Mitigating cognitive deficits with teriflunomide: unraveling PI3K-modulated behavioral outcomes in mice.

BACKGROUND: Alzheimer's disease is a leading neurological disorder that gradually impairs memory and cognitive abilities, ultimately leading to the inability to perform even basic daily tasks. Teriflunomide is known to preserve neuronal activity and protect mitochondria in the brain slices exposed to oxidative stress. The current research was undertaken to investigate the teriflunomide's cognitive rescuing abilities against scopolamine-induced comorbid cognitive impairment and its influence on phosphatidylinositol-3-kinase (PI3K) inhibition-mediated behavior alteration in mice. METHODS: Swiss albino mice were divided into 7 groups; vehicle control, scopolamine, donepezil + scopolamine, teriflunomide (10 mg/kg) + scopolamine; teriflunomide (20 mg/kg) + scopolamine, LY294002 and LY294002 + teriflunomide (20 mg/kg). Mice underwent a nine-day protocol, receiving scopolamine injections (2 mg/kg) for the final three days to induce cognitive impairment. Donepezil, teriflunomide, and LY294002 treatments were given continuously for 9 days. MWM, Y-maze, OFT and rota-rod tests were conducted on days 7 and 9. On the last day, blood samples were collected for serum TNF-α analysis, after which the mice were sacrificed, and brain samples were harvested for oxidative stress analysis. RESULTS: Scopolamine administration for three consecutive days increased the time required to reach the platform in the MWM test, whereas, reduced the percentage of spontaneous alternations in the Y-maze, number of square crossing in OFT and retention time in the rota-rod test. In biochemical analysis, scopolamine downregulated the brain GSH level, whereas it upregulated the brain TBARS and serum TNF-α levels. Teriflunomide treatment effectively mitigated all the behavioral and biochemical alterations induced by scopolamine. Furthermore, LY294002 administration reduced the memory function and GSH level, whereas, uplifted the serum TNF-α levels. Teriflunomide abrogated the memory-impairing, GSH-lowering, and TNF-α-increasing effects of LY294002. CONCLUSION: Our results delineate that the improvement in memory, locomotion, and motor coordination might be attributed to the oxidative and inflammatory stress inhibitory potential of teriflunomide. Moreover, PI3K inhibition-induced memory impairment might be attributed to reduced GSH levels and increased TNF-α levels.

Unraveling the mechanistic interplay of mediators orchestrating the neuroprotective potential of harmine.

Neurodegenerative diseases (NDDs) encompass a range of conditions characterized by the specific dysfunction and continual decline of neurons, glial cells, and neural networks within the brain and spinal cord. The majority of NDDs exhibit similar underlying causes, including oxidative stress, neuroinflammation, and malfunctioning of mitochondria. Elevated levels of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside decreased expression of brain-derived neurotrophic factor (BDNF) and glutamate transporter subtype 1 (GLT-1), constitute significant factors contributing to the pathogenesis of NDDs. Additionally, the dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) gene has emerged as a significant target for the treatment of NDDs at the preclinical level. It significantly contributes to developmental brain defects, early onset neurodegeneration, neuronal loss, and dementia in Down syndrome. Moreover, an impaired ubiquitin-proteosome system (UPS) also plays a pathological role in NDDs. Malfunctioning of UPS leads to abnormal protein buildup or aggregation of α-synuclein. α-Synuclein is a highly soluble unfolded protein that accumulates in Lewy bodies and Lewy neurites in Parkinson's disease and other synucleinopathies. Recent research highlights the promising potential of natural products in combating NDDs relative to conventional therapies. Alkaloids have emerged as promising candidates in the fight against NDDs. Harmine is a tricyclic ß-carboline alkaloid (harmala alkaloid) with one indole nucleus and a six-membered pyrrole ring. It is extracted from Banisteria caapi and Peganum harmala L. and exhibits diverse pharmacological properties, encompassing neuroprotective, antioxidant, anti-inflammatory, antidepressant, etc. Harmine has been reported to mediate its neuroprotective via reducing the level of inflammatory mediators, NADPH oxidase, AChE, BChE and reactive oxygen species (ROS). Whereas, it has been observed to increase the levels of BDNF, GLT-1 and anti-oxidant enzymes, along with protein kinase-A (PKA)-mediated UPS activation. This review aims to discuss the mechanistic interplay of various mediators involved in the neuroprotective effect of harmine.

