3 inflammasome is undeniably a principal instigator of the neuroinflammatory response, but the regulatory pathways controlling its activation are still unclear, besides less clarity for the interplay between different inflammatory proteins. Recent reports have suggested the involvement of GSK-3ß in regulating NLRP3 activation, but the exact mechanistic pathway remains vague. In the current review, we attempt to provide an elaborate description of crosstalk between inflammatory markers and GSK-3ß mediated neuroinflammation progression, linking it to regulatory transcription factors and posttranslational modification of proteins. The recent clinical therapeutic advances targeting these proteins are also discussed in parallel to provide a comprehensive view of the progress made in PD management and lacunas still existing in the field.

Piceatannol promotes neuroprotection by inducing mitophagy and mitobiogenesis in the experimental diabetic peripheral neuropathy and hyperglycemia-induced neurotoxicity.

Piceatannol (PCN), a SIRT1 activator, regulates multiple oxidative stress mechanism and has anti-inflammatory potential in various inflammatory conditions. However, its role in Diabetic insulted peripheral neuropathy (DN) remains unknown. Oxidative stress and mitochondrial dysfunction are major contributing factors to DN. Myriad studies have proven that sirtuin1 (SIRT1) stimulation convalesce nerve functions by activating mitochondrial functions like mitochondrial biogenesis and mitophagy. Diabetic neuropathy (DN) was provoked by injecting streptozotocin (STZ) at a dose of 55 mg/kg, i.p to male Sprague Dawley (SD) rats. Mechanical, thermal hyperalgesia was evaluated by using water immersion, Vonfrey Aesthesiometer, and Randall Sellito Calipers. Motor, sensory nerve conduction velocity was measured using Power Lab 4sp system whereas The Laser Doppler system was used to evaluate nerve blood flow. To induce hyperglycemia for the in vitro investigations, high glucose (HG) (30 mM) conditions were applied to Neuro2a cells. At doses of 5 and 10 µM, PCN was examined for its role in SIRT1 and Nrf2 activation. HG-induced N2A cells, reactive oxygen exposure, mitochondrial superoxides and mitochondrial membrane potentials were restored by PCN exposure, and their neurite outgrowth was enhanced. Peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) directed mitochondrial biogenesis was induced by increased SIRT1 activation by piceatannol. SIRT1 activation also enhanced Nrf2-mediated antioxidant signalling. Our study results inferred that PCN administration can counteract the decline in mitochondrial function and antioxidant activity in diabetic rats and HG-exposed N2A cells by increasing the SIRT1 and Nrf2 activities.

Quality by design (QbD) assisted Fabrication & evaluation of Simvastatin loaded Nano-Enabled thermogel for melanoma therapy.

Melanoma is a form of skin cancer that starts in melanocytes. Rampant chemo-resistance, metastasis, and inability to cross the skin barriers and accumulate within the tumor microenvironment render the conventional chemotherapeutic approaches ineffective. Simvastatin (SIM), a cholesterol synthesis inhibitor, has shown tremendous anticancer potential. Due to the lack of therapeutic alternatives, repositioning SIM in melanoma could be beneficial. Incorporating SIM within the nanoparticles promoted increased melanoma cell internalization, apoptosis, and sustained release profile. Further, the incorporation of nanoparticles into the thermogel facilitated depot formation over the upper dermal layers. Sol-to-gel transition at 34 °C was observed with a 14.03-fold increase in viscosity. This could be fruitful in limiting systemic exposure and preventing adverse effects. Entrapment of SIM in the PLGA NPs enhanced the cytotoxicity by 9.38-fold (p less than 0.05). Nuclear staining with DAPI showed blebbing, membrane shrinkage, and apoptosis confirmed by DCFDA and acridine orange/ethidium bromide staining. Ex vivo diffusion studies revealed the accumulation of C-6 loaded nanoparticles incorporated within the thermogel onto the upper dermal layer and depot formation up to 6 h. Thus, we conclude that SIM-loaded nanoparticulate thermogel could be an efficacious therapeutic alternative for melanoma.

Quality by design steered development of Niclosamide loaded liposomal thermogel for Melanoma: In vitro and Ex vivo evaluation.

