CB2 Cannabinoid Receptor as a Potential Target in Myocardial Infarction: Exploration of Molecular Pathogenesis and Therapeutic Strategies.

The lipid endocannabinoid system has recently emerged as a novel therapeutic target for several inflammatory and tissue-damaging diseases, including those affecting the cardiovascular system. The primary targets of cannabinoids are cannabinoid type 1 (CB1) and 2 (CB2) receptors. The CB2 receptor is expressed in the cardiomyocytes. While the pathological changes in the myocardium upregulate the CB2 receptor, genetic deletion of the receptor aggravates the changes. The CB2 receptor plays a crucial role in attenuating the advancement of myocardial infarction (MI)-associated pathological changes in the myocardium. Activation of CB2 receptors exerts cardioprotection in MI via numerous molecular pathways. For instance, delta-9-tetrahydrocannabinol attenuated the progression of MI via modulation of the CB2 receptor-dependent anti-inflammatory mechanisms, including suppression of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1ß. Through similar mechanisms, natural and synthetic CB2 receptor ligands repair myocardial tissue damage. This review aims to offer an in-depth discussion on the ameliorative potential of CB2 receptors in myocardial injuries induced by a variety of pathogenic mechanisms. Further, the modulation of autophagy, TGF-ß/Smad3 signaling, MPTP opening, and ROS production are discussed. The molecular correlation of CB2 receptors with cardiac injury markers, such as troponin I, LDH1, and CK-MB, is explored. Special attention has been paid to novel insights into the potential therapeutic implications of CB2 receptor activation in MI.

Sialic Acid Engineered Prodrug Nanoparticles for Codelivery of Bortezomib and Selenium in Tumor Bearing Mice.

Most cancer patients rarely benefit from monodrug therapy because of both cancer complexity and tumor environment. One of the main reasons for this failure is insufficient accumulation of the optimal dose at the tumorous site. Our investigation implies a promising strategy to engineer prodrug nanoparticles (NPs) of bortezomib (BTZ) and selenium (Se) using sialic acid (SAL) as a ligand to improve breast cancer therapy. BTZ was conjugated with SAL and HPMA (N-2-hydroxypropyl methacrylamide) to prepare a prodrug conjugate; BTZ-SAL-HPMA (BSAL-HP) and then fabricated into prodrug NPs with Se (Se_BSAL-HP prodrug NPs). The self-assembly of prodrug NPs functionalized with Se showed size (204.13 ± 0.02 nm) and zeta potential (-31.0 ± 0.11 mV) in dynamic light scattering (DLS) experiments and spherical shape in TEM and SEM analysis. Good stability and low pH drug release profile were characterized by Se_BSAL-HP prodrug NPs. The tumor-selective boronate-ester-based prodrug NPs of BTZ in combination with Se endowed a synergistic effect against cancer cells. Compared to prodrug conjugate, Se_BSAL-HP prodrug NPs exhibited higher cell cytotoxicity and enhanced cellular internalization with significant changes in mitochondria membrane potential (MMP). Elevated apoptosis was observed in the (G2/M) phase of the cell cycle for Se_BSAL-HP prodrug NPs (2.7-fold) higher than BTZ. In vivo studies were performed on Sprague-Dawley rats and resulted in positive trends. The increased therapeutic activity of Se_BSAL-HP prodrug NPs inhibited primary tumor growth and showed 43.05 fold decrease in tumor volume than the control in 4T1 tumor bearing mice. The surprising and remarkable outcomes for Se_BSAL-HP prodrug NPs were probably due to the ROS triggering effect of boronate ester and selenium given together.

N-2-Hydroxypropylmethacrylamide-Polycaprolactone Polymeric Micelles in Co-delivery of Proteasome Inhibitor and Polyphenol: Exploration of Synergism or Antagonism.

