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Abstract: Aims: We evaluated the in vitro antioxidant and antimicrobial potential of Schimpera arabica extract and fractions (2‐Hexadecen‐1‐ol and beta sitosterol). Methods and Results: Free radical scavenging activity was estimated by using ABTS and DPPH methods, reducing power and iron chelation was studied to investigate antioxidant potential of the extracts. Well‐diffusion method was utilized to evaluate the antimicrobial activity of the extracts. Gas chromatography‐mass spectroscopy analysis of the extract revealed the presence of 27 compounds. Phenolic and flavonoid contents were found in high amount (7·6–18 mg GAE, mg g−1; 3·2–10·8 mg catechin, mg g−1) in dry plant material. Conclusions: Among all the extracts, 2‐Hexadecen‐1‐ol and beta sitosterol were the major constituents of crude extract and exhibited significant antioxidant potential as well antimicrobial activity; however, all other fractions also exhibited fare degree of antioxidant potential. 93% DPPH was scavenged by 100 μg ml−1 of the ethyl acetate fraction; in ABTS assay chelation was 86·2 and 88% in ferric chloride reducing power assay. Significance and Impact of the Study: Schimpera arabica is naturally present and used in food preparation in most Arabian nations. The characterization of S. arabica would provide an insight into its medicinal use as home remedial for bacterial infection and as antioxidant. Significant and comparable antimicrobial activity was demonstrated by both 2‐Hexadecen‐1‐ol and beta sitosterol fractions. The results suggest that S. arabica contain a good amount of natural antioxidants of medicinal importance. However, further investigations are needed to characterize the further activity of 2‐Hexadecen‐1‐ol and beta sitosterol in vivo. [ABSTRACT FROM AUTHOR]

In this study we determined the treatment effect of clofibrate in low birth weight neonate with hyperbilirubinemia. In a randomized double blind placebo - controlled study, 60 low birth weight neonates who were jaundiced and had hyperbilirubinemia were selected. The treatment group received a single oral dose of clofibrate (100 mg/kg) and the control group received sterile water as placebo. Also both group received Phototherapy in addition of the treatment. Serum bilirubin level was measured at entrance to study and 12, 24, 48 and 72 hours of study. Serum bilirubin decreased in 72 hours in clofibrate group that it was nearly significant (p= 0.061), but there were no significant difference between two groups in 12, 24, 48 hours of study (p= 0.7, p= 0.22, p= 0.19 respectively). Duration of phototherapy in clofibrate group was significantly shorter than control group (p= 0.023). Based on physical exam and liver function tests no side effects were seen. Our result showed that there wasn't significant difference between two groups after administration of single dose of clofibrate (100 mg/ kg) in 12, 24, 48 and 72 hour. Although effect of clofibrate on treatment of jaundice wasn't significant between two groups, duration of phototherapy has been decreased significantly in clofibrate groups. [ABSTRACT FROM AUTHOR]

During the initiation of any legacy evolution project one of the key challenges faced by project engineer is with respect to estimating the effort, cost and time required for execution and completion of the project. Especially in this highly competitive world of software renovation markets, the ability to come up with accurate estimate for the project is one of the most desired competencies from any project engineer. One of the major inputs for the project engineer in deciding the estimated effort and time, cost is the size of the work product and individual decomposed code components coming out of the project. The accuracy in the project's estimation will depend on how accurately the size of components is estimated. One of the contributing factors for failure of software evolution projects is that, may projects get estimated based on personal working experience of project engineer. This paper presents components and size based effort estimation modeling that is beneficial in estimating a legacy code and components for evolution. [ABSTRACT FROM AUTHOR]