Genistein mitigates nitroglycerine-induced migraine: modulation of nitric oxide-mediated vasodilation and oxidative stress.

Migraine is a widespread brain condition described by frequent, recurrent episodes of incapacitating, moderate-to-severe headaches with throbbing pain that are usually one-sided. It is the 2nd most debilitating state lived with disability in terms of years, with a prevalence rate of 15-20%. Significant drops in estrogen levels have been associated with triggering acute migraine attacks in certain cases. Phytoestrogens are plant-derived compounds that resemble estrogen in structure, enabling them to imitate estrogen's functions in the body by attaching to estrogen receptors. Thus, the study was aimed to explore the protective effect of genistein against migraine. Moreover, the role of nitric oxide was also studied in the observed effect of genistein. Nitric oxide (NO) is implicated in migraine pathophysiology due to its role in promoting cerebral vasodilation and modulation of pain perception. Exploring L-NAME, a nitric oxide synthase inhibitor in migraine research helps scientists better understand the role of NO in migraine. Nitroglycerine treatment significantly increased the facial-unilateral head pain and spontaneous pain, as evidenced by the increased number of head scratching and groomings. Nitroglycerine treatment also induced anxiogenic behavior in mice. A significant reduction in the number of entries in the light phase and open arm, respectively. Biochemical analysis indicated a significant increase in inflammatory and oxidative stress in the nitroglycerin group. A significant increase and decrease in brain TBARS and GSH were observed with nitroglycerine treatment, respectively. Moreover, nitroglycerine treatment has uplifted the serum TNF-α level. Genistein (20 mg/kg) significantly mitigated the facial-unilateral head pain, spontaneous pain, photophobia, and anxiety-like behavior induced by nitroglycerine. Biochemical analysis showed that genistein (20 mg/kg) significantly abrogated the nitroglycerine-induced lipid peroxidation and increased serum TNF-α level. Genistein treatment also upregulated the brain GSH level and downregulated the serum TNF-α level. The L-NAME-mediated alleviation of the protective effect of genistein might be attributed to the vasodilatory effect of L-NAME. Conclusively, it can be suggested that genistein might provide relief from migraine pain by inhibiting nitric oxide-mediated vasodilation and oxidative stress.

Nucleic acids based integrated macromolecular complexes for SiRNA delivery: Recent advancements.

The therapeutic potential of small interfering RNA (siRNA) is monumental, offering a pathway to silence disease-causing genes with precision. However, the delivery of siRNA to target cells in-vivo remains a formidable challenge, owing to degradation by nucleases, poor cellular uptake and immunogenicity. This overview examines recent advancements in the design and application of nucleic acid-based integrated macromolecular complexes for the efficient delivery of siRNA. We dissect the innovative delivery vectors developed in recent years, including lipid-based nanoparticles, polymeric carriers, dendrimer complexes and hybrid systems that incorporate stimuli-responsive elements for targeted and controlled release. Advancements in bioconjugation techniques, active targeting strategies and nanotechnology-enabled delivery platforms are evaluated for their contribution to enhancing siRNA delivery. It also addresses the complex interplay between delivery system design and biological barriers, highlighting the dynamic progress and remaining hurdles in translating siRNA therapies from bench to bedside. By offering a comprehensive overview of current strategies and emerging technologies, we underscore the future directions and potential impact of siRNA delivery systems in personalized medicine.

Glycitein prevents reserpine-induced depression and associated comorbidities in mice: modulation of lipid peroxidation and TNF-α levels.

Depression is a debilitating mood disorder affecting millions worldwide and continues to pose a significant global health burden. Due to the multifaceted nature of depression, the current treatment regimens are not up to mark in terms of their multitargeting potential and least side effect profile. Molecules within the isoflavone class demonstrate promising potential in alleviating depression and associated conditions, offering a multifaceted approach to manage mental health concerns. Therefore, the current study was designed to explore the potential of glycitein, an isoflavone in managing reserpine-induced depression and associated comorbidities in mice. Reserpine (0.5 mg/kg; i.p.) administration for the first 3 days induced depression and associated comorbidities as evidenced by increased immobility time in forced swim test (FST) and tail suspension test (TST), along with reduced locomotor activity in the open field test (OFT) and increased latency to reach the platform in the Morris water maze (MWM) test. Reserpine treatment also upregulated and downregulated the brain thiobarbituric acid reactive substance (TBARS) and glutathione (GSH) levels, respectively. Furthermore, reserpine administration also uplifted the level of TNF-α in the serum samples. Glycitein (3 mg/kg and 6 mg/kg; p.o.) treatment for 5 days prevented the depressive effect of reserpine. It also improved the spatial memory at both dose levels. Moreover, in biochemical analysis, glycitein also reduced the brain TBARS and serum tumor necrosis factor-alpha (TNF-α) levels. Whereas, no significant effect was seen on the brain GSH level. Glycitein (6 mg/kg) was found to be more effective than the 3 mg/kg dose of glycitein. Overall results delineate that glycitein has the potential to manage depression and impaired memory by inhibiting lipid peroxidation and inflammatory stress.