Melanoma is the most malignant form of skin cancer across the globe. Conventional therapies are currently ineffective which could be attributed to the rampant chemo-resistance, metastasis, inability to cross the skin barriers and accumulate within the tumor microenvironment. This advent brings in the principles of drug repurposing by repositioning Niclosamide (NIC), an anthelmintic drug for skin cancer. Incorporation into the liposomes facilitated enhanced melanoma cell uptake and apoptosis. Cytotoxicity studies revealed 1.756-fold enhancement in SK-MEL-28 cytotoxicity by NIC-loaded liposomes compared to free drug. Qualitative and quantitative cell internalization indicated greater drug uptake within the melanoma cells illustrating the efficacy of liposomes as efficient carrier systems. Nuclear staining showed blebbing and membrane shrinkage. Elevated ROS levels and apoptosis shown by DCFDA and acridine orange-ethidium bromide staining revealed greater melanoma cell death by liposomes compared to free drug. Incorporating NIC liposomes into the thermogel system restricted the liposomes as a depot onto the upper skin layers. Sustained zero order release up to 48 h with liposomes and 23.58-fold increase in viscosity led to the sol-to-gel transition at 33℃ was observed with liposomal thermogel. Ex vivo gel permeation studies revealed that C-6 loaded liposomes incorporated within the thermogel successfully formed a depot over the upper skin layer for 6 h to prevent transdermal delivery and systemic adverse effects. Thus, it could be concluded that NIC loaded liposomal thermogel system could be an efficacious therapeutic alternative for the management of melanoma.

Nanotechnology based drug delivery systems: Does shape really matter?

As of today, the era of nanomedicine has brought numerous breakthroughs and overcome challenges in the treatment of various disorders. Various factors like size, charge and surface hydrophilicity have garnered significant attention by nanotechnologists. However, more exploration in the field of nanoparticle shape and geometry, one of the basic physical phenomenon is required. Tuning nanoparticle shape and geometry could potentially overcome pitfalls in therapeutics and biomedical fields. Thus, in this article, we unveil the importance of tuning nanoparticle shape selection across the delivery platforms. This article provides an in-depth understanding of nanoparticle shape modulation and advise the researchers on the ideal morphology selection tailored for each implication. We deliberated the importance of nanoparticle shape selection for specific implications with respect to organ targeting, cellular internalization, pharmacokinetics and bio-distribution, protein corona formation as well as RES evasion and tumor targeting. An additional section on the significance of shape transformation, a recently introduced novel avenue with applications in drug delivery was discussed. Furthermore, regulatory concerns towards nanoparticle shape which need to be addressed for harnessing their clinical translation will be explained.

Biomimetic nanotherapeutics: Employing nanoghosts to fight melanoma.

Melanoma is a cancer of melanocytes present at the basal layer of the skin. Nanomedicine has armed us with competent platform to manage such fatal neoplastic diseases. Nevertheless, it suffers from numerous pitfalls such as rapid clearance and opsonization of surface-functionalized carriers, biocompatibility and idiopathic reactions which could be difficult to predict in the patient. Biomimetic approach, a novel step towards personalized medicine bridges these drawbacks by employing endogenous cell membranes to traverse physiological barriers. Camouflaged carriers coated with natural cell membranes possess unique characteristics such as high circulatory periods, and the absence of allogenic and xenogenic responses. Proteins residing on the cell membranes render a diverse range of utilities to the coated nanoparticles including natural efficiency to identify cellular targets, homologous targeting, reticuloendothelial system evasion, biocompatibility and reduced adverse and idiopathic effects. In the present article, we have focused on cell membrane camouflaged nanocarriers for melanoma management. We have discussed various types of biomimetic systems, their processing and coating approaches, and their characterization. We have also enumerated novel avenues in melanoma treatment and the combination of biomimetic systems with smart nanoparticulate systems with the potential to bring breakthroughs in the near future. Additionally, immunotherapy-based biomimetic systems to combat melanoma have been highlighted. Hurdles towards clinical translation and ways to overcome them have been explained in detail.

Heat stress-induced neuroinflammation and aberration in monoamine levels in hypothalamus are associated with temperature dysregulation.

Heat Stress (HS) induces diverse pathophysiological changes, which include brain ischemia, oxidative stress and neuronal damage. The present study was undertaken with the objective to ascertain whether neuroinflammation in Hypothalamus (HTH) caused under HS affects monoamine levels and hence, its physiological role in thermoregulation. Rats were exposed to HS in a heat simulation environmental chamber (Ambient temperature, Ta=45±0.5°C and Relative Humidity, RH=30±10%) with real-time measurement of core temperature (Tc) and skin temperature (Ts). Animals were divided into two subgroups: Moderate HS (MHS) (Tc=40°C) and Severe HS (SHS)/Heat stroke (Tc=42°C). Rats with MHS showed an increase in Mean Arterial Pressure (MAP) and Heart Rate (HR) while fall in MAP and rise in HR was observed in rats with SHS. In addition, oxidative stress and an increase in pyknotic neurons were observed in HTH. High levels of Adrenocorticotropic-hormone (ACTH), Epinephrine (EPI), Norepinephrine (NE) and Dopamine (DA) in the systemic circulation and progressive increase in EPI and DA levels in HTH were recorded after the thermal insult. Moreover, a substantial increase in Glutamate (Glu) level was observed in HTH as well as in systemic circulation of heat stroke rats. We found a rise in NE whereas a fall in Serotonin (5-HT) level in HTH at MHS, without perturbing inflammatory mediators. However, rats with SHS exhibited significant elevations in NF-kB, IL-1ß, COX2, GFAP and Iba1 protein expression in HTH. In conclusion, the data suggest that SHS induces neuroinflammation in HTH, which is associated with monoamines and Glu imbalances, leading to thermoregulatory disruption.

