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Diabetic nephropathy (DN) is a serious microvascular consequence of diabetes mellitus (DM), posing an encumbrance to public health worldwide. Control over the onset and progress of DN depend heavily on early detection and effective treatment. DN is a major contributor to end-stage renal disease, and a complete cure is yet to be achieved with currently available options. Though some therapeutic molecules have exhibited promise in treating DN complications, their poor solubility profile, low bioavailability, poor permeation, high therapeutic dose and associated toxicity, and low patient compliance apprehend their clinical usefulness. Recent research has indicated nano-systems as potential theranostic platforms displaying futuristic promise in the diagnosis and treatment of DN. Early and accurate diagnosis, site-specific delivery and retention by virtue of ligand conjugation, and improved pharmacokinetic profile are amongst the major advantages of nano-platforms, defining their superiority. Thus, the emergence of nanoparticles has offered fresh approaches to the possible diagnostic and therapeutic strategies regarding DN. The present review corroborates an updated overview of different types of nanocarriers regarding potential approaches for the diagnosis and therapy of DN. [ABSTRACT FROM AUTHOR]

The Japanese encephalitis virus (JEV) is the most common cause of neurodegenerative disease in Southeast Asia and the Western Pacific region; approximately 1.15 billion people are at risk, and thousands suffer from permanent neurological disorders across Asian countries, with 10–15 thousand people dying each year. JEV crosses the blood-brain barrier (BBB) and forms a complex with receptors on the surface of neurons. GRP78, Src, TLR7, caveolin-1, and dopamine receptor D2 are involved in JEV binding and entry into the neurons, and these receptors also play a role in carcinogenic activity in cells. JEV binds to GRP78, a member of the HSP70 overexpressed on malignant cells to enter neurons, indicating a higher chance of JEV infection in cancer patients. However, JEV enters human brain microvascular endothelial cells via an endocytic pathway mediated by caveolae and the ezrin protein and also targets dopamine-rich areas for infection of the midbrain via altering dopamine levels. In addition, JEV complexed with CLEC5A receptor of macrophage cells is involved in the breakdown of the BBB and central nervous system (CNS) inflammation. CLEC5A-mediated infection is also responsible for the influx of cytokines into the CNS. In this review, we discuss the neuronal and macrophage surface receptors involved in neuronal death. [ABSTRACT FROM AUTHOR]

This study offers a detailed examination of the Eupen dam’s role in flood mitigation in Belgium’s Vesdre valley, analysing 18 moderate and extreme flood events from 1995-2022. Notable aspects of the methodology include adjustments for an ungauged sub-basin and a mass-balance approach to compute the unknown outflow data from the inflow time-series and reservoir level data. These 18 events evidence the dam’s performance hitherto, with respect to peak discharge attenuation (9-91%), peak delay (0-68 hours), outflow volume reduction (2-94%), as well as discharge reductions associated with various return periods (38-51%), given its multipurpose objectives. The research details how the dam’s effectiveness varies with operational decisions and antecedent reservoir conditions, marking a departure from conventional studies that tend to generalise data across multiple dams and events. By focusing on individual events, the study provides insights into the nuanced interplay between dam operations and flood management, demonstrating the benefits and limitations of multi-purpose reservoirs in flood control. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD. [Display omitted] • A decline in brain glucose levels and metabolism is pathologically linked to AD and dementia. • Insulin resistance and mitochondrial dysfunction are implicated in classic plaque and tangle pathologies of AD. • Aberrant IRS/PI3K/Akt/AMPK signaling and abnormal GLUT activities are directly linked to the etiology of neurodegeneration. • Defective glucose metabolism-induced polyol activation, AGEs accumulation and oxidative stress contribute to AD pathogenesis. • Abnormal glucose metabolism endorses cerebral autophagy/mitophagy dysregulation by hampering lysosome-mitochondrial functions. [ABSTRACT FROM AUTHOR]

