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OBJECTIVE: This study aimed to investigate the CYP24A1, AHR, CPEB4, TRIP13, and PIK3CA mRNA expression in the blood of colorectal cancer patients in Egypt. This was performed to elucidate if there's a link between this gene expression and other clinicopathological characteristics of the tumor. PATIENTS AND METHODS: A case-control study including 50 colorectal cancer patients and 50 healthy controls was conducted. Real-time polymerase chain reaction (rt-PCR) was utilized to assess the expression of CYP24A1, AHR, CPEB4, TRIP13, and PIK3CA mRNA in blood samples. RESULTS: Patients with colorectal cancer had significantly higher levels of mRNA for the genes CYP24A1, AHR, CPEB4, TRIP13, and PIK-3CA (p<0.001, p=0.021, p<0.001, and p<0.001, respectively) compared to controls. Remarkedly, the gene expression of AHR, TRIP13, and PIK-3CA genes did not exhibit a significant correlation with the tumor stages (p=0.379, p=0.095, and p=0.526, respectively). However, there was a strong correlation between CYP24A1 and CPEB4 gene expression and tumor stages (p<0.001 and p=0.002, respectively). CONCLUSIONS: Therefore, we can conclude that increased mRNA levels of CYP24A1, AHR, CPEB4, TRIP13, and PIK3CA in blood samples withdrawn from colorectal cancer patients could be a biomarker for the disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Cancer is a group of diseases characterized by uncontrolled cell division of abnormal cells that can result in death if not treated well. Cancer is considered to be a leading cause of mortalities throughout the globe and an important barrier to increase life span. This study was conducted to assess awareness among graduates studying in university of Hail related to cancer. MATERIALS AND METHODS: This is an online survey-based study conducted using online tool “Google Forms”. The inclusion criteria were that the participants should understand Arabic, must have 18 years or above age and currently living or a permanent resident of Hail city. RESULTS: Total 108 valid responses were included in this analysis, 56 were male and 52 were female participants. Around 106 of the participants were Saudi nationals among which 62 were the permanent resident of the Hail city and 46 were migrants which were not the permanent resident but moved into the city for the purpose of education or business. There was significant association between awareness level of individuals regarding cancer associated symptoms including weight loss, fatigue, inflammation and hair loss and common causes of cancers, including family history, radiation exposure, smoking, obesity, aging and fast-food exposure. However, there was no significance between awareness of cancer and other factors, including age, gender, marital status, education, nationality, residence and monthly income. CONCLUSIONS: Overall our study reveals that there is significant knowledge among Hail population but still there is a need to increase awareness level of general population to manage the disease more efficiently. [ABSTRACT FROM AUTHOR]

Precision medicine has revolutionized modern cancer therapeutic management by targeting specific molecular aberrations responsible for the onset and progression of tumorigenesis. ROS proto-oncogene 1 (ROS1) is a receptor tyrosine kinase (RTK) that can induce tumorigenesis through various signaling pathways, such as cell proliferation, survival, migration, and metastasis. It has emerged as a promising therapeutic target in various cancer types. However, there is very limited availability of specific ROS1 inhibitors for therapeutic purposes. Exploring repurposed drugs for rapid and effective treatment is a useful approach. In this study, we utilized an integrated approach of virtual screening and molecular dynamics (MD) simulations of repurposing existing drugs for ROS1 kinase inhibition. Using a curated library of 3648 FDA-approved drugs, virtual screening identified drugs capable of binding to ROS1 kinase domain. The results unveil two hits, Midostaurin and Alectinib with favorable binding profiles and stable interactions with the active site residues of ROS1. These hits were subjected to stability assessment through all-atom MD simulations for 200 ns. MD results showed that Midostaurin and Alectinib were stable with ROS1. Taken together, the study showed a rational framework for the selection of repurposed Midostaurin and Alectinib with ROS1 inhibitory potential for therapeutic management after further validation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Alrouji, Yasmin, Alhumaydhi, Sharaf, Shahwan and Shamsi.)

Neurodegenerative diseases (NDs) such as Alzheimer disease (AD) and Parkinson disease (PD) are group of diseases affecting the central nervous system (CNS) characterized by progressive neurodegenerations and cognitive impairment. Findings from different studies highlighted the beneficial and detrimental effects of serum uric acid on the development and progression of NDs. Therefore, this mini-review aims to discuss the beneficial and detrimental effects of uric on NDs. The neuroprotective effect of uric acid is mainly related to the antioxidant effect of uric acid which alleviates oxidative stress-induced neurodegeneration in AD and PD. However, long-term effect of hyperuricemia prompts for the development and progression of cognitive impairment. Hyperuricemia is associated with cognitive impairment and dementia, and gout increases dementia risk. In addition, hyperuricemia can cause cerebral vascular injury which is a risk factor for vascular dementia and cognitive impairment. Taken together, the relationship between uric acid and NDs risk remains conflicting. Hence, preclinical and clinical studies are indicated in this regard., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory impairment and cognitive dysfunctions. It has been shown that hypoglycemia can adversely affect AD neuropathology. It is well-known that chronic hyperglycemia in type 2 diabetes (T2D) is regarded as a potential risk factor for the development and progression of AD. However, the effect of recurrent hypoglycemia on the pathogenesis of AD was not deeply discussed, and how recurrent hypoglycemia affects AD at cellular and molecular levels was not intensely interpreted by the previous studies. The underlying mechanisms for hypoglycaemia-induced AD are diverse such as endothelial dysfunction, thrombosis, and neuronal injury that causing tau protein hyperphosphorylation and the accumulation of amyloid beta (Aβ) in the brain neurons. Of note, the glucagon hormone, which controls blood glucose, can also regulate the cognitive functions. Glucagon increases blood glucose by antagonizing the metabolic effect of insulin. Therefore, glucagon, through attenuation of hypoglycemia, may prevent AD neuropathology. Glucagon/GLP-1 has been shown to promote synaptogenesis, hippocampal synaptic plasticity, and learning and memory, while attenuating amyloid and tau pathologies. Therefore, activation of glucagon receptors in the brain may reduce AD neuropathology. A recent glucagon receptor agonist dasiglucagon which used in the management of hypoglycemia may be effective in preventing hypoglycemia and AD neuropathology. This review aims to discuss the potential role of dasiglucagon in treating hypoglycemia in AD, and how this drug reduce AD neuropathology., (© 2024. The Author(s).)