Breast cancer leads to the highest mortality among women resulting in a major clinical burden. Multidrug therapy is more efficient in such patients compared to monodrug therapy. Simultaneous combinatorial or co-delivery garnered significant interest in the past years. Caffeic acid (CFA) (a natural polyphenol) has received growing attention because of its anticarcinogenic and antioxidant potential. Bortezomib (BTZ) is a proteasome inhibitor and may be explored for treating breast cancer. Despite its high anticancer activity, the low water solubility and chemical instability restrict its efficacy against solid tumors. In the present study, we designed and investigated a HP-PCL (N-2-hydroxypropylmethacrylamide-polycaprolactone) polymeric micellar (PMCs) system for the simultaneous delivery of BTZ and CFA in the treatment of breast cancer. The designed BTZ+CFA-HP-PCL PMCs were fabricated, optimized, and characterized for size, zeta potential, surface morphology, and in vitro drug release. Developed nanosized (174.6 ± 0.24 nm) PMCs showed enhanced cellular internalization and cell cytotoxicity in both MCF-7 and MDA-MB-231 cells. ROS (reactive oxygen species) levels were highest in BTZ-HP-PCL PMCs, while CFA-HP-PCL PMCs significantly (p < 0.001) scavenged the ROS generated in 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. The mitochondrial membrane potential (MMP) assay revealed intense and significant green fluorescence in both types of cancer cells when treated with BTZ-HP-PCL PMCs (p < 0.001) indicating apoptosis or cell death. The pharmacokinetic studies revealed that BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs exhibited the highest bioavailability, enhanced plasma half-life, decreased volume of distribution, and lower clearance rate than the pure combination of drugs. In the organ biodistribution studies, the combination of BTZ+CFA showed higher distribution in the spleen and the heart. Overall findings of in vitro studies surprisingly resulted in better therapeutic efficiency of BTZ-HP-PCL PMCs than BTZ+CFA-HP-PCL PMCs. However, the in vivo tumor growth inhibition study performed in tumor-induced mice concluded that the tumor growth was inhibited by both BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs (p < 0.0001) more efficiently than pure BTZ and the combination (BTZ+CFA), which may be due to the conversion of boronate ester into boronic acid. Henceforth, the combination of BTZ and CFA provides further indications to be explored in the future to support the hypothesis that BTZ may work with polyphenol (CFA) in the acidic environment of the tumor.

Evaluation of the mosquito larvicidal potential and comparative assessment of the juice of Lantana camara Linn and Ocimum gratissimum Linn.

In the present study, the larvicidal efficacy of the juices of the weeds Lantana camara Linn (L. camara) and Ocimum gratissimum Linn (O. gratissimum) was evaluated against the larvae of the malaria vectors Aedes aegypti, Anopheles subpictus and Culex quinquefasciatus. The freshly prepared juices of leaves were prepared by grinding them and diluting them at concentrations of 25, 50, 75, and 100 ppm. Twenty larvae of each species were introduced in different sterile Petri dishes in aqueous media under a controlled environment for the assessment of biological activity. The larvicidal activity of both juices was evaluated at 6, 12 and 24 h post-exposure time points by observing the movement of each larva. The obtained data were subjected to probit analysis to determine the lethal concentrations that kill 50% and 90% (LC50 and LC90) of the treated larvae. The results revealed a noticeable larvicidal activity following 24 h of exposure. The juice of L. camara leaves exhibited an LC50 range of 47.47-52.06 ppm and an LC90 range of 104.33-106.70 ppm. Moreover, for the juice of O. gratissimum leaves, the LC50 range was 42.94-44.91 ppm and the LC90 range was 105.11-108.66 ppm. Taken together, the results indicate that the juices of L. camara and O. gratissimum leaves may be useful as effective, economical and eco-friendly larvicidal agents. However, additional studies are needed to explore the bioactive components of the weeds that exhibit larvicidal activity along with their mode of action.

Phloridzin attenuates lipopolysaccharide-induced cognitive impairment via antioxidant, anti-inflammatory and neuromodulatory activities.