In this paper, we analyze sum throughput and (asymptotic) sum ergodic rate performance of two co-existing downlink multiuser underlay secondary networks employing either fixed-rate transmission (FRT) or (channel aware) adaptive rate transmission (ART). In the considered scenario in which two secondary sources may transmit simultaneously, intelligent apportioning the interference temperature limit (ITL) is vital. We consider cases when this ITL apportioning is based on statistical properties of the channels, or on full (or partial) knowledge of the channel gains. For these cases, proper network management (NM) strategies are evolved to maximize sum throughput or sum ergodic rate of the secondary networks. Each NM strategy determines whether both secondary sources should transmit concurrently or not, and also determines their transmit powers. We demonstrate that a channel aware NM strategy is superior to an optimal fixed NM strategy. With secondary sources employing non-opportunistic user selection, in case of FRT (ART), we demonstrate that there exists a critical target-rate (ITL) below which it is advantageous to operate both secondary networks concurrently. We present closed form expressions of critical parameters that influence sum throughput and sum ergodic rate. Computer simulations are presented to corroborate the derived expressions. [ABSTRACT FROM AUTHOR]

In this letter, we derive an expression for the secrecy outage probability of a multiuser underlay downlink in which a selected idle secondary user serves as a friendly jammer to enhance physical-layer secrecy of secondary downlink communication in the presence of a passive eavesdropper. Secondary nodes constrain their transmit powers to ensure that the interference caused to the primary network is below an interference temperature limit $I_P$. We show that careful apportioning of $I_P$ between the secondary source and the selected jammer (which transmit simultaneously), and judicious choice of peak powers, is the key to improving secrecy performance. Computer simulation results demonstrate accuracy of the derived expressions. [ABSTRACT FROM PUBLISHER]

In this letter, we analyze the physical layer secrecy performance of a two-hop cooperative cognitive underlay relay network with a decode and forward relay and a passive eavesdropper. Unlike other works to date, we assume combining of direct and relayed signals at the destination and the eavesdropper. A closed-form expression is derived for secrecy outage probability. We show that ignoring the direct channel leads to pessimistic estimate of secrecy outage. Furthermore, we propose a power backoff method that is shown to improve secrecy outage performance. Computer simulation results demonstrate the accuracy of derived expressions. [ABSTRACT FROM PUBLISHER]

In the mammalian brain, glutamate is regarded to be the primary excitatory neurotransmitter due to its widespread distribution and wide range of metabolic functions. Glutamate plays key roles in regulating neurogenesis, synaptogenesis, neurite outgrowth, and neuron survival in the brain. Ionotropic and metabotropic glutamate receptors, neurotransmitters, neurotensin, neurosteroids, and others co-ordinately formulate a complex glutamatergic network in the brain that maintains optimal excitatory neurotransmission. Cognitive activities are potentially synchronized by the glutamatergic activities in the brain via restoring synaptic plasticity. Dysfunctional glutamate receptors and other glutamatergic components are responsible for the aberrant glutamatergic activity in the brain that cause cognitive impairments, loss of synaptic plasticity, and neuronal damage. Thus, controlling the brain's glutamatergic transmission and modifying glutamate receptor function could be a potential therapeutic strategy for cognitive disorders. Certain drugs that regulate glutamate receptor activities have shown therapeutic promise in improving cognitive functions in preclinical and clinical studies. However, several issues regarding precise functional information of glutamatergic activity are yet to be comprehensively understood. The present article discusses the scope of developing glutamatergic systems as prospective pharmacotherapeutic targets to treat cognitive disorders. Special attention has been given to recent developments, challenges, and future prospects. • Glutamate is the most abundant excitatory neurotransmitter in the brain. • Glutamate receptors and modulators formulate a complex glutamatergic network. • Glutamatergic system maintains cognitive functions by restoring synaptic plasticity. • Abnormal changes in the glutamatergic system could lead to cognitive decline. • Glutamatergic system can be targeted in drug development for cognitive disorders. [ABSTRACT FROM AUTHOR]