Tuberculosis (TB), an infectious disease caused by the Mycobacterium tuberculosis (Mtb), has been responsible for the deaths of millions of individuals around the globe. A vital protein in viral pathogenesis known as resuscitation promoting factor (RpfB) has been identified as a potential therapeutic target of anti-tuberculosis drugs. This study offered an in silico process to examine possible RpfB inhibitors employing a computational drug design pipeline. In this study, a total of 1228 phytomolecules were virtually tested against the RpfB of Mtb. These phytomolecules were sourced from the NP-lib database of the MTi-OpenScreen server, and five top hits (ZINC000044404209, ZINC000059779788, ZINC000001562130, ZINC000014766825, and ZINC000043552589) were prioritized for compute intensive docking with dock score ≤ - 8.5 kcal/mole. Later, molecular dynamics (MD) simulation and principal component analysis (PCA) were used to validate these top five hits. In the list of these top five hits, the ligands ZINC000044404209, ZINC000059779788, and ZINC000043552589 showed hydrogen bond formation with the functional residue Glu 292 of the RpfB protein suggesting biological significance of the binding. The RMSD study showed stable protein-ligand complexes and higher conformational consistency for the ligands ZINC000014766825, and ZINC000043552589 with RMSD 3-4 Å during 100 ns MD simulation. The overall analysis performed in the study suggested promising binding of these compounds with the RpfB protein of the Mtb at its functional site, further experimental investigation is needed to validate the computational finding., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cyclin-dependent kinase 5 (Cdk5) is a protein expressed in postmitotic neurons in the central nervous system (CNS). Cdk5 is activated by p35 and p39 which are neuron regulatory subunits. Cdk5/p35 complex is activated by calpain protease to form Cdk5/p35 which has a neuroprotective effect by regulating the synaptic plasticity and memory functions. However, exaggerated Cdk5 is implicated in different types of neurodegenerative diseases including Parkinson disease (PD). Therefore, modulation of Cdk5 signalling may mitigate PD neuropathology. Therefore, the aim of the present review was to discuss the critical role of Cdk5 in the pathogenesis of PD, and how Cdk5 inhibitors are effectual in the management of PD. In conclusion, overactivated Cdk5 is involved the development of neurodegeneration, and Cdk5/calpain inhibitors such as statins, metformin, fenofibrates and rosiglitazone can attenuate the progression of PD neuropathology., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

In present times, vanillin stands out as a promising therapeutic molecule that can be implicated in the treatment of neurodegenerative disorders (NDs), notably Alzheimer's disease (AD). This can be attributed to the highly potent scavenging activity of vanillin against reactive oxygen species (ROS). Oxidative stress leads to generation of ROS that serves a critical role in AD's pathological progression. It is apparent from various studies that diets rich in polyphenols prevent oxidative stress associated with AD development, implying the crucial role of vanillin in AD therapeutics. It is crucial to maintain iron balance to manage AD associated oxidative stress, unveiling the significance of human transferrin (hTf) that maintains iron homeostasis. Here, we have performed an integrated study of spectroscopic and computational approaches to get insight into the binding mechanism of vanillin with hTf. In the preliminary study, molecular docking deciphered that vanillin primarily occupies the hTf binding pocket, forming multiple interactions with its key residues. Moreover, the binding mechanism was evaluated at an atomistic level employing comprehensive molecular dynamic (MD) simulation. MD analysis demonstrated that binding of vanillin to hTf stabilizes its structure, without inducing any significant alterations in its native conformation. The docked complex was maintained throughout the simulations without changing its original conformation. Essential dynamics analysis further confirms that hTf achieved a stable conformation with vanillin. The outcomes were further supplemented by fluorescence spectroscopy which confirms the formation of stable hTf-vanillin complex. Taken together, the current study unveils the interaction mechanism of vanillin with hTf and providing a platform to use vanillin in AD therapeutics in the context of iron homeostasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Alrouji, Yasmin, Alhumaydhi, Sharaf, Shahwan, Furkan, Khan and Shamsi.)

Parkinson's disease (PD) is a common neurodegenerative disease developed due to the degeneration of dopaminergic neurons in the substantia nigra. There is no single effective treatment in the management of PD. Therefore, repurposing effective and approved drugs like metformin could be an effective strategy for managing PD. However, the mechanistic role of metformin in PD neuropathology was not fully elucidated. Metformin is an insulin-sensitizing agent used as a first-line therapy in the management of type 2 diabetes mellitus (T2DM) and has the ability to reduce insulin resistance (IR). Metformin may have a beneficial effect on PD neuropathology. The neuroprotective effect of metformin is mainly mediated by activating adenosine monophosphate protein kinase (AMPK), which reduces mitochondrial dysfunction, oxidative stress, and α-synuclein aggregation. As well, metformin mitigates brain IR a hallmark of PD and other neurodegenerative diseases. However, metformin may harm PD neuropathology by inducing hyperhomocysteinemia and deficiency of folate and B12. Therefore, this review aimed to find the potential role of metformin regarding its protective and detrimental effects on the pathogenesis of PD. The mechanistic role of metformin in PD neuropathology was not fully elucidated. Most studies regarding metformin and its effectiveness in PD neuropathology were observed in preclinical studies, which are not fully translated into clinical settings. In addition, metformin effect on PD neuropathology was previously clarified in T2DM, potentially linked to an increasing PD risk. These limitations hinder the conclusion concerning the therapeutic efficacy of metformin and its beneficial and detrimental role in PD. Therefore, as metformin does not cause hypoglycemia and is a safe drug, it should be evaluated in non-diabetic patients concerning PD risk., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Human transferrin (Htf) is vital in maintaining iron within the brain cells; any disruption results in the development of neurodegenerative diseases (NDs) and other related pathologies, especially Alzheimer's disease (AD). Ellagic acid (EA), a naturally occurring phenolic antioxidant, possesses neuroprotective potential and is present in a broad variety of fruits and vegetables. The current work explores the binding mechanism of dietary polyphenol, EA, with Htf by a combination of experimental and computational approaches. Molecular docking studies unveiled the binding of EA to Htf with good affinity. Molecular dynamic (MD) simulation further provided atomistic details of the binding process, demonstrating a stable Htf-EA complex formation without causing substantial alterations to the protein's conformation. Furthermore, fluorescence binding measurements indicated that EA forms a high-affinity interaction with Htf. Isothermal titration calorimetric measurements advocated the spontaneous nature of binding and also revealed the binding process to be exothermic. In conclusion, the study deciphered the binding mechanism of EA with Htf. The results demonstrated that EA binds with Htf with an excellent affinity spontaneously, thereby laying the groundwork for potential applications of EA in the realm of therapeutics for NDs in the context of iron homeostasis., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Ephedra foeminea is traditionally used to treat breast cancer in several Arab countries. Scientific studies have reported different effects of this plant on some cancer cell lines. The current study determined the anti-cancer potential of the methanolic extract of Ephedra foeminea against four different types of breast cancer cell lines in-vitro . The extract was prepared by maceration and phytoconstituents were identified by LC-MS analysis. The IC 50 value was determined against MDA-MB-231, MCF-7, 4 T1, and MCF-10 cell lines using the MTT assay. Further investigations were carried out using IC 50 concentration of the extract (40.09 µg/ml) to determine live/dead cells by acridine orange/ethidium bromide staining. The effect on the expression of reactive oxygen species (ROS) was evaluated by flow cytometry. The results were analyzed using one-way ANOVA followed by Tukey's test. The LC-MS analysis revealed the presence of 34 and 30 phytoconstituents in positive and negative modes respectively. The Ephedra foeminea extract was most effective against 4 T1 cells in a dose-dependent manner (P < 0.001) with an IC 50 value of 40.09 µg/ml and showed negligible effect against MCF-10 cells. It increased apoptosis in 77.84 % of 4 T1 cells, as determined by acridine orange/ethidium bromide staining. The extract also increased the ROS expression in the 39.57 % of 4 T1 cells. The study results showed that Ephedra foeminea extract possesses an anti-cancer effect against 4 T1 cells by increasing the expression of ROS and inducing apoptosis in the 4 T1 cells. The result suggests Ephedra foemenia methanolic extract possesses a reasonable anti-cancer effect due to its effect on apoptosis and oxidative pathways. The results confirm the traditional belief that Ephedra is effective against breast cancerز., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Human transferrin (htf) plays a crucial role in regulating the balance of iron within brain cells; any disruption directly contributes to the development of Neurodegenerative Diseases (NDs) and other related pathologies, especially Alzheimer's Disease (AD). In recent times, a transition towards natural compounds is evident to treat diseases and this shift is mainly attributed to their broad therapeutic potential along with minimal side effects. Capsaicin, a natural compound abundantly found in red and chili peppers, possess neuroprotective potential. The current work targets to decipher the interaction mechanism of capsaicin with htf using experimental and computational approaches. Molecular docking analysis revealed that capsaicin occupies the iron binding pocket of htf, with good binding affinity. Further, the binding mechanism was investigated atomistically using Molecular dynamic (MD) simulation approach. The results revealed no significant alterations in the structure of htf implying the stability of the complex. In silico observations were validated by fluorescence binding assay. Capsaicin binds to htf with a binding constant ( K ) of 3.99 × 10 6  M -1 , implying the stability of the htf-capsaicin complex. This study lays a platform for potential applications of capsaicin in treatment of NDs in terms of iron homeostasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Alrouji, Alhumaydhi, Venkatesan, Sharaf, Shahwan and Shamsi.)