BACKGROUND: Lipopolysaccharide (LPS) is known to produce neuroinflammation and memory impairment. Although phloridzin (a phenolic phytoconstituent) shows antioxidant- and anti-inflammatory activities, its ameliorative potential in LPS-mediated neuroinflammation and memory dysfunction remains unexplored. OBJECTIVES: To investigate the protective effect of phloridzin against LPS-mediated memory impairment and neuroinflammation in mice. METHODS: Different groups of mice were treated with LPS (250 µg/kg) via intraperitoneal (ip) route to induce cognitive impairments. The animals were administered with phloridzin (10-20 mg/kg, oral) or donepezil (1 mg/kg, intraperitoneal), and memory functions were evaluated by Morris water maze (MWM) and Y-maze. At the end of the behavioral experiments, the animals were sacrificed and different biochemical parameters like acetylcholinesterase (AChE), brain derived neurotropic factor (BDNF), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD) and glutathione (GSH) concentration in the hippocampus and the cerebral cortex were estimated. RESULTS: While LPS administered animals showed significantly decreased memory retention in both MWM and Y maze, a significant reversal in all the parameters were observed following treatment with phloridzin. LPS-treated animals showed significantly decreased level of antioxidants (SOD and GSH), neurotropic factor (BDNF) and cholinergic transmission (increased AChE) and increased levels of inflammatory/oxidative markers (TNF-α, IL-6 and MDA) in hippocampus and cortex. These changes were alleviated after the treatment with phloridzin. CONCLUSIONS: Phloridzin may have neuroprotective role against LPS-induced neuroinflammation and memory impairment by virtue of its antioxidant, anti-inflammatory, and enhanced cholinergic signalling activity in the hippocampus and cerebral cortex.

Sialic Acid Conjugated Chitosan Nanoparticles: Modulation to Target Tumour Cells and Therapeutic Opportunities.

Targeted delivery of therapeutics forestalls the dreadful delocalized effects, drug toxicities and needless immunosuppression. Cancer cells are bounteous with sialic acid and the differential expression of glycosyl transferase, glycosidase and monosaccharide transporter compared to healthy tissues. The current study entails the development and characterisation of sialic acid (SA)-labelled chitosan nanoparticles encapsulating gemcitabine (GEM). Chitosan (CS) was conjugated with SA using coupling reaction and characterised spectroscopically. Furthermore, different concentrations of chitosan and tripolyphosphate (TPP) were optimised to fabricate surface modified chitosan nanoparticles. SA conjugated chitosan nanoparticles encapsulating GEM (SA-CS_GEM NPs) of 232 ± 9.69 nm with narrow distribution (PDI < 0.5) and zeta potential of - 19 ± 0.97 mV was fabricated. GEM was successfully loaded in the SA-CS NPs, depicting prolonged and biphasic drug release pattern more elated at low pH. Pronounced cellular uptake (FITC tagged) and cytotoxicity (IC50 487.4 nM) was observed in SA-CS_GEM NPs against A549 cells. IC50 for SA-CS_GEM NPs plunged with an increase in the time points from 24 to 72 h. Concentration-dependent haemolytic study confirmed significant haemocompatibility of SA-CS_GEM NPs. Pharmacokinetic study was performed on Sprague-Dawley rats and the kinetic parameters were calculated using PKSolver 2.0. Results demonstrated a consequential refinement of 2.98 times in modified SA-CS_GEM NPs with a significant increase in retention time, bioavailability and elimination half-life, and decrease in elimination rate constant and volume of distribution in comparison to CS_GEM NPs. Therefore, SA-CS shell core nanoparticles could be a beneficial approach to target and treat NSCLC (non-small cell lung cancer) and direct for research possibilities to target the other tumour cells.

Efficacy of combination therapy of inositols, antioxidants and vitamins in obese and non-obese women with polycystic ovary syndrome: an observational study.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women of both developed and developing countries. It is associated with insulin resistance, hyperinsulinemia, hyperandrogenism, oxidative stress and various long-term complications. The present study was undertaken to evaluate the efficacy and safety of the supplementation (Trazer F ForteTM-CORONA Remedies Pvt. Ltd.) providing combination of insulin sensitising agents (myo-inositol, D-chiro-inositol and chromium picolinate), antioxidants (N-acetylcysteine and lycopene) and vitamins (vitamin D, biotin and folic acid) in women with PCOS. After 12 weeks of supplementation, a significant improvement was observed in menstrual cyclicity, acne and hirsutism in both obese and lean PCOS patients. A significant reduction was observed in body weight and BMI of obese subjects. However, both parameters remain unchanged in lean subjects. We suggest that combination therapy of insulin sensitising agents, antioxidants and vitamins may be a fruitful approach for the management of PCOS.Impact statementWhat is already known on this subject? Monotherapy of insulin sensitising agents, antioxidants and vitamins is beneficial in the treatment of PCOS.What do the results of this study add? Combined use of insulin sensitising agents (myo-inositol, D-chiro-inositol and chromium picolinate), antioxidants (N-acetylcysteine and lycopene), and vitamins (vitamin D, biotin and folic acid) is safe and effective in obese and non-obese women with PCOS.What are the implications of these findings for clinical practice and/or further research? Since PCOS is a multifactorial and a complex endocrine disorder, combination therapy can be used for the comprehensive management of PCOS.