• Flavonoids exhibit therapeutic potential against different types of cancer cells. • Poor pharmacokinetics and biopharmaceutical traits limit their therapeutic effects. • Nanocarrier-based formulations of flavonoids display promise to resolve these issues. • Flavonoid nanoformulations showed a better therapeutic effect over free flavonoids. • Site-specific targeting by functionalized nanocarriers boosts therapeutic efficacy. Flavonoids are an interesting class of biomolecules, which exhibit cancer-inhibitory effects through both chemopreventive and chemotherapeutic activities. However, their therapeutic efficacy is affected by poor pharmacokinetics (PK) and biopharmaceutical attributes. One of the most promising approaches to resolve these issues is to formulate flavonoids in nanosystems. Different flavonoid nanoformulations have shown therapeutic superiority over free flavonoids. Functionalization of nanoparticles (NPs) further improves their therapeutic efficacy by facilitating site-specific delivery and reducing nonspecific toxicities. In this review, we highlight recent developments in the field of flavonoid-based NPs to gain translational insights into the potential applications of flavonoid-based nanocarriers in cancer management. [ABSTRACT FROM AUTHOR]

The emergence of a novel coronavirus viz., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 and its subsequent substantial spread produced the coronavirus disease 2019 (COVID-19) pandemic worldwide. Given its unprecedented infectivity and pathogenicity, the COVID-19 pandemic had a devastating impact on human health, and its clinical management has been a great challenge, which has led to the development and speedy trials of several vaccine candidates against SARS-CoV-2 at an exceptional pace. As a result, several COVID-19 vaccines were made commercially available in the first half of 2021. Although several COVID-19 vaccines showed promising results, crucial insights into their epidemiology, protective mechanisms, and the propensities of reinfection are not largely reviewed. In the present report, we provided insights into the prospects of vaccination against COVID-19 and assessed diverse vaccination strategies including DNA, mRNA, protein subunits, vector-based, live attenuated, and inactivated whole/viral particle-based vaccines. Next, we reviewed major aspects of various available vaccines approved by the World Health Organization and by the local administrations to use against COVID-19. Moreover, we comprehensively assessed the success of these approved vaccines and also their untoward effects, including the possibility of reinfection. We also provided an update on the vaccines that are under development and could be promising candidates in the future. Conclusively, we provided insights into the COVID-19 vaccine epidemiology, their potency, and propensity for SARS-CoV-2 reinfection, while a careful review of their current status, strategies, success, and future challenges was also presented. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most prominent neurodegenerative diseases, which impairs cognitive function in afflicted individuals. AD results in gradual decay of neuronal function as a consequence of diverse degenerating events. Several neuroimmune players (such as cytokines and growth factors that are key players in maintaining CNS homeostasis) turn aberrant during crosstalk between the innate and adaptive immunities. This aberrance underlies neuroinflammation and drives neuronal cells toward apoptotic decline. Neuroinflammation involves microglial activation and has been shown to exacerbate AD. This review attempted to elucidate the role of cytokines, growth factors, and associated mechanisms implicated in the course of AD, especially with neuroinflammation. We also evaluated the propensities and specific mechanism(s) of cytokines and growth factors impacting neuron upon apoptotic decline and further shed light on the availability and accessibility of cytokines across the blood-brain barrier and choroid plexus in AD pathophysiology. The pathogenic and the protective roles of macrophage migration and inhibitory factors, neurotrophic factors, hematopoietic-related growth factors, TAU phosphorylation, advanced glycation end products, complement system, and glial cells in AD and neuropsychiatric pathology were also discussed. Taken together, the emerging roles of these factors in AD pathology emphasize the importance of building novel strategies for an effective therapeutic/neuropsychiatric management of AD in clinics. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is one of the principal manifestations of metabolic syndrome and its prevalence with modern lifestyle is increasing incessantly. Chronic hyperglycemia can induce several vascular complications that were referred to be the major cause of morbidity and mortality in DM. Although several therapeutic targets have been identified and accessed clinically, the imminent risk of DM and its prevalence are still ascending. Substantial pieces of evidence revealed that histone deacetylase (HDAC) isoforms can regulate various molecular activities in DM via epigenetic and post-translational regulation of several transcription factors. To date, 18 HDAC isoforms have been identified in mammals that were categorized into four different classes. Classes I, II, and IV are regarded as classical HDACs, which operate through a Zn-based mechanism. In contrast, class III HDACs or Sirtuins depend on nicotinamide adenine dinucleotide (NAD+) for their molecular activity. Functionally, most of the HDAC isoforms can regulate β cell fate, insulin release, insulin expression and signaling, and glucose metabolism. Moreover, the roles of HDAC members have been implicated in the regulation of oxidative stress, inflammation, apoptosis, fibrosis, and other pathological events, which substantially contribute to diabetes-related vascular dysfunctions. Therefore, HDACs could serve as the potential therapeutic target in DM towards developing novel intervention strategies. This review sheds light on the emerging role of HDACs/isoforms in diabetic pathophysiology and emphasized the scope of their targeting in DM for constituting novel interventional strategies for metabolic disorders/complications. [ABSTRACT FROM AUTHOR]