Neurodegenerative diseases such as Alzheimer's disease (AD) pose a significant global health challenge that requires the exploration of innovative therapeutic strategies. Triggering receptor expressed on myeloid cells-2 (TREM2) is one of the critical proteins involved in immune regulation and neuroinflammation. It has emerged as a promising therapeutic target to develop treatments for neurodegenerative disorders like AD. Here, we employed a comprehensive virtual screening approach to identify potential small molecule inhibitors among FDA-approved drugs for TREM2. The docking study reveals significant binding affinity, ranging from -7.8 kcal/mol to -8.5 kcal/mol, for the elucidated hits against TREM2, accompanied by several crucial interactions. Among the repurposed drugs identified in the initial screening, Carpipramine, Clocapramine, and Pimozide stood out due to their notable binding potential and favorable drug profiling. Further, we conducted molecular dynamics (MD) simulations on the selected molecules that probed their structural dynamics and stability within the TREM2 binding pocket. The structural parameters and hydrogen bond dynamics remained remarkably stable throughout the simulated trajectories. Furthermore, we performed principal component analysis (PCA) and constructed free energy landscapes (FELs) to gain deeper insights into ligand binding and conformational flexibility of TREM2. The findings revealed that the elucidated molecules, Carpipramine, Clocapramine, and Pimozide, exhibited an exceptional fit within the binding pocket of TREM2 with remarkable stability and interaction patterns throughout the 500 ns simulation window. Interestingly, these molecules possessed a spectrum of anti-neurodegenerative properties and favorable drug profiles, which suggest their potential as promising drug candidates for repurposing in the treatment of AD.Communicated by Ramaswamy H. Sarma.

Background: Neurodegeneration is a term describing an irreversible process of neuronal damage. In recent decades, research efforts have been directed towards deepening our knowledge of numerous neurodegenerative disorders, with a particular focus on conditions such as Alzheimer's disease (AD). Human transferrin (htf) is a key player in maintaining iron homeostasis within brain cells. Any disturbance in this equilibrium gives rise to the emergence of neurodegenerative diseases and associated pathologies, particularly AD. Limonene, a natural compound found in citrus fruits and various plants, has shown potential neuroprotective properties., Objective: In this study, our goal was to unravel the binding of limonene with htf, with the intention of comprehending the interaction mechanism of limonene with htf., Methods: Binding was scrutinized using fluorescence quenching and UV-Vis spectroscopic analyses. The binding mechanism of limonene was further investigated at the atomic level through molecular docking and extensive 200 ns molecular dynamic simulation (MD) studies., Results: Molecular docking uncovered that limonene interacted extensively with the deep cavity located within the htf binding pocket. MD results indicated that binding of limonene to htf did not induce substantial structural alterations, ultimately forming stable complex. The findings from fluorescence binding indicated a pronounced interaction between limonene and htf, limonene binds to htf with a binding constant (K) of 0.1×105 M-1. UV spectroscopy also advocated stable htf-limonene complex formation., Conclusions: The study deciphered the binding mechanism of limonene with htf, providing a platform to use limonene in AD therapeutics in context of iron homeostasis.

Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for controlling cellular oxidative stress. Any dysregulation of SOD1 activity is linked with cancer pathogenesis and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Among the inhibitors known to be effective against SOD1, LCS-1 stands out; however, its efficacy, specificity, and safety profiles are somewhat restricted. In this study, we used PubChem library to retrieve compounds that exhibited a structural similarity of at least 90 % with LCS-1. These compounds underwent molecular docking analyses to examine their interaction patterns and binding affinities with SOD1. Further, we applied filters based on physicochemical and ADMET properties, refining the selection process. Our analysis revealed that selected compounds interact with crucial residues of SOD1 active site. To gain further insights into conformational stability and dynamics of the SOD1-ligand complexes, we conducted all-atom molecular dynamics (MD) simulations for 100 ns. We identified two compounds, CID:133306073 and CID:133446715, as potential scaffolds with promising inhibitory properties against SOD1. Both compounds hold significant potential for further exploration as therapeutic SOD1 inhibitors. Further studies are warranted to fully harness their therapeutic potential in targeting SOD1 for cancer and ALS treatment, offering new avenues for improved patient outcomes and disease management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Identifying novel therapeutic agents is a fundamental challenge in contemporary drug development, especially in the context of complex diseases like cancer, neurodegenerative disorders, and metabolic syndromes. Here, we present a comprehensive computational study to identify potential inhibitors of SIRT1 (Sirtuin 1), a critical protein involved in various cellular processes and disease pathways. Leveraging the concept of drug repurposing, we employed a multifaceted approach that integrates molecular docking and molecular dynamics (MD) simulations to predict the binding affinities and dynamic behavior of a diverse set of FDA-approved drugs from DrugBank against the SIRT1. Initially, compounds were shortlisted based on their binding affinities and interaction analyses to identify safe and promising binding partners for SIRT1. Among these candidates, Doxercalciferol and Timiperone emerged as potential candidates, displaying notable affinity, efficiency, and specificity towards the binding pocket of SIRT1. Extensive evaluation revealed that these identified compounds boast a range of favorable biological properties and prefer binding to the active site of SIRT1. To delve deeper into the interactions, all-atom MD simulations were conducted for 500 nanoseconds (ns). These simulations assessed the conformational dynamics, stability, and interaction mechanism of the SIRT1-Doxercalciferol and SIRT1-Timiperone complexes. The MD simulations illustrated that the SIRT1-Doxercalciferol and SIRT1-Timiperone complexes maintain stability over a 500 ns trajectory. These insightful outcomes propose that Doxercalciferol and Timiperone hold promise as viable scaffolds for developing potential SIRT1 inhibitors, with implications for tackling complex diseases such as cancer, neurodegenerative disorders, and metabolic syndromes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Alrouji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Parkinson's disease (PD) is a neurodegenerative disease characterized by deposition of α-synuclein and aggregation of Lewy bodies. Cholesterol is involved with PD neuropathology in bidirectional ways that could be protective or harmful. Thus, the objective of the present review was to verify the potential role of cholesterol in PD neuropathology. Deregulation of ion channels and receptors induced by cholesterol alteration suggests a possible mechanism for the neuroprotective effects of cholesterol against PD development. However, high serum cholesterol level increases PD risk indirectly by 27-hydroxycholesterol which induces oxidative stress, inflammation, and apoptosis. Besides, hypercholesterolemia triggers the accumulation of cholesterol in macrophages and immune cells leading to the release of pro-inflammatory cytokines with progression of neuroinflammation subsequently. Additionally, cholesterol increases aggregation of α-synuclein and induces degeneration of dopaminergic neurons (DN) in the substantia nigra (SN). Hypercholesterolemia may lead to cellular Ca 2+ overload causing synaptic and the development of neurodegeneration. In conclusion, cholesterol has bidirectional effects on PD neuropathology and might be protective or harmful., (© 2023. Fondazione Società Italiana di Neurologia.)

Bruton's tyrosine kinase (BTK) is a non-receptor protein kinase that plays a crucial role in various biological processes, including immune system function and cancer development. Therefore, inhibition of BTK has been proposed as a therapeutic strategy for various complex diseases. In this study, we aimed to identify potential inhibitors of BTK by using a drug repurposing approach. To identify potential inhibitors, we performed a molecular docking-based virtual screening using a library of repurposed drugs from DrugBank. We then used various filtrations followed by molecular dynamics (MD) simulations, principal component analysis (PCA), and Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) analysis to further evaluate the binding interactions and stability of the top-ranking compounds. Molecular docking-based virtual screening approach identified several repurposed drugs as potential BTK inhibitors, including Eltrombopag and Alectinib, which have already been approved for human use. All-atom MD simulations provided insights into the binding interactions and stability of the identified compounds, which will be helpful for further experimental validation and optimization. Overall, our study demonstrates that drug repurposing is a promising approach to identify potential inhibitors of BTK and highlights the importance of computational methods in drug discovery., (© 2023. Springer Nature Limited.)