Lactoferrin Coupled Lower Generation PAMAM Dendrimers for Brain Targeted Delivery of Memantine in Aluminum-Chloride-Induced Alzheimer's Disease in Mice.

Lower generation PAMAM dendrimers have an immense potential for drug delivery with lower toxicity, but these dendrimers yet need certain basic ameliorations. In this study, the brain delivery potential of the synthesized PAMAM-Lf (lower generation PAMAM and lactoferrin conjugate) loaded with memantine (MEM) was explored and evaluated in vitro and in vivo in the disease-induced mouse model. The developed nanoscaffolds were characterized for size, zeta potential and in vitro release. Increase in the average size from 11.54 ± 0.91 to 131.72 ± 4.73 nm, respectively, was observed for drug-loaded PAMAM (i.e., PAMAM-MEM) and PAMAM-Lf (i.e., MEM-PAMAM-Lf).  Release profile of MEM from MEM-PAMAM-Lf was slow and sustained up to 48 h. In vivo biodistribution in the Sprague-Dawley rat model revealed that the brain uptake of MEM-PAMAM-Lf was significantly higher than that of MEM alone. The behavioral response study in the healthy rats did not result in any significant changes. The in vivo study in an AlCl3-induced Alzheimer's (AD) mice model showed a significant improvement in behavioral responses. Optical density, which reflects the acetylcholinesterase (AChE) activity, was highest in the AL group 0.16 ± 0.01 (higher than the CON group, 0.09 ± 0.02; p < 0.05). No significant suppression of AChE activity was recorded in all the other treated groups. Similarly, the DOPAmine and 3,4 dihydroxyphenylacetic acid (DOPAC) levels were unaffected by the developed formulations. The study reported improved brain bioavailability of MEM in AlCl3-induced Alzheimer's mice leading to improved memory, with the resultant mechanism behind in a descriptive manner. This study is among the preliminary studies reporting the memory improvement aspect of PAMAM-Lf conjugates for MEM in AlCl3-AD induced mice. The formulation developed was beneficial in AD-induced mice and had a significant impact on the memory aspects.

Nano-Co-Delivery of Berberine and Anticancer Drug Using PLGA Nanoparticles: Exploration of Better Anticancer Activity and In Vivo Kinetics.

PURPOSE: Combinatorial approach can be beneficial for cancer treatment with better patient recovery. Co-delivery of natural and synthetic anticancer drug not only valuable to achieve better anticancer effectivity but also to ascertain toxicity. This study was aimed to co-deliver berberine (natural origin) and doxorubicin (synthetic origin) utilizing conjugation/encapsulation strategy through poly (lactic-co-glycolic acid) (PLGA) nanoparticles. METHODS: Doxorubicin was efficiently conjugated to PLGA via carbodiimide chemistry and the PLGA-doxorubicin conjugate (PDC) was used for encapsulation of berberine (PDBNP). RESULTS: Significant anti-proliferative against MDA-MB-231 and T47D breast cancer cell lines were observed with IC50 of 1.94 ± 0.22 and 1.02 ± 0.36 µM, which was significantly better than both the bio-actives (p < 0.05). The ROS study revealed that the PDBNP portrayed the slight increase in the reactive oxygen species (ROS) pattern in MDA-MB-231 cell line in a dose-dependent manner, while in T47D cells, no significant change in ROS was seen. PDBNP exhibits significant alteration (depolarization) in mitochondrial membrane permeability and arrest of cell cycle progression at sub G1 phase while the Annexin V/PI assay followed by confocal microscopy resulted into cell death mode to be because of necrosis against MDA-MB-231 cells. In vivo studies in Sprague Dawley rats revealed almost 14-fold increase in half life and a significant increase in plasma drug concentration. CONCLUSION: The overall approach of PLGA based co-delivery of doxorubicin and berberine witnessed synergetic effect and reduced toxicity as evidenced by preliminary toxicity studies.

Boosted Memory and Improved Brain Bioavailability of Rivastigmine: Targeting Effort to the Brain Using Covalently Tethered Lower Generation PAMAM Dendrimers with Lactoferrin.