The present study evaluated the therapeutic potential of myricitrin (Myr), a glycosyloxyflavone extracted from Myrica esculenta bark, against diabetic nephropathy. Myr exhibited a significant hypoglycemic effect in high fat-fed and a single low-dose streptozotocin-induced type 2 diabetic (T2D) rats. Myr was found to improve glucose uptake by the skeletal muscle via activating IRS-1/PI3K/Akt/GLUT4 signaling in vitro and in vivo. Myr significantly attenuated high glucose (HG)-induced toxicity in NRK cells and in the kidneys of T2D rats. In this study, hyperglycemia caused nephrotoxicity via endorsing oxidative stress and inflammation resulting in the induction of apoptosis, fibrosis, and inflammatory damages. Myr was found to attenuate oxidative stress via scavenging/neutralizing oxidative radicals and improving endogenous redox defense through Nrf-2 activation in both in vitro and in vivo systems. Myr was also found to attenuate diabetes-triggered renal inflammation via suppressing NF-κB activation. Myr inhibited hyperglycemia-induced apoptosis and fibrosis in renal cells evidenced by the changes in the expressions of the apoptotic and fibrotic factors. The molecular docking predicted the interactions between Myr and different signal proteins. An in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) study predicted the drug-likeness character of Myr. Results suggested the possibility of Myr to be a potential therapeutic agent for diabetic nephropathy in the future. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a life-threatening metabolic syndrome. Over the past few decades, the incidence of diabetes has climbed exponentially. Several therapeutic approaches have been undertaken, but the occurrence and risk still remain unabated. Several plant-derived small molecules have been proposed to be effective against diabetes and associated vascular complications via acting on several therapeutic targets. In addition, the biocompatibility of these phytochemicals increasingly enhances the interest of exploiting them as therapeutic negotiators. However, poor pharmacokinetic and biopharmaceutical attributes of these phytochemicals largely restrict their clinical usefulness as therapeutic agents. Several pharmaceutical attempts have been undertaken to enhance their compliance and therapeutic efficacy. In this regard, the application of nanotechnology has been proven to be the best approach to improve the compliance and clinical efficacy by overturning the pharmacokinetic and biopharmaceutical obstacles associated with the plant-derived antidiabetic agents. This review gives a comprehensive and up-to-date overview of the nanoformulations of phytochemicals in the management of diabetes and associated complications. The effects of nanosizing on pharmacokinetic, biopharmaceutical and therapeutic profiles of plant-derived small molecules, such as curcumin, resveratrol, naringenin, quercetin, apigenin, baicalin, luteolin, rosmarinic acid, berberine, gymnemic acid, emodin, scutellarin, catechins, thymoquinone, ferulic acid, stevioside, and others have been discussed comprehensively in this review. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) imparts nephrotoxicity via triggering oxidative stress and pathological signal transductions in renal cells. The present study was performed to explore the protective mechanism of carnosic acid (CA), a naturally occurring antioxidant compound, against cadmium chloride (CdCl2)-provoked nephrotoxicity employing suitable in vitro and in vivo assays. CA (5 µM) exhibited an anti-apoptotic effect against CdCl2 (40 µM) in normal kidney epithelial (NKE) cells evidenced from cell viability, image, and flow cytometry assays. In this study, CdCl2 treatment enhanced oxidative stress by triggering free radical production, suppressing the endogenous redox defence system, and inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) activation in NKE cells and mouse kidneys. Moreover, CdCl2 treatment significantly endorsed apoptosis and fibrosis via activation of apoptotic and transforming growth factor (TGF)-β1/mothers against decapentaplegic homolog (Smad)/collagen IV signalling pathways, respectively. In contrast, CA treatment significantly attenuated Cd-provoked nephrotoxicity via inhibiting free radicals, endorsing redox defence, suppressing apoptosis, and inhibiting fibrosis in renal cells in both in vitro and in vivo systems. In addition, CA treatment significantly (p < 0.05–0.01) restored blood and urine parameters to near-normal levels in mice. Histological findings further confirmed the protective role of CA against Cd-mediated nephrotoxicity. Molecular docking predicted possible interactions between CA and Nrf2/TGF-β1/Smad/collagen IV. Hence, CA was found to be a potential therapeutic agent to treat Cd-mediated nephrotoxicity. [ABSTRACT FROM AUTHOR]