Mechanistic interplay of different mediators involved in mediating the anti-depressant effect of isoflavones.

Depression is one of the most prevalent severe CNS disorders, which negatively affects social lives, the ability to work, and the health of people. As per the World Health Organisation (WHO), it is a psychological disorder that is estimated to be a leading disease by 2030. Clinically, various medicines have been formulated to treat depression but they are having a setback due to their side effects, slow action, or poor bioavailability. Nowadays, flavonoids are regarded as an essential component in a variety of nutraceutical, pharmaceutical and medicinal. Isoflavones are a distinctive and important subclass of flavonoids that are generally obtained from soybean, chickpeas, and red clover. The molecules of this class have been extensively explored in various CNS disorders including depression and anxiety. Isoflavones such as genistein, daidzein, biochanin-A, formononetin, and glycitein have been reported to exert an anti-depressant effect through the modulation of different mediators. Fatty acid amide hydrolase (FAAH) mediated depletion of anandamide and hypothalamic-pituitary-adrenal (HPA) axis-mediated modulation of brain-derived neurotrophic factor (BDNF), monoamine oxidase (MAO) mediated depletion of biogenic amines and inflammatory signaling are the important underlying pathways leading to depression. Upregulation in the levels of BDNF, anandamide, antioxidants and monoamines, along with inhibition of MAO, FAAH, HPA axis, and inflammatory stress are the major modulations produced by different isoflavones in the observed anti-depressant effect. Therefore, the present review has been designed to explore the mechanistic interplay of various mediators involved in mediating the anti-depressant action of different isoflavones.

Neuroprotective potential of formononetin, a naturally occurring isoflavone phytoestrogen.

The increased prevalence of neurological illnesses is a burgeoning challenge to the public healthcare system and presents greater financial pressure. Formononetin, an O-methylated isoflavone, has gained a lot of attention due to its neuroprotective potential explored in several investigations. Formononetin is widely found in legumes and several types of clovers including Trifolium pratense L., Astragalus membranaceus, Sophora tomentosa, etc. Formononetin modulates various endogenous mediators to confer neuroprotection. It prevents RAGE activation that results in the inhibition of neuronal damage via downregulating the level of ROS and proinflammatory cytokines. Furthermore, formononetin also increases the expression of ADAM-10, which affects the pathology of neurodegenerative disease by lowering tau phosphorylation, maintaining synaptic plasticity, and boosting hippocampus neurogenesis. Besides these, formononetin also increases the expression of antioxidants, Nrf-2, PI3K, ApoJ, and LRP1. Whereas, reduces the expression of p65-NF-κB and proinflammatory cytokines. It also inhibits the deposition of Aß and MAO-B activity. An inhibition of Aß/RAGE-induced activation of MAPK and NOX governs the protection elicited by formononetin against inflammatory and oxidative stress-induced neuronal damage. Besides this, PI3K/Akt and ER-α-mediated activation of ADAM10, ApoJ/LRP1-mediated clearance of Aß, and MAO-B inhibition-mediated preservation of dopaminergic neurons integrity are the major modulations produced by formononetin. This review covers the biosynthesis of formononetin and key molecular pathways modulated by formononetin to confer neuroprotection.

Signaling Pathways Involved in the Neuroprotective Effect of Osthole: Evidence and Mechanisms.