Currently, there is no treatment strategy which can reverse the process of neuro-degeneration in progression of Alzheimer's disease (AD). Practically, it is desired to achieve and maintain high therapeutic doses in the brain, but it is hard due to selective permeability of the blood-brain barrier (BBB). In the present study, lactoferrin (Lf) was conjugated to polyamidoamine generation 3.0 (PAMAM G3.0) dendrimers for the effective delivery of rivastigmine (RIV) to the brain. Conjugation of PAMAM G3.0 with lactoferrin was confirmed by FT-IR, 1H NMR, and 2D-NMR spectroscopy as well as AFM techniques. Further, RIV was loaded into PAMAM G3.0 and PAMAM-Lf conjugates. RP-HPLC was used to quantify the drug loading and release as well. Spectroscopic analysis confirmed PAMAM-Lf conjugation, the size of the conjugate was 100.04 ± 3.1 nm, and after RIV loading, the size was increased up to 216.13 ± 2.3 nm. Atomic force microscopic results revealed that the root-mean-square roughness ( Rq) and surface roughness ( Ra) were 6.31 and 5.27 nm, respectively, along with other parameters, Skewness and Kurtosis, which were 0.522 and 2.50, respectively. In vitro drug release from the PAMAM-Lf-RIV conjugate was sustained up to more than 100 h, and that of naive RIV was quite rapid (approxmately 99% release was observed in 8 h). Ex vivo hemotoxicity of the PAMAM-Lf-RIV conjugate was almost 9.8-fold lesser than the PAMAM G3.0 ( p < 0.0001), 7.77 times that of PAMAM-enc-RIV and 5 times that of naïve RIV ( p < 0.0001), respectively. The in vivo targeting potency of the conjugate was investigated in a rat model. Bioavailability of the RIV was enhanced 7.87 times compared to RIV along with improved pharmacokinetic parameters. Brain uptake of the drug was improved when treated with PAMAM-Lf-RIV over the RIV and PAMAM-enc-RIV, almost 8 and 4.2 times, respectively, after 4 h of the administration. Additionally, the behavioral studies revealed that PAMAM-Lf-RIV significantly enhanced the overall locomotor activity with higher ambulations over the pure drug and PAMAM-enc-RIV formulation. The outcome of the novel object recognition test was an indirect evidence of memory improvement. Conclusively, the development and characterization of PAMAM-Lf-RIV resulted in improved brain uptake and brain bioavailability with boosted memory, which can be beneficial in the treatment of Alzheimer's.

Chitosan Engineered PAMAM Dendrimers as Nanoconstructs for the Enhanced Anti-Cancer Potential and Improved In vivo Brain Pharmacokinetics of Temozolomide.

PURPOSE: To establish a platform for the possibility of effective and safe delivery of Temozolomide (TMZ) to brain via surface engineered (polyamidoamine) PAMAM dendrimer for the treatment of glioblastoma. METHODS: The present study aims to investigate the efficacy of PAMAM-chitosan conjugate based TMZ nanoformulation (PCT) against gliomas in vitro as well as in vivo. The prepared nanoconjugated formulation was characterized by 1H NMR, FT-IR spectroscopy and for surface morphological parameters. The reported approach was also designed in such a way to ensure toxicity before in vivo delivery through conducting the hemolytic study. RESULT: Surface morphology was found as per nanoformulation via size, pdi and zeta potential measurement. PCT was more efficacious in terms of IC50 values compared to pure TMZ against U-251 and T-98G glioma cell lines. The in vivo pharmacokinetic parameters proved sustained release fashion such as half-life (t1/2) of 22.74 h (PCT) rather than15.35 h (TMZ) only. Higher concentration was found in heart than brain in bio-distribution studies. This study exhibits the potential applicability of dendrimer and CS in improving the anticancer activity and delivery of TMZ to brain. CONCLUSION: The attractive ex vivo cytotoxicity against two glioma cell lines; U-251 and T-98G and phase solubility studies of TMZ revealed remarkable results. In vivo studies of prepared nanoformulation were significant and promising that explored the double concentration of TMZ in brain due to surface functionality of dendrimer. The reported work is novel and non- obvious as none of such approaches using chitosan anchored dendrimer for TMZ delivery has been reported earlier.

Galactose-Anchored Gelatin Nanoparticles for Primaquine Delivery and Improved Pharmacokinetics: A Biodegradable and Safe Approach for Effective Antiplasmodial Activity against P. falciparum 3D7 and in Vivo Hepatocyte Targeting.