The strong association between gut microbiota (GM) and brain functions such as mood, behaviour, and cognition has been well documented. Gut-brain axis is a unique bidirectional communication system between the gut and brain, in which gut microbes play essential role in maintaining various molecular and cellular processes. GM interacts with the brain through various pathways and processes including, metabolites, vagus nerve, HPA axis, endocrine system, and immune system to maintain brain homeostasis. GM dysbiosis, or an imbalance in GM, is associated with several neurological disorders, including anxiety, depression, and Alzheimer's disease (AD). Conversely, AD is sustained by microglia-mediated neuroinflammation and neurodegeneration. Further, GM and their products also affect microglia-mediated neuroinflammation and neurodegeneration. Despite the evidence connecting GM dysbiosis and AD progression, the involvement of GM in modulating microglia-mediated neuroinflammation in AD remains elusive. Importantly, deciphering the mechanism/s by which GM regulates microglia-dependent neuroinflammation may be helpful in devising potential therapeutic strategies to mitigate AD. Herein, we review the current evidence regarding the involvement of GM dysbiosis in microglia activation and neuroinflammation in AD. We also discuss the possible mechanisms through which GM influences the functioning of microglia and its implications for therapeutic intervention. Further, we explore the potential of microbiota-targeted interventions, such as prebiotics, probiotics, faecal microbiota transplantation, etc., as a novel therapeutic strategy to mitigate neuroinflammation and AD progression. By understanding and exploring the gut-brain axis, we aspire to revolutionize the treatment of neurodegenerative disorders, many of which share a common theme of microglia-mediated neuroinflammation and neurodegeneration., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Coumarins, abundantly distributed in a plethora of biologically active compounds, serve as a fundamental motif in numerous natural products, drugs, and therapeutic leads. Despite their small size, they exhibit a diverse range of biological activities, intriguing researchers with their immense pharmacological potential., Purpose: This study consolidates the evidence regarding the essential role of coumarins in modern drug discovery, exploring their broad-spectrum pharmaceutical effects, structural versatility, and mechanisms of action across various domains., Methods: For literature search, we utilized PubMed, Google scholar, and SciFinder databases. Keyword and keyword combinations such as "coumarins", "natural coumarins", "specific natural coumarins for particular diseases", and "therapeutic effects" were employed to retrieve relevant studies. The search encompassed articles published between 2005 and 2023. Selection criteria included studies reporting on the pharmacological activities of natural coumarins against various diseases., Results: The results highlight the therapeutic potential of natural coumarins against various diseases, demonstrating anti-cancer, anti-oxidant, and anti-inflammatory activities. They also act as monoamine oxidase inhibitors and phosphodiesterase inhibitors, and as anti-thrombotic, anti-diabetic, and hepatoprotective agents. They also show efficacy against diabetic nephropathy, neurodegenerative diseases, microbial infections and many other diseases., Conclusion: This review underscores the significant role of natural coumarins in medicinal chemistry and drug discovery. Their diverse biological activities and structural versatility make them promising therapeutic agents. This study serves as a catalyst for further research in the field, aiming to address emerging challenges and opportunities in drug development., 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 © 2024 Elsevier GmbH. All rights reserved.)

Wnt signaling is one of the key regulators of bone development and homeostasis. Wnt signaling regulates key biological events, including stem cell fate and osteoblast and osteoclast activity, leading to the maintenance of bone mass and strength. Wnt ligands are secreted glycoproteins that bind to Frizzled (FZD) receptors and their coreceptors, lipoprotein receptor-related proteins-5/6 (LRP5/6). Binding of Wnts to FZD triggers canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) pathways. In canonical Wnt signaling, stabilized β-catenin translocates to the nucleus, where it promotes osteoblast differentiation by activating target genes, including Runx2 and Osterix. The negative regulators of Wnt or so-called Wnt antagonists, including CXXC5, sFRP, sclerostin, DKK1, and Notum, compete for Fzd binding, attenuating Wnt signaling. The critical roles of Wnt signaling in bone homeostasis have been established by various bone diseases caused by mutations in Wnt signaling pathways. Loss-of-function mutations in the LRP5 gene cause osteoporosis-pseudoglioma syndrome, whereas gain-of-function mutations are linked to osteopetrosis characterized by high bone density. Sclerosteosis and Van Buchem disease are caused by mutations affecting the SOST gene, which encodes sclerostin, a natural inhibitor of Wnt signalling. Loss-of-function mutations in SOST result in excessive bone growth, markedly increased bone density, and other skeletal abnormalities due to uncontrolled Wnt activity. Considering the clinical relevance of Wnt signaling, targeting Wnt inhibitors is being intensely pursued using small molecules that act by inhibiting endogenous Wnt agonists. We used a computational biology approach to review current data on pharmacophores of Wnt antagonists, assessing their potential as therapeutic candidates for postmenopausal osteoporosis., 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 © 2024 Elsevier Inc. All rights reserved.)