Neurodegenerative diseases constitute a major threat to human health and are usually accompanied by progressive structural and functional loss of neurons. Abnormalities in synaptic plasticity are involved in neurodegenerative disorders. Aberrant cell signaling cascades play a predominant role in the initiation, progress as well as in the severity of these ailments. Notch signaling is a pivotal role in the maintenance of neural stem cells and also participates in neurogenesis. PI3k/Akt cascade regulates different biological processes including cell proliferation, apoptosis, and metabolism. It regulates neurotoxicity and mediates the survival of neurons. Moreover, the activated BDNF/TrkB cascade is involved in promoting the transcription of genes responsible for cell survival and neurogenesis. Despite significant progress made in delineating the underlying pathological mechanisms involved and derangements in cellular metabolic promenades implicated in these diseases, satisfactory strategies for the clinical management of these ailments are yet to be achieved. Therefore, the molecules targeting these cell signaling cascades may emerge as useful leads in developing newer management strategies. Osthole is an important ingredient of traditional Chinese medicinal plants, often found in various plants of the Apiaceae family and has been observed to target these aforementioned mediators. Until now, no review has been aimed to discuss the possible molecular signaling cascades involved in osthole-mediated neuroprotection at one platform. The current review aimed to explore the interplay of various mediators and the modulation of the different molecular signaling cascades in osthole-mediated neuroprotection. This review could open new insights into research involving diseases of neuronal origin, especially the effect on neurodegeneration, neurogenesis, and synaptic plasticity. The articles gathered to compose the current review were extracted by using the PubMed, Scopus, Science Direct, and Web of Science databases. A methodical approach was used to integrate and discuss all published original reports describing the modulation of different mediators by osthole to confer neuroprotection at one platform to provide possible molecular pathways. Based on the inclusion and exclusion criteria, 32 articles were included in the systematic review. Moreover, literature evidence was also used to construct the biosynthetic pathway of osthole. The current review reveals that osthole promotes neurogenesis and neuronal functioning via stimulation of Notch, BDNF/Trk, and P13k/Akt signaling pathways. It upregulates the expression of various proteins, such as BDNF, TrkB, CREB, Nrf-2, P13k, and Akt. Activation of Wnt by osthole, in turn, regulates downstream GSK-1ß to inhibit tau phosphorylation and ß-catenin degradation to prevent neuronal apoptosis. The activation of Wnt and inhibition of oxidative stress, Aß, and GSK-3ß mediated ß-catenin degradation by osthole might also be involved in mediating the protection against neurodegenerative diseases. Furthermore, it also inhibits neuroinflammation by suppressing MAPK/NF-κB-mediated transcription of genes involved in the generation of inflammatory cytokines and NLRP-3 inflammasomes. This review delineates the various underlying signaling pathways involved in mediating the neuroprotective effect of osthole. Modulation of Notch, BDNF/Trk, MAPK/NF-κB, and P13k/Akt signaling pathways by osthole confers protection against neurodegenerative diseases. The preclinical effects of osthole suggest that it could be a valuable molecule in inspiring the development of new drugs for the management of neurodegenerative diseases and demands clinical studies to explore its potential. An effort has been made to unify the varied mechanisms and target sites involved in the neuroprotective effect of osthole. The comprehensive description of the molecular pathways in the present work reflects its originality and thoroughness. The reviewed literature findings may be extrapolated to suggest the role of othole as a "biological response modifier" which contributes to neuroprotection through kinase modulatory, immunomodulatory, and anti-oxidative activity, which is documented even at lower doses. The current review attempts to emphasize the gaps in the existing literature which can be explored in the future.

Beyond Molecular Recognition: A Perylene Bisimide Derivative as a Functional Mimic of Chlorpyrifos.

Supramolecular assemblies of perylene bisimide derivative (PBI-SAH) have been developed which show 'turn-on' detection of chlorpyrifos in aqueous media, apple residue and blood serum. Differently from the already reported fluorescent probes for the detection of CPF, PBI-SAH assemblies also show affinity for acetylcholinesterase (AChE) which endow the PBI-SAH molecules with mixed inhibitory potential to restrict the AChE catalysed hydrolysis of acetylthiocholine (ATCh) in MG-63 cell lines (in vitro) and in mice (in vivo). The molecular docking studies support the inhibitory activity of PBI-SAH assemblies and their potential to act as safe insecticide with high benefit to harm ratio. The insecticidal potential of PBI-SAH derivative has been examined against Spodoptera litura (S. litura) and these studies demonstrate its excellent insecticidal activity (100 % mortality in nineteen days). To the best of our knowledge, this is the first report regarding development of PBI-SAH assemblies which not only detect chlorpyrifos but also mimic AChE inhibitory activity of CPF to show promising aptitude as safe insecticide.