Primaquine phosphate (PQ) is mainly used as a radical cure therapy to eradicate relapse of malaria at the liver stage, which is particularly caused by P. falciparum and P. vivax. In the present study, PQ-loaded galactosylated gelatin nanoparticles (Gel-LA-PQ-NPs) were formulated using a one-step desolvation technique. The mean particle size of Gel-LA-PQ-NPs was found to be 93.48 ± 6.36 nm with a zeta potential of 4.80 ± 0.20 mV having 69.90 ± 1.53% encapsulation efficiency. Electron microscopy demonstrated that the NPs were spherical in shape and uniformly distributed without any cluster formation. The in vitro release of PQ from Gel-LA-PQ-NPs has been facilitated in sustained manner, and the release was three times slower than the naïve drug. The prepared nanoparticles (Gel-LA-PQ-NPs) were significantly (p < 0.0001) less hemolytic than the pure drug PQ. The hematological ex vivo study further supported that the developed Gel-LA-PQ-NPs were safer than PQ. The in vitro antiplasmodium assay revealed that the IC50 value against the blood stage of asexual P. falciparum 3D7 strains was significantly (p < 0.01) less (2.862 ± 0.103 µM) for Gel-LA-PQ-NPs than naïve PQ (3.879 ± 0.655 µM). In vivo pharmacokinetic parameters of Gel-LA-PQ-NPs such as half-life and AUC were significantly higher for Gel-LA-PQ-NPs, i.e., with higher bioavailability. Galactosylation of the NPs led to liver targeting of the PQ in animal studies. Approximately eight-fold higher accumulation of PQ was observed in liver compared to pure drug (i.e., PQ). Conclusively, the prepared galactosylated gelatin nanocarrier holds the promising potential and hepatic targetability of an antimalarial, maintaining its safety and biocompatibility.

Current Progress on Central Cholinergic Receptors as Therapeutic Targets for Alzheimer's Disease.

Acetylcholine (ACh) is ubiquitously present in the nervous system and has been involved in the regulation of various brain functions. By modulating synaptic transmission and promoting synaptic plasticity, particularly in the hippocampus and cortex, ACh plays a pivotal role in the regulation of learning and memory. These procognitive actions of ACh are mediated by the neuronal muscarinic and nicotinic cholinergic receptors. The impairment of cholinergic transmission leads to cognitive decline associated with aging and dementia. Therefore, the cholinergic system has been of prime focus when concerned with Alzheimer's disease (AD), the most common cause of dementia. In AD, the extensive destruction of cholinergic neurons occurs by amyloid-ß plaques and tau protein-rich neurofibrillary tangles. Amyloid-ß also blocks cholinergic receptors and obstructs neuronal signaling. This makes the central cholinergic system an important target for the development of drugs for AD. In fact, centrally acting cholinesterase inhibitors like donepezil and rivastigmine are approved for the treatment of AD, although the outcome is not satisfactory. Therefore, identification of specific subtypes of cholinergic receptors involved in the pathogenesis of AD is essential to develop future drugs. Also, the identification of endogenous rescue mechanisms to the cholinergic system can pave the way for new drug development. In this article, we discussed the neuroanatomy of the central cholinergic system. Further, various subtypes of muscarinic and nicotinic receptors involved in the cognition and pathophysiology of AD are described in detail. The article also reviewed primary neurotransmitters that regulate cognitive processes by modulating basal forebrain cholinergic projection neurons.

Pathophysiological and therapeutic implications of neuropeptide S system in neurological disorders.

Neuropeptide S (NPS) is a 20 amino acids-containing neuroactive molecule discovered by the reverse pharmacology method. NPS is detected in specific brain regions like the brainstem, amygdala, and hypothalamus, while its receptor (NPSR) is ubiquitously expressed in the central nervous system (CNS). Besides CNS, NPS and NPSR are also expressed in the peripheral nervous system. NPSR is a G-protein coupled receptor that primarily uses Gq and Gs signaling pathways to mediate the actions of NPS. In animal models of Parkinsonism and Alzheimer's disease, NPS exerts neuroprotective effects. NPS suppresses oxidative stress, anxiety, food intake, and pain, and promotes arousal. NPSR facilitates reward, reinforcement, and addiction-related behaviors. Genetic variation and single nucleotide polymorphism in NPSR are associated with depression, schizophrenia, rheumatoid arthritis, and asthma. NPS interacts with several neurotransmitters including glutamate, noradrenaline, serotonin, corticotropin-releasing factor, and gamma-aminobutyric acid. It also modulates the immune system via augmenting pro-inflammatory cytokines and plays an important role in the pathogenesis of rheumatoid arthritis and asthma. In the present review, we discussed the distribution profile of NPS and NPSR, signaling pathways, and their importance in the pathophysiology of various neurological disorders. We have also proposed the areas where further investigations on the NPS system are warranted.