This work aimed to reveal the protective mechanism of CA against Dox (doxorubicin)-induced cardiotoxicity. In isolated murine cardiomyocytes, CA showed a concentration-dependent cytoprotective effect against Dox. Dox treatment significantly (p < 0.01) increased the formation of reactive oxygen species (ROS), increased NO levels, activated NADPH oxidase, and inactivated the cellular redox defense mechanism in cardiac cells, resulting in augmented oxidative stress in cardiomyocytes and rat hearts. Dox-induced oxidative stress significantly (p < 0.01) upregulated several pathogenic signal transductions, which induced apoptosis, inflammation, and fibrosis in cardiomyocytes and murine hearts. In contrast, CA significantly (p < 0.05–0.01) reciprocated Dox-induced cardiac apoptosis, inflammation, and fibrosis by suppressing oxidative stress and interfering with pathological signaling events in both isolated murine cardiomyocytes and rat hearts. CA treatment significantly (p < 0.05–0.01) countered Dox-mediated pathological changes in blood parameters in rats. Histological examinations backed up the pharmacological findings. In silico chemometric investigations predicted potential interactions between CA and studied signal proteins, as well as the drug-like features of CA. Thus, it would be concluded that CA has the potential to be regarded as an effective agent to alleviate Dox-mediated cardiotoxicity in the future. [Display omitted] [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is considered to be one of the most difficult subtypes of breast cancer (BC) to treat. The sheer absence of certain receptors makes it very tough to target, leaving high-dose chemotherapy as probably the sole therapeutic option at the cost of nonspecific toxic effects. Carnosic acid (CA) has been established as a potential chemotherapeutic agent against a range of cancer cells. However, its in vivo chemotherapeutic potential is significantly challenged due to its poor pharmacokinetic attributes. In this study, poly(lactic- co -glycolic) acid (PLGA) nanoparticles (NPs) were formulated to circumvent the biopharmaceutical limitations of CA. CA-loaded polymeric NPs (CA-PLGA NPs) have been evaluated as a potential therapeutic option in the treatment of TNBC. Different in vitro studies exhibited that CA-PLGA NPs significantly provoked oxidative-stress-mediated apoptotic death in MDA-MB-231 cells. The improved anticancer potential of CA-PLGA NPs over CA was found to be associated with improved cellular uptake of the nanoformulation by TNBC cells. In vivo studies also established the improvement in the chemotherapeutic efficacy of CA-nanoformulation over that of free CA without showing any sign of systemic toxicity. Thus, CA-PLGA NPs emerge as a promising candidate to fix two bugs with a single code, resolving biopharmaceutical attributes of CA as well as introducing a treatment option for TNBC.