β-secretase 1 (BACE1) is an enzyme that is involved in generating beta-amyloid peptides and is believed to have a significant role in the development of Alzheimer's disease (AD). Therefore, BACE1 has gained attention as a potential therapeutic target for treating AD. Modern drug discovery studies are being conducted to identify potential inhibitors of BACE1, with the goal of reducing the production of beta-amyloid peptides and, thus, slowing the progression of AD. Here, we used a multistep virtual screening methodology to identify phytoconstituents from the IMPPAT library that could inhibit the activity of BACE1. Molecular docking was employed to select initial hits based on their binding affinity toward BACE1. Screening for PAINS patterns, ADMET and PASS properties, was then used to identify potential molecules for BACE1 inhibition. In the end, we discovered two natural compounds, Peiminine and 27-Deoxywithaferin A, which demonstrated a strong affinity, effectiveness, and specific interactions for the BACE1-active site. The elucidated molecules also displayed drug likeliness. A 200 ns molecular dynamics (MD) simulation was conducted to investigate the interaction mechanism, complex stability, and conformational dynamics of BACE1 with Peiminine and 27-Deoxywithaferin A. The MD simulations demonstrated that BACE1 was stable during the simulation with Peiminine and 27-Deoxywithaferin A. Overall, the results suggested that Peiminine and 27-Deoxywithaferin A hold significant potential as scaffolds in drug development efforts targeting BACE1 for the purpose of treating AD., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Parkinson's disease (PD) usually occurs due to the degeneration of dopaminergic neurons in the substantia nigra (SN). Management of PD is restricted to symptomatic improvement. Consequently, a novel treatment for managing motor and non-motor symptoms in PD is necessary. Abundant findings support the protection of dipeptidyl peptidase 4 (DPP-4) inhibitors in PD. Consequently, this study aims to reveal the mechanism of DPP-4 inhibitors in managing PD. DPP-4 inhibitors are oral anti-diabetic agents approved for managing type 2 diabetes mellitus (T2DM). T2DM is linked with an increased chance of the occurrence of PD. Extended usage of DPP-4 inhibitors in T2DM patients may attenuate the development of PD by inhibiting inflammatory and apoptotic pathways. Thus, DPP-4 inhibitors like sitagliptin could be a promising treatment against PD neuropathology via anti-inflammatory, antioxidant, and anti-apoptotic impacts. DPP-4 inhibitors, by increasing endogenous GLP-1, can also reduce memory impairment in PD. In conclusion, the direct effects of DPP-4 inhibitors or indirect effects through increasing circulating GLP-1 levels could be an effective therapeutic strategy in treating PD patients through modulation of neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurogenesis., (© 2023. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Sphingosine kinase 1 (SphK1) has been widely recognized as a significant contributor to various types of cancer, including breast, lung, prostate, and hematological cancers. This research aimed to find a potential SphK1 inhibitor through a step-by-step virtual screening of PF543 (a known SphK1 inhibitor)-like compounds obtained from the PubChem library with the Tanimoto threshold of 80 %. The virtual screening process included several steps, namely physicochemical and ADMET evaluation, PAINS filtering, and molecular docking, followed by molecular dynamics (MD) simulation and principal component analysis (PCA). The results showed that compound CID:58293960 ((3R)-1,1-dioxo-2-[[3-[(4-phenylphenoxy)methyl]phenyl]methyl]-1,2-thiazolidine-3-carboxylic acid) demonstrated high potential as SphK1 inhibitor. All-atom MD simulations were performed for 100 ns to evaluate the stability and structural changes of the docked complexes in an aqueous environment. The analysis of the time evolution data of structural deviations, compactness, PCA, and free energy landscape (FEL) indicated that the binding of CID:58293960 with SphK1 is relatively stable throughout the simulation. The results of this study provide a platform for the discovery and development of new anticancer therapeutics targeting SphK1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Notably, peripheral inflammatory disorders and neuroinflammation are associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) is associated with inflammatory disorders due to hyperglycaemia-induced oxidative stress and the release of pro-inflammatory cytokines. Particularly, insulin resistance (IR) in T2DM promotes the degeneration of dopaminergic neurons in the substantia nigra (SN). Thus, T2DM-induced inflammatory disorders predispose to the development and progression of PD, and their targeting may reduce PD risk in T2DM. Therefore, this narrative review aims to find the potential link between T2DM and PD by investigating the role of inflammatory signalling pathways, mainly the nuclear factor kappa B (NF-κB) and the nod-like receptor pyrin 3 (NLRP3) inflammasome. NF-κB is implicated in the pathogenesis of T2DM, and activation of NF-κB with induction of neuronal apoptosis was also confirmed in PD patients. Systemic activation of NLRP3 inflammasome promotes the accumulation of α-synuclein and degeneration of dopaminergic neurons in the SN. Increasing α-synuclein in PD patients enhances NLRP3 inflammasome activation and the release of interleukin (IL)-1β followed by the development of systemic inflammation and neuroinflammation. In conclusion, activation of the NF-κB/NLRP3 inflammasome axis in T2DM patients could be the causal pathway in the development of PD. The inflammatory mechanisms triggered by activated NLRP3 inflammasome lead to pancreatic β-cell dysfunction and the development of T2DM. Therefore, attenuation of inflammatory changes by inhibiting the NF-κB/NLRP3 inflammasome axis in the early T2DM may reduce future PD risk., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Parkinson's disease (PD) is a progressive neurodegenerative disease (NDD) caused by dopaminergic neuron degeneration in the substantia nigra (SN). Orexin is a neuropeptide that plays a role in the pathogenesis of PD. Orexin has neuroprotective properties in dopaminergic neurons. In PD neuropathology, there is also degeneration of orexinergic neurons in the hypothalamus, in addition to dopaminergic neurons. However, the loss of orexinergic neurons in PD began after the degeneration of dopaminergic neurons. Reduced activity of orexinergic neurons has been linked to developing and progressing motor and non-motor symptoms in PD. In addition, the dysregulation of the orexin pathway is linked to the development of sleep disorders. The hypothalamic orexin pathway regulates various aspects of PD neuropathology at the cellular, subcellular, and molecular levels. Finally, non-motor symptoms, particularly insomnia and disturbed sleep, promote neuroinflammation and the accumulation of neurotoxic proteins as a result of defects in autophagy, endoplasmic reticulum (ER) stress, and the glymphatic system. As a result, this review aimed to highlight the potential role of orexin in PD neuropathology., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Holarrhena pubescens seeds are used in the treatment of various diseases, especially diabetes and associated complications, in different parts of the world. The present study was undertaken to determine the hypolipidemic and antihyperlipidemic effects of methanolic extract of H. pubescens seeds in rats. The extract was subjected to LC-MS analysis to determine the chemical constituents. The hypolipidemic action was studied by determining the effect of 28-day oral administration of seed extract on serum cholesterol, serum triglycerides, and serum HDL-cholesterol levels. The antihyperlipidemic action was studied in rats fed with a high-fat diet containing cholesterol and saturated fat, and the same lipid parameters were estimated during 28-day treatment. To elucidate its probable mechanism of action, in vitro studies on the inhibition of lipid accumulation in preadipocytes, DPP-IV inhibitory effect, and lipase enzyme inhibition were studied. The seed extract reduced serum levels of cholesterol and triglycerides in both normal rats and animals fed with a high-fat diet without a significant effect on HDL-cholesterol levels. The seed extract was highly effective in inhibiting lipase enzyme activity but showed a modest effect on the inhibition of lipid accumulation and DPP-IV. The results demonstrated that H. pubescens seed extract has hypolipidemic and antihyperlipidemic effects mediated probably through inhibition of lipase enzyme activity.

Achillea fragrantissima , a desert plant commonly known as yarrow, is traditionally used as an antimicrobial agent in folklore medicine in Saudi Arabia. The current study was undertaken to determine its antibiofilm activity against methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug-resistant Pseudomonas aeruginosa (MDR- P. aeruginosa ) using in vitro and in vivo studies. A biofilm model induced through an excision wound in diabetic mice was used to evaluate its effect in vivo. The skin irritation and cytotoxic effects of the extract were determined using mice and HaCaT cell lines, respectively. The Achillea fragrantissima methanolic extract was analyzed with LC-MS to detect different phytoconstituents, which revealed the presence of 47 different phytoconstituents. The extract inhibited the growth of both tested pathogens in vitro. It also increased the healing of biofilm-formed excision wounds, demonstrating its antibiofilm, antimicrobial, and wound-healing action in vivo. The effect of the extract was concentration-dependent, and its activity was stronger against MRSA than MDR- P. aeruginosa . The extract formulation was devoid of a skin irritation effect in vivo and cytotoxic effect on HaCaT cell lines in vitro.

Objectives: The present study is aimed at determining the effect of cigarette smoking (CS) on serum uric acid (UA) levels quantitatively before and after smoking cessation among people with MS (pwMS). Additionally, a possible correlation between UA levels and both disability progression and disease severity was also investigated. A retrospective cross-sectional study was conducted using the Nottingham University Hospitals MS Clinics database. It involves 127 people with definite MS recorded when reporting the latest smoking status and the clinical diagnosis. All necessary demographics and clinical characteristics were collected. We found that smoker pwMS had significantly lower serum UA levels than non-smoker pwMS ( p -value = 0.0475), and this reduction was recovered after smoking cessation ( p -value = 0.0216). However, the levels of disability or disease severity were not correlated with the levels of serum UA in current smoker pwMS, measured by the expanded disability status scale (EDSS; r = -0.24; p -value = 0.38), multiple sclerosis impact scale 29 (MSIS-29; r = 0.01; p -value = 0.97) and MS severity score (MSSS; r = -0.16; p -value = 0.58), respectively. Our result suggests that the reduction in UA levels is more likely a consequence of oxidative stress triggered by many risk factors, including CS, and could be considered a potential indicator of smoking cessation. In addition, the absence of a correlation between UA levels and disease severity and disability suggests that UA is not an optimal biomarker for disease severity and disability prediction among current smoker, ex-smoker or non-smoker pwMS.