Remote Estimation of Blood Pressure Using Millimeter-Wave Frequency-Modulated Continuous-Wave Radar.

This paper proposes to remotely estimate a human subject's blood pressure using a millimeter-wave radar system. High blood pressure is a critical health threat that can lead to diseases including heart attacks, strokes, kidney disease, and vision loss. The commonest method of measuring blood pressure is based on a cuff that is contact-based, non-continuous, and cumbersome to wear. Continuous remote monitoring of blood pressure can facilitate early detection and treatment of heart disease. This paper investigates the possibility of using millimeter-wave frequency-modulated continuous-wave radar to measure the heart blood pressure by means of pulse wave velocity (PWV). PWV is known to be highly correlated with blood pressure, which can be measured by pulse transit time. We measured PWV using a two-millimeter wave radar focused on the subject's chest and wrist. The measured time delay provided the PWV given the length from the chest to the wrist. In addition, we analyzed the measured radar signal from the wrist because the shape of the pulse wave purveyed information on blood pressure. We investigated the area under the curve (AUC) as a feature and found that AUC is strongly correlated with blood pressure. In the experiment, five human subjects were measured 50 times each after performing different activities intended to influence blood pressure. We used artificial neural networks to estimate systolic blood pressure (SBP) and diastolic blood pressure (SBP) with both PWV and AUC as inputs. The resulting root mean square errors of estimated blood pressure were 3.33 mmHg for SBP and 3.14 mmHg for DBP.

Neuroprotective potential of biochanin-A and review of the molecular mechanisms involved.

Biochanin-A is a naturally occurring plant phytoestrogen, which mimics specific the agonistic activity of estrogens. Biochanin-A is known to possess numerous activities, including neuroprotective, anti-diabetic, hepatoprotective, anti-inflammatory, antioxidant, and antimicrobial activities, along with the anticancer activity. Neuroinflammation is thought to play a pivotal pathological role in neurodegenerative disease. Sustained neuroinflammatory processes lead to progressive neuronal damage in Parkinson's and Alzheimer's disease. Activation of PI3K/Akt cascade and inhibition of MAPK signaling cascade have been observed to be responsible for conferring protection against neuroinflammation in neurodegenerative diseases. An increased oxidative stress promotes neuronal apoptosis via potentiating the TLR-4/NF-κB and inhibiting PI3K/Akt signaling mediated increase in pro-apoptotic and decreases in antiapoptotic proteins. Various authors have explored biochanin-A's neuroprotective effect by using various cell lines and animal models. Biochanin-A has been reported to mediate its neuroprotective via reducing the level of oxidants, inflammatory mediators, MAPK, TLR-4, NF-κB, NADPH oxidase, AchE, COX-2 and iNOS. Whereas, it has been observed to increase the level of anti-oxidants, along with phosphorylation of PI3K and Akt proteins. The current review has been designed to provide insights into the neuroprotective effect of biochanin-A and possible signaling pathways leading to protection against neuroinflammation and apoptosis in the central nervous system. This review will be helpful in guiding future researchers to further explore biochanin A at a mechanistic level to obtain useful lead molecules.

Exploring the possible mechanism involved in the anti-nociceptive effect of ß-sitosterol: modulation of oxidative stress, nitric oxide and IL-6.

Β-sitosterol is a phytosterol, documented to possess various activities including protection against inflammation, diabetes and Alzheimer's disease. The current investigation was designed to explore the analgesic potential of ß-sitosterol and the possible molecular mechanism involved in the observed effect. ß-sitosterol was administered at varying doses of 10, 20, and 40 mg/kg before subjecting the mice to acetic acid and formalin challenges. The number of writhings in acetic acid and the number of flinchings and foot tappings were quantified in the formalin test. For mechanistic studies, substance P (cyclooxygenase-2 (COX-2) stimulator) and L-Nitro arginine methyl ester (L-NAME) (nitric oxide synthetases (NOS) inhibitor) and L-arginine (nitric oxide precursor) were administered before ß-sitosterol treatment. ß-sitosterol (10, 20, 40 mg/kg) treatment significantly reduced acetic acid-induced writhings and ameliorated the formalin-induced inflammatory phase dose-dependently. Whereas, 40 mg/kg dose of ß-sitosterol abrogated the formalin-induced neurogenic phase. Substance-P abrogated the effect of ß-sitosterol in both neurogenic and inflammatory phases. Whereas, L-arginine only abrogated the inflammatory phase. In biochemical analysis, ß-sitosterol treatment reduced the level of interleukin-6 (IL-6), thiobarbituric acid reactive substances (TBARS) and increased the level of reduced glutathione (GSH). Furthermore, L-arginine and substance-P abrogated the GSH increasing and TBARS lowering effect of ß-sitosterol (40 mg/kg). Overall, the current study delineated that ß-sitosterol may induce an anti-nociceptive effect via inhibiting the IL-6, oxidative stress, cyclo-oxygenase and nitric oxide.