Positive Association of D Allele of ACE Gene With High Altitude Pulmonary Edema in Indian Population.

OBJECTIVE: High altitude pulmonary edema (HAPE) is a potentially fatal high altitude illness occurring as a result of hypobaric hypoxia with an unknown underlying genetic mechanism. Recent studies have shown a possible association between HAPE and polymorphisms in genes of the renin-angiotensin-aldosterone system (RAAS), which play a key role in sensitivity of an individual toward HAPE. METHODS: For the present investigation, study groups consisted of HAPE patients (HAPE) and acclimatized control subjects (rCON). Four single-nucleotide polymorphisms (SNPs) were genotyped using restriction fragment length polymorphism (RFLP) analysis in genes of the RAAS pathway, specifically, renin (REN) C(-4063)T (rs41317140) and RENi8-83 (rs2368564), angiotensin (AGT) M(235)T (rs699), and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) (rs1799752). RESULTS: Only the I/D polymorphism of the ACE gene showed a significant difference between the HAPE and rCON groups. The frequency of the D allele was found to be significantly higher in the HAPE group. Arterial oxygen saturation levels were significantly lower in the HAPE group compared with the rCON group and also decreased in the I/D and D/D genotypes compared with the I/I genotype in these groups. The other polymorphisms occurring in the REN and AGT genes were not significantly different between the 2 groups. CONCLUSIONS: These findings demonstrate a possible association of the I/D polymorphism of the ACE gene with the development of HAPE, with D/D being the at-risk genotype.

Superpulsed (Ga-As, 904 nm) low-level laser therapy (LLLT) attenuates inflammatory response and enhances healing of burn wounds.

Low-level laser therapy (LLLT) using superpulsed near-infrared light can penetrate deeper in the injured tissue and could allow non-pharmacological treatment for chronic wound healing. This study investigated the effects of superpulsed laser (Ga-As 904 nm, 200 ns pulse width; 100 Hz; 0.7 mW mean output power; 0.4 mW/cm(2) average irradiance; 0.2 J/cm(2) total fluence) on the healing of burn wounds in rats, and further explored the probable associated mechanisms of action. Irradiated group exhibited enhanced DNA, total protein, hydroxyproline and hexosamine contents compared to the control and silver sulfadiazine (reference care) treated groups. LLLT exhibited decreased TNF-α level and NF-kB, and up-regulated protein levels of VEGF, FGFR-1, HSP-60, HSP-90, HIF-1α and matrix metalloproteinases-2 and 9 compared to the controls. In conclusion, LLLT using superpulsed 904 nm laser reduced the inflammatory response and was able to enhance cellular proliferation, collagen deposition and wound contraction in the repair process of burn wounds. Photomicrographs showing no, absence inflammation and faster wound contraction in LLLT superpulsed (904 nm) laser treated burn wounds as compared to the non-irradiated control and silver sulfadiazine (SSD) ointment (reference care) treated wounds.

Effect of fly ash on persistence, mobility and bio-efficacy of metribuzin and metsulfuron-methyl in crop fields.

Field evaluation of two fly ashes (40t/ha) on persistence, mobility and bioactivity of metribuzin and metsulfuron-methyl was studied in soybean and wheat crops, respectively. Metribuzin was applied as pre-emergence at 0.5kg/ha, while metsulfuron-methyl was applied post-emergence at 8g/ha. Results suggested that metribuzin in surface (0-15cm) soil of fly ash unamended plots reached below detectable limit in 60 days, while herbicide persisted till 112 days in surface soil of fly ash amended plots. No metribuzin leached down to subsurface (15-30cm) soil in fly ash amended plots, while traces of metribuzin (0.6-1.2µg/kg) were recovered in subsurface soil of fly ash unamended plot. Metsulfuron-methyl in surface soil persisted till 15 days in control and 20 days in fly ash amended plots and no metsulfuron-methyl leached down to subsurface soil. Fly ash amendment had no adverse effect on the bioactivity of herbicides and yield of soybean and wheat. The study suggested that fly ash amendment to soil can be exploited to retain applied herbicides in surface soil.