Lycopene alleviates BCG-induced depressive phenotypes in mice by disrupting 5-HT3 receptor - IDO1 interplay in the brain.

The 5-HT3 receptor and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme play a crucial role in the pathogenesis of depression as their activation reduces serotonin contents in the brain. Since molecular docking analysis revealed lycopene as a potent 5-HT3 receptor antagonist and IDO1 inhibitor, we hypothesized that lycopene might disrupt the interplay between the 5-HT3 receptor and IDO1 to mitigate depression. In mice, the depression-like phenotypes were induced by inoculating Bacillus Calmette-Guerin (BCG). Lycopene (intraperitoneal; i.p.) was administered alone or in combination with 5-HT3 receptor antagonist ondansetron (i.p.) or IDO1 inhibitor minocycline (i.p.), and the behavioral screening was performed by the sucrose preference test, open field test, tail suspension test, and splash test which are based on the different principles. Further, the brains were subjected to the biochemical analysis of serotonin and its precursor tryptophan by the HPLC. The results showed depression-like behavior in BCG-inoculated mice, which was reversed by lycopene administration. Moreover, prior treatment with ondansetron or minocycline potentiated the antidepressant action of lycopene. Minocycline pretreatment also enhanced the antidepressant effect of ondansetron indicating the regulation of IDO1 activity by 5-HT3 receptor-triggered signaling. Biochemical analysis of brain samples revealed a drastic reduction in the levels of tryptophan and serotonin in depressed animals, which were restored following treatment with lycopene and its combination with ondansetron or minocycline. Taken together, the data from molecular docking, behavioral experiments, and biochemical estimation suggest that lycopene might block the 5-HT3 receptor and consequently inhibit the activity of IDO1 to ameliorate BCG-induced depression in mice.

Exploration of hemocompatibility and intratumoral accumulation of paclitaxel after loco-regional administration of thermoresponsive hydrogel composed of poloxamer and xanthan gum: An application to dose-dense chemotherapy.

Although paclitaxel is a front-line chemotherapeutic agent for the treatment of metastatic breast cancer, its intravenous therapy produces deleterious adverse effects. In an attempt to address the issue, the present study aimed to develop a paclitaxel loaded thermosensitive/thermoresponsive hydrogel (PTXNp-TGel) for loco-regional administration to breast tumors to provide dose-dense chemotherapy. Poloxamer and xanthan gum were used to prepare TGel by the cold method. In vitro and in vivo performance of PTXNp-TGel was compared with TGel, pure drug loaded TGel (PTX-TGel) and marketed formulation, Taxol®. The formulated PTXNp-TGel showed acceptable gelation temperature and time (37 °C and 57 s), lower viscosity at room temperature and higher viscosity at body temperature to support sol-gel transition with increasing temperature, and sustained drug release up to 21 days. Additionally, PTXNp-TGel showed negligible hemolytic toxicity as compared to PTX-TGel and Taxol®. Intratumoral administration of PTXNp-TGel produced significantly higher antitumor activity as indicated by lowest relative tumor volume (1.50) and relative antitumor proliferation rate (27.71 %) in comparison with PTX-TGel, Taxol®, and PTXNp (p < 0.05). Finally, insignificant body weight loss during the experimental period, lack of hematotoxicity, nephrotoxicity, and hepatotoxicity imply improved therapeutic performance of the locally administrated dose-dense therapy of PTXNp-TGel as compared to Taxol®.

Carboxymethylated Gums and Derivatization: Strategies and Significance in Drug Delivery and Tissue Engineering.