Prognostic Nutritional Index Prior to Rectal Cancer Resection Predicts Overall Survival.

Prognostic nutritional index (PNI) correlates with postoperative complications and survival in colorectal cancers. Separate studies for rectal cancers are not available where the majority have preoperative radiation, operated by minimally invasive approaches and have diverting ostomies.Consecutive rectal resections between October 2014 and December 2017 from a single center were included. PNI was calculated as 10 x (serum Albumin) + 0.005 x TLC (per mm3) before operation. Multivariate cox regression was used with overall survival (OS) as the dependent variable. Interaction terms of PNI with neoadjuvant therapy, surgical approach and postoperative complications were used to assess specific subgroups.Three-hundred forty elective rectal resections were included with a mean PNI of 46.711 (SD - 6.692), and a median follow up of 44 mo. In multivariable regression, PNI predicted OS (HR - 0.943; p-0.001). Interaction of PNI with preoperative radiation or surgical approach (open, laparoscopic, or robotic) did not change its influence on survival. PNI predicted survival with similar hazard even in patients without major postoperative complicationsDespite routine diversion after rectal resections, PNI predicted OS with an absolute survival benefit of 1.2% at 3-year for every unit increase in PNI irrespective of preoperative therapy or surgical approach.

Identification of plant-based multitargeted leads for Alzheimer's disease: In-vitro and in-vivo validation of Woodfordia fruticosa (L.) Kurz.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disease with no availability of disease-modifying therapeutics. The complex etiology and recent failures in clinical trials indicate the need for multitargeted agents. PURPOSE: The present study aims to discover new plant-based multitargeted anti-AD leads. METHODS: A library of plant extracts was screened for inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1). The secondary metabolites of active extracts were also tested, followed by enzyme-kinetics and molecular modeling to understand the mechanism of inhibition. The most active extract was investigated for in-vivo anti-dementia activity in behavioral mice models. RESULTS: Among the library of 105 extracts, Woodfordia fruticosa (SBE-80) and Bergenia ciliata (SBE-65) extracts displayed significant inhibition of all three enzymes. Gallic acid, one of the constituents of both plants, shows moderate inhibition of AChE and BACE-1. Catechin-3-O-gallate (CG), another constituent of SBE-65, inhibits EeAChE, rHuAChE, and eqBChE with IC50's of 29.9, 1.77, and 8.4 µM, respectively; along with a mild-inhibition of BACE-1. Ellagic acid, the constituent of SBE-80, inhibits BACE-1 with an IC50 value of 16 µM. The W. fruticosa extract SBE-80 at the dose of 25 mg/kg QD × 9 (PO) displayed memory-enhancing activity in Morris Water Maze and Passive Avoidance Test in Swiss albino mice. Treatment with SBE-80 also inhibits AChE in-vivo; whereas, a non-significant decrease in the serum TBARS was observed. CONCLUSION: W. fruticosa is identified for the first time as an anti-AD lead candidate. The in-vitro and in-vivo data presented herein and the documented safety profile of W. fruticosa indicate its strong potential for preclinical development as a botanical drug for dementia/AD.

Mechanistic interplay of various mediators involved in mediating the neuroprotective effect of daphnetin.