Human Islet amyloid polypeptide (hIAPP) from pancreatic β cells in the islet of Langerhans has different physiological functions including inhibiting the release of insulin and glucagon. Type 2 diabetes mellitus (T2DM) is an endocrine disorder due to relative insulin insufficiency and insulin resistance (IR) is associated with increased circulating hIAPP. Remarkably, hIAPP has structural similarity with amyloid beta (Aβ) and can engage in the pathogenesis of T2DM and Alzheimer's disease (AD). Therefore, the present review aimed to elucidate how hIAPP acts as a link between T2DM and AD. IR, aging and low β cell mass increase expression of hIAPP which binds cell membrane leading to the aberrant release of Ca 2+ and activation of the proteolytic enzymes leading to a series of events causing loss of β cells. Peripheral hIAPP plays a major role in the pathogenesis of AD, and high circulating hIAPP level increase AD risk in T2DM patients. However, there is no hard evidence for the role of brain-derived hIAPP in the pathogenesis of AD. Nevertheless, oxidative stress, mitochondrial dysfunction, chaperon-mediated autophagy, heparan sulfate proteoglycan (HSPG), immune response, and zinc homeostasis in T2DM could be the possible mechanisms for the induction of the aggregation of hIAPP which increase AD risk. In conclusion, increasing hIAPP circulating levels in T2DM patients predispose them to the development and progression of AD. Dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists attenuate AD in T2DM by inhibiting expression and deposition of hIAP., (© 2023. The Author(s).)

Helminths are metazoan parasites affecting about one third of the worldwide population. Chronic helminth infections (CHIs) confer immunological tolerance to harmless and self-antigens mediated by regulatory T cells (Treg) that are up-regulated. In coronavirus disease 2019 (COVID-19), abnormal adaptive immune response and unrestrained innate immune response could result in local and systemic immune-mediated tissue damage. COVID-19 and CHIs establish complicated immune interactions due to SARS-CoV-2-induced immunological stimulation and CHIs-induced immunological tolerance. However, COVID-19 severity in patients with CHIs is mild, as immuno-suppressive anti-inflammatory cytokines counterbalance the risk of cytokine storm. Here, an overview of the interplay between helminths and COVID-19 severity is given. CHIs through helminth-derived molecules may suppress SARS-CoV-2 entry and associated hyperinflammation through attenuation of the TLR4/NF-kB signalling pathway. In addition, CHIs may reduce the COVID-19 severity by reducing the SARS-CoV-2 entry points at ACE2/DPP4/CD147 axis in the initial phase and immunomodulation in the late phase of the disease by suppressing TLR4/NF-kB signalling pathway., (© 2023 The Authors. Parasite Immunology published by John Wiley & Sons Ltd.)

Microtubule affinity regulating kinase 4 (MARK4), 752 amino acids long, belonging to the AMPK superfamily, plays a vital role in regulating microtubules due to its potential to phosphorylate microtubule-associated proteins (MAP's) and thus, MARK4 plays a key role in Alzheimer's disease (AD) pathology. MARK4 is a druggable target for cancer, neurodegenerative diseases, and metabolic disorders. In this study, we have evaluated the MARK4 inhibitory potential of Huperzine A (HpA), an acetylcholinesterase inhibitor (AChEI), a potential AD drug. Molecular docking revealed the key residues governing the MARK4-HpA complex formation. The structural stability and conformational dynamics of the MARK4-HpA complex was assessed by employing Molecular dynamics (MD) simulation. The results suggested that the binding of HpA with MARK4 leads to minimal structural alterations in the native conformation of MARK4, implying the stability of the MARK4-HpA complex. Isothermal titration calorimetry (ITC) studies deciphered that HpA binds to MARK4 spontaneously. Moreover, the kinase assay depicted significant inhibition of MARK by HpA (IC 50  = 4.91 μM), implying it to be a potent MARK4 inhibitor that can be implicated in the treatment of MARK4-directed diseases., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is an advanced neurodegenerative disease (NDD) caused by the degeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). As PD is an age-related disorder, the majority of PD patients are associated with musculoskeletal disorders with prolonged use of analgesic and anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, NSAIDs can affect PD neuropathology in different ways. Thus, the objective of the present narrative review was to clarify the potential role of NSAIDs in PD according to the assorted view of preponderance. Inhibition of neuroinflammation and modulation of immune response by NSAIDs could be an effective way in preventing the development of NDD. NSAIDs affect PD neuropathology in different manners could be beneficial or detrimental effects. Inhibition of cyclooxygenase 2 (COX2) by NSAIDs may prevent the development of PD. NSAIDs afforded a neuroprotective role against the development and progression of PD neuropathology through the  modulation of neuroinflammation. Though, NSAIDs may lead to neutral or harmful effects by inhibiting neuroprotective prostacyclin (PGI2) and accentuation of pro-inflammatory leukotrienes (LTs). In conclusion, there is still a potential conflict regarding the effect of NSAIDs on PD neuropathology., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cancer is a hard-to-treat disease with a high reoccurrence rate that affects health and lives globally. The condition has a high occurrence rate and is the second leading cause of mortality after cardiovascular disorders. Increased research and more profound knowledge of the mechanisms contributing to the disease's onset and progression have led to drug discovery and development. Various drugs are on the market against cancer; however, the drugs face challenges of chemoresistance. The other major problem is the side effects of these drugs. Therefore, using complementary and additional medicines from natural sources is the best strategy to overcome these issues. The naturally occurring phytochemicals are a vast source of novel drugs against various ailments. The modes of action by which phytochemicals show their anti-cancer effects can be the induction of apoptosis, the onset of cell cycle arrest, kinase inhibition, and the blocking of carcinogens. This review aims to describe different phytochemicals, their classification, the role of phytochemicals as anti-cancer agents, the mode of action of phytochemicals, and their role in various types of cancer.

The study developed a simple and inexpensive method to induce biofilm formation in-vivo for the evaluation of the antibiofilm activity of pharmacological agents using Swiss albino mice. Animals were made diabetic using streptozocin and nicotinamide. A cover slip containing preformed biofilm along with MRSA culture was introduced into the excision wound in these animals. The method was effective in developing biofilm on the coverslip after 24 h incubation in MRSA broth which was confirmed by microscopic examination and a crystal violet assay. Application of preformed biofilm along with microbial culture induced a profound infection with biofilm formation on excision wounds in 72 h. This was confirmed by macroscopic, histological, and bacterial load determination. Mupirocin, a known antibacterial agent effective against MRSA was used to demonstrate antibiofilm activity. Mupirocin was able to completely heal the excised wounds in 19 to 21 days while in the base-treated group, healing took place between 30 and 35 days. The method described is robust and can be reproduced easily without the use of transgenic animals and sophisticated methods such as confocal microscopy.