Despite advancements in oncology, predicting recurrence-free survival (RFS) in head and neck (H&N) cancer remains challenging due to the heterogeneity of tumor biology and treatment responses. This study aims to address the research gap in the prognostic efficacy of traditional clinical predictors versus advanced radiomics features and to explore the potential of weighted fusion techniques for enhancing RFS prediction. We utilized clinical data, radiomic features from CT and PET scans, and various weighted fusion algorithms to stratify patients into low- and high-risk groups for RFS. The predictive performance of each model was evaluated using Kaplan-Meier survival analysis, and the significance of differences in RFS rates was assessed using confidence interval (CI) tests. The weighted fusion model with a 90% emphasis on PET features significantly outperformed individual modalities, yielding the highest C-index. Additionally, the incorporation of contextual information by varying peritumoral radii did not substantially improve prediction accuracy. While the clinical model and the radiomics model, individually, did not achieve statistical significance in survival differentiation, the combined feature set showed improved performance. The integration of radiomic features with clinical data through weighted fusion algorithms enhances the predictive accuracy of RFS outcomes in head and neck cancer. Our findings suggest that the utilization of multi-modal data helps in developing more reliable predictive models and underscore the potential of PET imaging in refining prognostic assessments. This study propels the discussion forward, indicating a pivotal step toward the adoption of precision medicine in cancer care.

This review explores the recent advancements in the design and synthesis of pseudo-natural products (pseudo-NPs) by employing innovative principles and strategies, heralding a transformative era in chemistry and biology. Pseudo-NPs, produced through in silico fragmentation and the de novo recombination of natural product fragments, reveal compounds endowed with distinct biological activities. Their advantage lies in transcending natural product structures, fostering diverse possibilities. Research in this area over the past decade has yielded unconventional combinations of natural product fragments, leading to the identification of novel compounds possessing unique scaffolds and biological significance, thereby contributing to the discovery of new therapeutics. The pseudo-NPs exert potent biological effects through various signaling pathways. In chemical biology and medicinal chemistry, designing pseudo-NPs is an important strategy, harnessing molecular hybridization and bioinspired synthesis to generate diverse compounds with remarkable biological activities, underscoring their immense potential in drug discovery and development., 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 © 2024 Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases. The effective coordination of mitochondrial turnover processes, notably mitophagy and biogenesis, is assumed to be critically important for cellular resilience and longevity. However, the age-associated decrease in mitophagy impedes the elimination of dysfunctional mitochondria, consequently impairing mitochondrial biogenesis. This deleterious cascade results in the accumulation of damaged mitochondria and deterioration of cellular functions. Both excitotoxicity and oxytosis/ferroptosis have been demonstrated to contribute significantly to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). Excitotoxicity, characterized by excessive glutamate signaling, initiates a cascade of events involving calcium dysregulation, energy depletion, and oxidative stress and is intricately linked to mitochondrial dysfunction. Furthermore, emerging concepts surrounding oxytosis/ferroptosis underscore the importance of iron-dependent lipid peroxidation and mitochondrial engagement in the pathogenesis of neurodegeneration. This review not only discusses the individual contributions of excitotoxicity and ferroptosis but also emphasizes their convergence with mitochondrial dysfunction, a key driver of neurodegenerative diseases. Understanding the intricate crosstalk between excitotoxicity, oxytosis/ferroptosis, and mitochondrial dysfunction holds potential to pave the way for mitochondrion-targeted therapeutic strategies. Such strategies, with a focus on bioenergetics, biogenesis, mitophagy, and oxidative stress, emerge as promising avenues for therapeutic intervention.