Daphnetin is a 7, 8 dihydroxy coumarin isolated from different medicinal plants of the Thymelaeaceae family and exhibits copious pharmacological activities including neuroprotection, anti-cancer, anti-malarial, anti-inflammatory, anti-parasitic and anti-arthritic activity. It has been proved to be an effective neuroprotective agent in several preclinical animal studies and cell line examinations. It is found to interact with different cellular mediators and signaling pathways to confer protection against neurodegeneration. The reactive oxygen species and inflammatory mediators are the major culprits of different neurodegenerative diseases. Oxidative stress activates the pro-apoptotic proteins and inhibits anti-apoptotic proteins, leading to neuronal cell death. Daphnetin restores cellular redox balance by upregulating the antioxidants level (GSH and SOD), anti-apoptotic protein (Bcl-2), as well as by reducing the levels of proinflammatory cytokines, executioner caspase-3, pro-apoptotic-Bax, and oxidative stress markers. Furthermore, activation of Nrf-2/HO-1 signaling and upregulation of HSP-70 governs the protection elicited by daphnetin against oxidative stress-induced neuronal apoptosis. Daphnetin modulated inhibition of JNK-MAPK, JAK-STAT, and TLR-4/NF-κB signaling pathways also contributed to its neuroprotective effect. The positive effects of daphnetin have been also related to its AChE, BChE, and BACE-1 inhibitory potential. The present review has been designed to explore the mechanistic interplay of various mediators in mediating the neuroprotective effects of daphnetin.

Daphnetin, a natural coumarin averts reserpine-induced fibromyalgia in mice: modulation of MAO-A.

Fibromyalgia is a common, chronic, and generalized pain syndrome that is often associated with comorbid depression. The etiology of fibromyalgia is complex; most researchers have documented that the hallmark symptoms are due to the central nervous system's abnormal functioning. Neurotransmitters such as serotonin, norepinephrine, and glutamate, have been reported to be key regulators of fibromyalgia syndrome. Daphnetin is a 7, 8 dihydroxy coumarin widely distributed in Thymelaeaceae family plants, possessing various activities such as anti-arthritic, anti-tumor, anti-malarial, and anti-parasitic. The present study was designed to explore the potential of daphnetin against reserpine-induced fibromyalgia in mice. In mice, a fibromyalgia-like state was achieved by injecting reserpine (0.5 mg/kg, s.c) continuously for 3 days. All behavioral tests were conducted on the 4th and 6th day of experimentation. Reserpine administration significantly increased the mechanical hypersensitivity in electronic von Frey (eVF) and pressure application measurement (PAM) tests. It also increased the immobility period and time to reach the platform in force swim test (FST) and Morris water maze (MWM) test, respectively. In the biochemical analysis, reserpine treatment upregulated the monoamine oxidase-A (MAO-A) activity and level of glutamate, tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), and thiobarbituric acid reactive substances (TBARS). Whereas, it decreased the level of glutathione (GSH), dopamine, serotonin, and norepinephrine. Daphnetin pretreatment attenuated the behavioral and biochemical changes induced by reserpine. Thus, the current investigation results delineate that daphnetin might exert its protective effect by inhibiting inflammatory stress and MAO-A-mediated neurotransmitter depletion and oxidative stress.

Biological Evaluation of Aegle marmelos Fruit Extract and Isolated Aegeline in Alleviating Pain-Depression Dyad: In Silico Analysis of Aegeline on MAO-A and iNOS.

Pain and depression have been assessed to co-occur in up to 80% of patients, and this comorbidity is more debilitating and pricier for the patients as compared to either of these disorders alone. Aegle marmelos is a well-known medicinal plant with a broad spectrum of pharmacological activities. Aegeline is a relatively unexplored molecule present in Aegle marmelos. Therefore, the current investigation aims to explore the potential of Aegle marmelos fruit extract (AMFE) and isolated aegeline against the reserpine-induced pain-depression dyad. In the current investigation, aegeline was isolated from AMFE, followed by spectroscopic characterization, i.e., using NMR and mass analyses. AMFE (200 mg kg-1 p.o) and aegeline (10 mg kg-1 p.o.) were administered to reserpinized (0.5 mg kg-1 s.c.) mice, and clorgyline (3 mg kg-1 i.p.) was taken as the standard drug. AMFE and aegeline significantly alleviated the reserpine-induced reduction in a pain threshold and an increase in immobility as observed in behavioral tests of pain and depression, respectively. In silico molecular docking studies of aegeline showed a good binding interaction at the active sites of MAO-A and iNOS. The in vivo analysis showed that AMFE and aegeline treatment significantly decreased the monoamine oxidase-A (MAO-A) activity, serum interleukin-6 (IL-6) level, and lipid peroxidation, along with an increase in the reduced glutathione level in comparison to the reserpine-treated group. Immunofluorescence studies also showed that AMFE and aegeline abrogated the reserpine-induced increase in iNOS expression. Conclusively, the results delineate that AMFE and aegeline might exert a protective effect via downregulating the MAO-A hyperactivity, IL-6 level, oxidative and nitrosative stress.