Natural polysaccharides have been widely exploited in drug delivery and tissue engineering research. They exhibit excellent biocompatibility and fewer adverse effects; however, it is challenging to assess their bioactivities to that of manufactured synthetics because of their intrinsic physicochemical characteristics. Studies showed that the carboxymethylation of polysaccharides considerably increases the aqueous solubility and bioactivities of inherent polysaccharides and offers structural diversity, but it also has some limitations that can be resolved by derivatization or the grafting of carboxymethylated gums. The swelling ratio, flocculation capacity, viscosity, partition coefficient, metal absorption properties, and thermosensitivity of natural polysaccharides have been improved as a result of these changes. In order to create better and functionally enhanced polysaccharides, researchers have modified the structures and properties of carboxymethylated gums. This review summarizes the various ways of modifying carboxymethylated gums, explores the impact that molecular modifications have on their physicochemical characteristics and bioactivities, and sheds light on various applications for the derivatives of carboxymethylated polysaccharides.

Mechanisms of emerging resistance associated with non-antibiotic antimicrobial agents: a state-of-the-art review.

Although the development of resistance by microorganisms to antimicrobial drugs has been recognized as a global public health concern, the contribution of various non-antibiotic antimicrobial agents to the development of antimicrobial resistance (AMR) remains largely neglected. The present review discusses various chemical substances and factors other than typical antibiotics, such as preservatives, disinfectants, biocides, heavy metals and improper chemical sterilization that contribute to the development of AMR. Furthermore, it encompasses the mechanisms like co-resistance and co-selection, horizontal gene transfer, changes in the composition and permeability of cell membrane, efflux pumps, transposons, biofilm formation and enzymatic degradation of antimicrobial chemicals which underlie the development of resistance to various non-antibiotic antimicrobial agents. In addition, the review addresses the resistance-associated changes that develops in microorganisms due to these agents, which ultimately contribute to the development of resistance to antibiotics. In order to prevent the indiscriminate use of chemical substances and create novel therapeutic agents to halt resistance development, a more holistic scientific approach might provide diversified views on crucial factors contributing to the persistence and spread of AMR. The review illustrates the common and less explored mechanisms contributing directly or indirectly to the development of AMR by non-antimicrobial agents that are commonly used.

Neuroinflammation in the Central Nervous System: Exploring the Evolving Influence of Endocannabinoid System.

Neuroinflammation is a complex biological process that typically originates as a protective response in the brain. This inflammatory process is triggered by the release of pro-inflammatory substances like cytokines, prostaglandins, and reactive oxygen and nitrogen species from stimulated endothelial and glial cells, including those with pro-inflammatory functions, in the outer regions. While neuronal inflammation is common in various central nervous system disorders, the specific inflammatory pathways linked with different immune-mediated cell types and the various factors influencing the blood-brain barrier significantly contribute to disease-specific characteristics. The endocannabinoid system consists of cannabinoid receptors, endogenous cannabinoids, and enzymes responsible for synthesizing and metabolizing endocannabinoids. The primary cannabinoid receptor is CB1, predominantly found in specific brain regions such as the brainstem, cerebellum, hippocampus, and cortex. The presence of CB2 receptors in certain brain components, like cultured cerebellar granular cells, Purkinje fibers, and microglia, as well as in the areas like the cerebral cortex, hippocampus, and cerebellum is also evidenced by immunoblotting assays, radioligand binding, and autoradiography studies. Both CB1 and CB2 cannabinoid receptors exhibit noteworthy physiological responses and possess diverse neuromodulatory capabilities. This review primarily aims to outline the distribution of CB1 and CB2 receptors across different brain regions and explore their potential roles in regulating neuroinflammatory processes.

A review on challenges and issues with carboxymethylation of natural gums: The widely used excipients for conventional and novel dosage forms.

Diverse properties of natural gums have made them quite useful for various pharmaceutical applications. However, they suffer from various problems, including unregulated hydration rates, microbial degradation, and decline in viscosity during warehousing. Among various chemical procedures for modification of gums, carboxymethylation has been widely studied due to its simplicity and efficiency. Despite the availability of numerous research articles on natural gums and their uses, a comprehensive review on carboxymethylation of natural gums and their applications in the pharmaceutical and other biomedical fields is not published until now. This review outlines the classification of gums and their derivatization methods. Further, we have discussed various techniques of carboxymethylation, process of determination of degree of substitution, and functionalization pattern of substituted gums. Detailed information about the application of carboxymethyl gums as drug delivery carriers has been described. The article also gives a brief account on tissue engineering and cell delivery potential of carboxymethylated gums.