The tau-tubulin kinase 1 (TTBK1) protein is a casein kinase 1 superfamily member located at chromosome 6p21.1. It is expressed explicitly in the brain, particularly in the cytoplasm of cortical and hippocampal neurons. TTBK1 has been implicated in the phosphorylation and aggregation of tau in Alzheimer's disease (AD). Considering its significance in AD, TTBK1 has emerged as a promising target for AD treatment. In the present study, we identified novel TTBK1 inhibitors using various computational techniques. We performed a virtual screening-based docking study followed by E-pharmacophore modeling, cavity-based pharmacophore, and ligand design techniques and found ZINC000095101333 , LD7 , LD55 , and LD75 to be potential novel TTBK1 lead inhibitors. The docking results were complemented by Molecular Mechanics/Generalized Born Surface Area (MMGBSA) calculations. The molecular dynamics (MD) simulation studies at a 500 ns scale were carried out to monitor the behavior of the protein toward the identified ligands. Pharmacological and ADME/T studies were carried out to check the drug-likeness of the compounds. In summary, we identified a new series of compounds that could effectively bind the TTBK1 receptor. The newly designed compounds are promising candidates for developing therapeutics targeting TTBK1 for AD.

This review explores the significance of trifluoromethylnitrones in synthesizing fluorine-containing compounds, with a particular focus on trifluoromethylated heterocycles. It explores the versatility of trifluoromethylnitrones, especially in [3 + 2] cycloaddition reactions, highlighting their unique reactivity with various dienophile substrates. Trifluoromethylnitrones are valuable precursors for the rapid synthesis of medicinally important trifluoromethylated heterocycles, including isoxazolidines, dihydroisoxazoles, oxathiazolidines, β-lactams, and aziridines. These heterocycles, in turn, serve as synthons for synthesizing trifluoromethylated lactams and aminoalcohols. Additionally, nitrone chemistry extends to synthesizing trifluoromethylated nucleosides and trifluorinated organoborane heterocycles, demonstrating their versatility. While sharing similarities with trifluorodiazoethane reactivity, trifluoromethylnitrones offer distinct advantages by enabling the synthesis of heterocycles typically inaccessible with trifluorodiazoethane.

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by a mutation in the huntingtin (HTT) gene, resulting in the production of a mutant huntingtin protein (mHTT). The accumulation of mHTT leads to the development of toxic aggregates in neurons, causing cell dysfunction and, eventually, cell death. Peptide therapeutics target various aspects of HD pathology, including mHTT reduction and aggregation inhibition, extended CAG mRNA degradation, and modulation of dysregulated signaling pathways, such as BDNF/TrkB signaling. In addition, these peptide therapeutics also target the detrimental interactions of mHTT with InsP3R1, CaM, or Caspase-6 proteins to mitigate HD. This Perspective provides a detailed perspective on anti-HD therapeutic peptides, highlighting their design, structural characteristics, neuroprotective effects, and specific mechanisms of action. Peptide therapeutics for HD exhibit promise in preclinical models, but further investigation is required to confirm their effectiveness as viable therapeutic strategies, recognizing that no approved peptide therapy for HD currently exists.