This study aims to describe the therapeutic potential of C. nocturnum leaf extracts against diabetes and neurological disorders via the targeting of α-amylase and acetylcholinesterase (AChE) activities, followed by computational molecular docking studies to establish a strong rationale behind the α-amylase and AChE inhibitory potential of C. nocturnum leaves-derived secondary metabolites. In our study, the antioxidant activity of the sequentially extracted C. nocturnum leaves extract was also investigated, in which the methanolic fraction exhibited the strongest antioxidant potential against DPPH (IC 50 39.12 ± 0.53 µg/mL) and ABTS (IC 50 20.94 ± 0.82 µg/mL) radicals. This extract strongly inhibited the α-amylase (IC 50 188.77 ± 1.67 µg/mL) and AChE (IC 50 239.44 ± 0.93 µg/mL) in a non-competitive and competitive manner, respectively. Furthermore, in silico analysis of compounds identified in the methanolic extract of the leaves of C. nocturnum using GC-MS revealed high-affinity binding of these compounds with the catalytic sites of α-amylase and AChE, with binding energy ranging from -3.10 to -6.23 kcal/mol and from -3.32 to -8.76 kcal/mol, respectively. Conclusively, the antioxidant, antidiabetic, and anti-Alzheimer activity of this extract might be driven by the synergistic effect of these bioactive phytoconstituents.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are significant public health burdens. Many studies have revealed the possibility of common pathophysiology between T2DM and AD. Thus, in recent years, studies deciphering the action mechanism of anti-diabetic drugs with their future use in AD and related pathologies are on high demand. Drug repurposing is a safe and effective approach owing to its low cost and time-saving attributes. Microtubule affinity regulating kinase 4 (MARK4) is a druggable target for various diseases and is found to be linked with AD and diabetes mellitus. MARK4 plays a vital role in energy metabolism and regulation and thus serves as an irrefutable target to treat T2DM. The present study was intended to identify the potent MARK4 inhibitors among FDA-approved anti-diabetic drugs. We performed structure-based virtual screening of FDA-approved drugs to identify the top hits against MARK4. We identified five FDA-approved drugs having an appreciable affinity and specificity toward the binding pocket of MARK4. Among these identified hits, two drugs, linagliptin, and empagliflozin, favorably bind to the MARK4 binding pocket, interacting with its critical residues and thus subjected to detailed analysis. All-atom detailed molecular dynamics (MD) simulations revealed the dynamics of binding of linagliptin and empagliflozin with MARK4. Kinase assay showed significant inhibition of MARK4 kinase activity in the presence of these drugs, implying them as potent MARK4 inhibitors. In conclusion, linagliptin and empagliflozin may be promising MARK4 inhibitors, which can further be exploited as potential lead molecules against MARK4-directed neurodegenerative diseases., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Phages are highly ubiquitous biological agents, which means they are ideal tools for molecular biology and recombinant DNA technology. The development of a phage display technology was a turning point in the design of phage-based vaccines. Phages are now recognized as universal adjuvant-free nanovaccine platforms. Phages are well-suited for vaccine design owing to their high stability in harsh conditions and simple and inexpensive large-scale production. The aim of this review is to summarize the overall breadth of the antiviral therapeutic perspective of phages contributing to the development of phage-based vaccines for COVID-19. We show that phage vaccines induce a strong and specific humoral response by targeted phage particles carrying the epitopes of SARS-CoV-2. Further, the engineering of the T4 bacteriophage by CRISPR (clustered regularly interspaced short palindromic repeats) presents phage vaccines as a valuable platform with potential capabilities of genetic plasticity, intrinsic immunogenicity, and stability.

Background: Tyrosine-protein kinase Fyn (Fyn) is a critical signaling molecule involved in various cellular processes, including neuronal development, synaptic plasticity, and disease pathogenesis. Dysregulation of Fyn kinase has been implicated in various complex diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, as well as different cancer types. Therefore, identifying small molecule inhibitors that can inhibit Fyn activity holds substantial significance in drug discovery., Objective: The aim of this study was to identify potential small-molecule inhibitors among bioactive phytoconstituents against tyrosine-protein kinase Fyn., Methods: Through a comprehensive approach involving molecular docking, drug likeliness filters, and molecular dynamics (MD) simulations, we performed a virtual screening of a natural compounds library. This methodology aimed to pinpoint compounds potentially interacting with Fyn kinase and inhibiting its activity., Results: This study finds two potential natural compounds: Dehydromillettone and Tanshinone B. These compoundsdemonstrated substantial affinity and specific interactions towards the Fyn binding pocket. Their conformations exhibitedcompatibility and stability, indicating the formation of robust protein-ligand complexes. A significant array of non-covalentinteractions supported the structural integrity of these complexes., Conclusion: Dehydromillettone and Tanshinone B emerge as promising candidates, poised for further optimization as Fynkinase inhibitors with therapeutic applications. In a broader context, this study demonstrates the potential of computationaldrug discovery, underscoring its utility in identifying compounds with clinical significance. The identified inhibitors holdpromise in addressing a spectrum of cancer and neurodegenerative disorders. However, their efficacy and safety necessitatevalidation through subsequent experimental studies.

Diabetic retinopathy (DR) is one of the chronic complications of diabetes. It includes retinal blood vessels' damage. If untreated, it leads to loss of vision. The existing treatment strategies for DR are expensive, invasive, and need expertise during administration. Hence, there is a need to develop a non-invasive topical formulation that can penetrate deep to the posterior segment of retina and treat the damaged retinal vessels. In addition, it should also provide sustained release. In recent years, novel drug delivery systems (NDDS) have been explored for treating DR and found successful. In this study, chitosan (CS) modified 5-Fluorouracil Nanostructured Lipid Carriers (CS-5-FU-NLCs) were prepared by modified melt emulsification-ultrasonication method and optimized by Box-Behnken Design. The size, polydispersity index, zeta potential and entrapment efficiency of CS-5-FU-NLCs were 163.2 ± 2.3 nm, 0.28 ± 1.52, 21.4 ± 0.5 mV and 85.0 ± 0.2 %, respectively. The in vitro drug release and ex vivo permeation study confirmed higher and sustained drug release in CS-5-FU-NLCs as compared to 5-FU solution. HET-CAM Model ensured the non-irritant nature of CS-5-FU-NLCs. In vivo ocular studies of CS-5-FU-NLCs confirmed antiangiogenic effect of 5-FU by CAM model and diabetic retinopathy induced rat model, indicating successful delivery of 5-FU to the retina., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of infection worldwide. Clove oil's ability to inhibit the growth of MRSA was studied through in vitro and in vivo studies. The phytochemical components of clove oil were determined through gas chromatography-mass spectrometry (GC-MS) analysis. The antibacterial effects of clove oil and its interaction with imipenem were determined by studying MIC , MBC, and FIC indices in vitro. The in vivo wound-healing effect of the clove oil and infection control were determined using excision wound model rats. The GC-MS analysis of clove oil revealed the presence of 16 volatile compounds. Clove oil showed a good antibacterial effect in vitro but no interaction was observed with imipenem. Clove bud oil alone or in combination with imipenem healed wounds faster and reduced the microbial load in wounds. The findings of this study confirmed the antibacterial activity of clove oil in vitro and in vivo and demonstrated its interaction with imipenem.