Involvement of Oxidative Stress and Nerve Growth Factor in Behavioral and Biochemical Deficits of Experimentally Induced Musculoskeletal Pain in Mice: Ameliorative Effects of Heraclin.

Musculoskeletal pain is a widespread complex regional pain syndrome associated with altered emotional and cognitive functioning along with heightened physical disability that has become a global health concern. Effective management of this disorder and associated disabilities includes accurate diagnosis of its biomarkers and instituting mechanism-based therapeutic interventions. Herein, we explored the role of heraclin, a plant-derived molecule, in musculoskeletal pain and its underlying mechanistic approaches in an experimental mouse model. Reserpine (0.5 mg/kg) for 3 consecutive days evoked hyperalgesia, motor incoordination, lack of exploratory behavior, anxiety, and cognition lapse in mice. Reserpine-challenged mice displayed higher serum cytokine level, altered brain neurotransmitter content, elevated brain and muscle oxidative stress, and upregulated brain nerve growth factor receptor expression. Treatment with heraclin (10 mg/kg for 5 consecutive days) exerted analgesic effect and improved motor coordination and memory deficits in mice. Heraclin arrested serum cytokine rise, normalized brain neurotransmitter content, reduced tissue oxidative stress, and downregulated the nerve growth factor receptor expression. Therefore, it may be suggested that heraclin exerts beneficial effects against reserpine-induced musculoskeletal pain disorder possibly through the attenuation of NGFR-mediated pain and inflammatory signaling. Graphical Abstract.

Skimmetin/osthole mitigates pain-depression dyad via inhibiting inflammatory and oxidative stress-mediated neurotransmitter dysregulation.

Pain and depression are often co-existing pathological states that promote mutual severity resulting in limited efficacy of current treatment strategies. Thus, there is a need to develop an efficacious alternate treatment regimen for pain-depression dyad. Skimmetin and osthole are molecules of natural origin that have been explored for an anti-hyperglycemic, anti-bacterial, anti-fungal, and anti-diabetic activities in preclinical studies. in animal models. The current study has been designed to explore the beneficial effect of skimmetin/osthole in reserpine-induced pain-depression dyad in mice. Female Swiss albino mice (n = 6) were challenged with reserpine (0.5 mg/kg s.c.) for the first 3 days to induce a pain-depression dyad-like state. Skimmetin (10 mg/kg i.p.) and osthole (10 mg/kg i.p.) were administered for 5 days consecutively, starting from the first day of study. Reserpine treatment significantly reduced the pain threshold in the pressure application measurement (PAM) and electronic von frey (eVF) test. In forced swim test (FST) and Morris water maze (MWM) test mice displayed an increased immobility time and latency to reach platform respectively. Biochemical results showed an increased level of TNF-α, IL-1ß, TBARS, glutamate, and reduced level of GSH, norepinephrine, and serotonin in the reserpine treated group. Reserpine treatment also increased brain MAO-A activity. Skimmetin/osthole treatment was found to attenuate the behavioral and biochemical alterations induced by reserpine. The results of the current investigation delineated that skimmetin/osthole may exert anti-nociceptive, anti-depressant, and improved cognition via inhibiting inflammatory and oxidative stress-mediated neurotransmitter dysregulation.

Compliance and perception about personal protective equipment among health care workers involved in the surgery of COVID-19 negative cancer patients during the pandemic.

BACKGROUND: Health care workers (HCWs) are at risk of getting infected while at work, for example, operating room (OR), hence it is pertinent that they don all the appropriate personal protective equipment (PPE) to minimize the chance of getting infected. METHODS: A COVID-19 specific briefing and debriefing form was created and used in the OR along with the World Health Organization surgical safety checklist to reinforce the use of appropriate PPE. An audit was subsequently done to understand the compliance to PPE use, followed by a survey based on the findings of the audit to understand the issues related to noncompliance. RESULTS: The form was used in 183 out of the 238 (77%) surgeries performed during a months' time. The overall compliance for PPE usage was 96.3%. Noncompliance was seen most often for eye protection (45/567) (P = .01). The survey revealed that this was mostly among surgeons mainly due to discomfort, poor visibility, and frequent fogging. CONCLUSIONS: Our HCW were adapting well to the new normal of donning appropriate PPE in the OR, except for the eye protection due to discomfort and visibility related issues. This is important to know so that necessary changes could be introduced to better the compliance.