Antibiotic resistance against Mycobacterium tuberculosis ( M.tb. ) has been a significant cause of death worldwide. The Enhanced intracellular survival (EIS) protein of the bacteria is an acetyltransferase that multiacetylates aminoglycoside antibiotics, preventing them from binding to the bacterial ribosome. To overcome the EIS-mediated antibiotics resistance of M.tb ., we compiled 888 alkaloids and derivatives from five different databases and virtually screened them against the EIS receptor. The compound library was filtered down to 87 compounds, which underwent additional analysis and filtration. Moreover, the top 15 most prominent phytocompounds were obtained after the drug-likeness prediction and ADMET screening. Out of 15, nine compounds confirmed the maximum number of hydrogen bond interactions and reliable binding energies during molecular docking. Additionally, the Molecular dynamics (MD) simulation of nine compounds showed the three most stable complexes, further verified by re-docking with mutated protein. The density functional theory (DFT) calculation was performed to identify the HOMO-LUMO energy gaps of the selected three potential compounds. Finally, our selected top lead compounds i.e., Alkaloid AQC2 (PubChem85634496), Nobilisitine A (ChEbi68116), and N-methylcheilanthifoline (ChEbi140673) demonstrated more favourable outcomes when compared with reference compounds (i.e., 39b and 2i) in all parameters used in this study. Therefore, we anticipate that our findings will help to explore and develop natural compound therapy against multi and extensively drug-resistant strains of M.tb .Communicated by Ramaswamy H. Sarma.

The design and development of new small-molecule glycation inhibitors are essential for preventing various chronic diseases, including diabetes mellitus, immunoinflammation, cardiovascular, and neurodegenerative diseases. 4-Thiazolidinone or thiazolidine-4-one is a well-known heterocyclic compound with the potential to inhibit the formation of advanced glycation end products. In the present work, we report the synthesis and characterization of four new 5-arylidene 3-cyclopropyl-2-(phenylimino)thiazolidin-4-one ( 1 - 4 ) compounds and their human serum albumin glycation inhibitory activity. One of the compounds 5-(2 H -1,3-benzodioxol-5-ylmethylidene)-3-cyclopropyl-2-(phenylimino)-1,3-thiazolidin-4-one ( 3 ) showed potent inhibition in the synthesis of initial, intermediary, and final products of glycation reactions. Besides, conformational changes in the α-helix and β-sheet (due to hyperglycemia) were also found to be reversed upon the addition of ( 3 ). Experimental findings were complemented by computational [molecular docking, ADME/Tox, and density functional theory (DFT)] studies. The docking scores of the compounds were in order 1 > 3 > 2 > 4 , indicating the importance of the polar group at the 5-arylidene moiety. The results of ADME/Tox and DFT calculations revealed the safe nature of the compounds with high drug-likeness and stability. Overall, we speculate that the results of this study could provide valuable insights into the biological activity of 4-thiazolidinones., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Axenic cultures of two strains, JC673 T and JC717, both belonging to the phylum Planctomycetota , were isolated from distinct geographical locations in India. Strain JC673 T was obtained from algal mats of a wetland situated in the state of Kerala, India, while strain JC717 originated from the Central Marine Fisheries Research Institute (CMFRI), state of Tamil Nadu, India. The two strains share 99.9% 16S rRNA gene sequence similarity and are most closely related to Gemmata obscuriglobus UQM 2246 T (99.3% 16S rRNA gene sequence identity). The newly isolated strains are Gram-negative, grow aerobically and tolerate up to 4% ( w / v ) NaCl and a pH of up to 9.0. Cells are spherical and form pink-pigmented colonies. The respiratory quinone is MK-6. Major fatty acids are C 18:0 , C 16:1 ω5c and C 16:0 . Polar lipids include phosphatidylcholine, phosphatidylethanolamine, several unidentified amino lipids, unidentified phospholipids, additional unidentified lipids, and an unidentified choline lipid. The polyamine spermidine is produced by the two strains. The strains have a genome size of about 8.2 Mb with a DNA G+C content of 67.6%. Solvent-based culture extracts of the isolates showed antimicrobial activity against three bacterial test strains. Their phylogenetic position along with differences in morphological, physiological, and genomic features support the classification as a new species of the genus Gemmata , for which we propose the name Gemmata algarum sp. nov. Strain JC673 T (=KCTC 72851 T = NBRC 114340 T ) and JC717 are the type and non-type strain of the new species, respectively.