Frankincense ( Boswellia sacra oleo gum resin) is reported to possess antimicrobial activity against several pathogens in-vitro. The antimicrobial effects of frankincense oil and its interaction with imipenem and gentamicin against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant P. aeruginosa were determined through in-vitro methods and an in-vivo study using a rat pneumonia model. Frankincense oil was subjected to GC-MS analysis to determine the different volatile components. Antibacterial effects against MRSA and MDR- P. aeruginosa was evaluated and its MIC and MBC were determined. For the rat pneumonia model (in-vivo), oil was administered at a dose of 500 mg/kg and 1000 mg/kg followed by determination of CFU in lung tissue and histological studies. Frankincense oil did not show a very potent inhibitory effect against MRSA or MDR- P. aeruginosa ; the oil did not affect the zone of inhibition or FIC when combined with imipenem or gentamicin indicating a lack of interaction between the oil and the antibiotics. Furthermore, there was no interaction between the antibiotics and the frankincense oil in the in-vivo model. The result of the study revealed that frankincense oil has a weak inhibitory effect against MRSA and MDR- P. aeruginosa , and it did not show any interaction with imipenem or gentamicin., Competing Interests: The authors declare no conflict of interest.

Present study deciphers development of oral polysaccharide-based colon targeted solid self-nanoemulsifying drug delivery system (S-SNEDDS) of xanthohumol (XH). Several studies have shown that XH has anti-inflammatory and antioxidant properties, suggesting that it could be a good candidate for the treatment of colorectal diseases (CRD). Despite its potential, XH has a low aqueous solubility. As a result, its bioavailability is constrained by the dissolution rate. The liquid (L)-SNEDDS was constituted using Labrafac PG as oil, Tween 80 as surfactant and Transcutol P as co-surfactant. The L-SNEDDS was then adsorbed onto the surface of guar gum and pectin and developed into S-SNEDDS powder. Ternary phase diagram was used to optimize the process of developing L-SNEDDS. The formulation showed mean droplet size of 118.96 ± 5.94 nm and zeta potential of -19.08 ± 0.95 mV and drug loading of 94.20 ± 4.71%. Dissolution studies carried out in medium containing rat caecal contents (RCC) represented the targeted release of S-SNEDDS powder. It was observed that S-SNEDDS showed less than 10% release XH in initial 5 h and rapid release occurred between the 5th and 10th hour. Results of cytotoxicity studies revealed good cytotoxicity of XH loaded S-SNEDDS for Caco2 cells as compared to raw-XH.

Ulcerative colitis (UC) is a chronic inflammatory life-threatening and premalignant disorder with no cure that even might end up with surgical removal of a large section or even all of the colon. It is characterized by relapsing-remitting courses of intestinal inflammation and mucosal damage in which oxidative stress and exaggerated inflammatory response play a significant role. Most of the current medications to maintain remission are symptomatic and have many adverse reactions. Therefore, the potential for improved management of patients with UC continues to increase. Yet, the benefits of using the antiarthritic agent diacetylrhein to counteract inflammation in UC are still obscure. Hence, our study was designed to explore its potential role in UC using a model of dextran sodium sulfate-induced acute colitis in rats. Our results revealed that diacetylrhein targeted the NLRP3 and inhibited the inflammasome assembly. Consequently, caspase-1 activity and the inflammatory cytokines IL-1β and IL-18 were inhibited leading to a curbed pyroptosis process. Additionally, diacetylrhein revealed a significant antiapoptotic potential as revealed by the levels of pro-apoptotic and anti-apoptotic proteins. Concomitant to these effects, diacetylrhein also interrupted NFκB signals leading to improved microscopic features of inflamed colon and decreased colon weight to length ratio, indices of disease activity, and macroscopic damage. Additionally, a reduction in the myeloperoxidase activity, IL-6, and TGF-β alongside an increase in the gene expression of Ocln and ZO-1 were detected. To conclude diacetylrhein showed a significant antioxidant and anti-inflammatory potential and therefore might represent a promising agent in the management of acute UC., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Idiopathic pulmonary fibrosis is a fatal lung disorder in which the etiology and pathogenesis are still unobvious. Effective treatments are urgently needed considering that lung transplantation is the only treatment that could improve outcomes. This study aimed to investigate the therapeutic significance of the dual administration of pimitespib, an HSP90 inhibitor, and nifuroxazide, a STAT3 inhibitor, against bleomycin-induced pulmonary fibrosis in rats. Our results revealed that pimitespib/nifuroxazide inhibited bleomycin-induced alterations in the structure and the function of the lungs. They demonstrated significant decreases in the BALF total and differential cell counts, LDH activity, and total protein. Concurrently, there was a reduction in the accumulation of collagen as proved by decreased hydroxyproline and the gene expression of COL1A1 accompanied by lower levels of PDGF-BB, TIMP-1, and TGF-β. The levels of IL-6 were also downregulated. Pimitespib-induced inhibition of HSP90 led to subsequent inhibition of HIF-1α and STAT3 client proteins since the closed HSP90 would not enclose its client proteins. Therefore, pimitespib resulted in the repression of HIF-1α/CREB-p300 HAT as well as the STAT3/CREB-p300 HAT nuclear interactions. On the other hand, nifuroxazide resulted in a notable decline in pSTAT3 and HIF-1α levels. Subsequently, the combined effects of both drugs led to a substantial reduction in ECM deposition. Herein, pimitespib augmented nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop. Our findings also disclose that this novel loop is a promising therapeutic attack site for possible pulmonary fibrosis repression studies. Therefore, the use of pimitespib/nifuroxazide embodies an evolutionary perspective in managing pulmonary fibrosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Tick sialome is comprised of a rich cocktail of bioactive molecules that function as a tool to disarm host immunity, assist blood-feeding, and play a vibrant role in pathogen transmission. The adaptation of the tick's blood-feeding behavior has lead to the evolution of bioactive molecules in its saliva to assist them to overwhelm hosts' defense mechanisms. During a blood meal, a tick secretes different salivary molecules including vasodilators, platelet aggregation inhibitors, anticoagulants, anti-inflammatory proteins, and inhibitors of complement activation; the salivary repertoire changes to meet various needs such as tick attachment, feeding, and modulation or impairment of the local dynamic and vigorous host responses. For instance, the tick's salivary immunomodulatory and cement proteins facilitate the tick's attachment to the host to enhance prolonged blood-feeding and to modulate the host's innate and adaptive immune responses. Recent advances implemented in the field of "omics" have substantially assisted our understanding of host immune modulation and immune inhibition against the molecular dynamics of tick salivary molecules in a crosstalk between the tick-host interface. A deep understanding of the tick salivary molecules, their substantial roles in multifactorial immunological cascades, variations in secretion, and host immune responses against these molecules is necessary to control these parasites. In this article, we reviewed updated knowledge about the molecular mechanisms underlying host responses to diverse elements in tick saliva throughout tick invasion, as well as host defense strategies. In conclusion, understanding the mechanisms involved in the complex interactions between the tick salivary components and host responses is essential to decipher the host defense mechanisms against the tick evasion strategies at tick-host interface which is promising in the development of effective anti-tick vaccines and drug therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ali, Zeb, Alouffi, Zahid, Almutairi, Ayed Alshammari, Alrouji, Termignoni, Vaz and Tanaka.)