Non-enzymatic glycation of biomolecules by reducing sugars led to several products, including the advanced glycation end products (AGEs), the accumulation of which has been linked to various life-threatening diseases. The binding of AGEs to their respective protein receptors for advanced glycation end products (RAGE) can initiate a cascade of reactions, which may alter physiological conditions. The present work investigates the potential of 4-thiazolidinones as RAGE inhibitors. We performed an extensive computational study to identify the structural requirements needed to act as RAGE inhibitors. To achieve this goal, 4-thiazolidinone-based compounds available in PubChem, ZINC15, ChEMBL, and ChEBI databases were screened against RAGE (PDB: 4LP5), leading to the identification of top five drug-like candidates with a high binding affinity to RAGE V-domain catalytic region. Drug likeness, absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the top-scoring compounds have been studied and discussed. Global molecular descriptors, chemical reactivity, hardness, softness, etc., have been estimated. Finally, molecular dynamics (MD) simulations at 100 ns were carried out to check the stability and other properties. Overall, we believe that the identified compounds can potentially attenuate RAGE-AGE interactions.Communicated by Ramaswamy H. Sarma.

Pulicaria arabica has been traditionally utilized in folk medicine for various purposes such as ulcer treatments as well as antidiarrheal agent. Herein, the chemical profiles of Pulicaria arabica essential oils (PAEOs) and the in vitro antiproliferative effect of PAEOs were investigated. Hydrodistillation was employed to prepare PAEOs which were then characterized by GC/MS, while the antiproliferative effects were investigated by MTT assay as well as flow cytometric and RT-PCR analysis. Sixty-four (99.99 %) constituents were recognized from PAEOs. Carvotanacetone (36.97 %), (-)-carvomenthone (27.20 %) and benzene, 2-(1,1-dimethylethyl)-1,4-dimethoxy- (6.92 %) were the main components. PAEOs displayed IC 50 values ranging from 30 to 50 μg/mL. DNA content analysis revealed that A549 cells exposed to PAEOs exhibited an increase in G1 cells population. The flow cytometry analysis results also showed that the PAEOs antiproliferative effect was mediated via apoptosis induction. Furthermore, a modulation in the pro-apoptotic markers (caspase-3 and Bax) and anti-apoptotic (Bcl-2) was also observed. In conclusion, PAEOs exhibited a moderate anti-proliferative effect on A549 cells through modulating the cell cycle progression and apoptosis initiation. These findings could offer a potential therapeutic use of PAEOs in lung cancer treatment., 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., (© 2023 The Author(s).)

A novel cellulolytic strain JC656 T was isolated from the rhizosphere soil of Alisma plantago-aquatica of floating island (Phumdis) of Loktak lake, Manipur, India. The 16S rRNA gene sequence similarities between strain JC656 T and other Sinomonas type strains ranged between 98.5 and 97.3%, wherein strain JC656 T exhibited the highest sequence similarity (98.5%) to Sinomonas notoginsengisoli KCTC 29237 T . Colonies were yellow-colored and grew aerobically. Cells were gram-positive, rod-shaped and non-motile. The optimal growth of the strain JC656 T occured at 28 °C and pH 7. Strain JC656 T contained MK-9 as the predominant isoprenoid quinone and anteiso-C 15:0 , iso-C 16:0 and anteiso-C 17:0 as the major fatty acids. Diphosphatidylglycerol, phosphatidylinositol, phosphatidylglycerol, phosphatidylmonomethylethanolamine and a glycolipid were the polar lipids. Strain JC656 T contained lysine, alanine, glutamine, diaminopimelic acid (DAP) and two unidentified amino acids as characteristic cell wall amino acids. The genome size of strain JC656 T was 3.9 Mb with a DNA G + C content of 69.9 mol %. For the affirmation of the strain's taxonomic status, a detailed phylogenomic study was done. Based on its phylogenetic position and morphological, physiological, and genomic features, strain JC656 T represents a new species of the genus Sinomonas, for which we propose the name Sinomonas cellulolyticus sp. nov. The type strain JC656 T  = (KCTC 49339 T  = NBRC 114142 T )., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Khat ( Catha edulis ) is an evergreen shrub whose buds and leaves give a state of delight and euphoria when chewed. Cathinone, an amphetamine-like stimulant that is among the active ingredients in khat, is able to downregulate glutamate transporter subtype I (GLT-1). Neurobehavioral dysfunctions such as altered locomotor activity, anorexia, and nociception have been observed in animals exposed to cathinone. Interestingly, treatment with a β-lactam antibiotic such as ceftriaxone, which upregulates GLT-1, normalizes cathinone-induced conditioned place preference, and alters repetitive movements in rats. However, little is known about the role of the glutamatergic system in memory dysfunction and anxiety-like behaviors in mice exposed to khat. We found here that clavulanic acid, a β-lactam-containing compound and GLT-1 upregulator, would modulate the neurobehavioral changes, including memory impairment and anxiety-like behaviors, associated with repeated exposure of mice to khat. Our data supported that clavulanic acid could improve memory impairment and anxiety-like behaviors through upregulating GLT-1 in the nucleus accumbens (NAc), an effect abolished with a selective GLT-1 blocker. This upregulation was associated with restored glutamate/cystine antiporter expression in the NAc using a Western blotting assay. Cathine and cathinone were identified in khat extract using the gas chromatography technique. Our work provides preclinical insight into the efficacy of β-lactam-containing compounds for the attenuation of neurobehavioral changes induced by khat exposure.

Fentanyl is a highly potent opioid analgesic that is approved medically to treat acute and chronic pain. There is a high potential for overdose-induced organ toxicities, including liver toxicity, and this might be due to the increase of recreational use of opioids. Several preclinical studies have demonstrated the efficacy of beta-lactams in modulating the expression of glutamate transporter-1 (GLT-1) in different body organs, including the liver. The upregulation of GLT-1 by beta-lactams is associated with the attenuation of hyperglutamatergic state, which is a characteristic feature of opioid use disorders. A novel experimental beta-lactam compound with no antimicrobial properties, MC-100093, has been developed to attenuate dysregulation of glutamate transport, in part by normalizing GLT-1 expression. A previous study showed that MC-100093 modulated hepatic GLT-1 expression with subsequent attenuation of alcohol-increased fat droplet content in the liver. In this study, we investigated the effects of fentanyl overdose on liver metabolites, and determined the effects of MC-100093 and ceftriaxone in the liver of a fentanyl overdose mouse model. Liver samples from control, fentanyl overdose, and fentanyl overdose ceftriaxone- or MC-100093-treated mice were analyzed for metabolomics using gas chromatography-mass spectrometry. Heatmap analysis revealed that both MC-100093 and ceftriaxone attenuated the effects of fentanyl overdose on several metabolites, and MC-100093 showed superior effects. Statistical analysis showed that MC-100093 reversed the effects of fentanyl overdose in some metabolites. Moreover, enrichment analysis revealed that the altered metabolites were strongly linked to the glucose-alanine cycle, the Warburg effect, gluconeogenesis, glutamate metabolism, lactose degradation, and ketone body metabolism. The changes in liver metabolites induced by fentanyl overdose were associated with liver inflammation, an effect attenuated with ceftriaxone pre-treatments. Ceftriaxone normalized fentanyl-overdose-induced changes in liver interleukin-6 and cytochrome CYP3A11 (mouse homolog of human CYP3A4) expression. Our data indicate that fentanyl overdose impaired liver metabolites, and MC-100093 restored certain metabolites.