Search

Objective: Lifestyle habits after middle age significantly impact the maintenance of cognitive function in older adults. Nutritional intake is closely related to lifestyle habits; therefore, nutrition is a pivotal factor in the prevention of dementia in the preclinical stages. Matcha green tea powder (matcha), which contains epigallocatechin gallate, theanine, and caffeine, has beneficial effects on cognitive function and mood. We conducted a randomized, double-blind, placebo-controlled clinical study over 12 months to examine the effect of matcha on cognitive function and sleep quality., Methods: Ninety-nine participants, including 64 with subjective cognitive decline and 35 with mild cognitive impairment were randomized, with 49 receiving 2 g of matcha and 50 receiving a placebo daily. Participants were stratified based on two factors: age at baseline and APOE genotype. Changes in cognitive function and sleep quality were analyzed using a mixed-effects model., Results: Matcha consumption led to significant improvements in social acuity score (difference; -1.39, 95% confidence interval; -2.78, 0.002) (P = 0.028) as evaluated by the perception of facial emotions in cognitive function. The primary outcomes, that is, Montreal Cognitive Assessment and Alzheimer's Disease Cooperative Study Activity of Daily Living scores, showed no significant changes with matcha intervention. Meanwhile, Pittsburgh Sleep Quality Index scores indicated a trend toward improvement with a difference of 0.86 (95% confidence interval; -0.002, 1.71) (P = 0.088) between the groups in changes from baseline to 12 months., Conclusions: The present study suggests regular consumption of matcha could improve emotional perception and sleep quality in older adults with mild cognitive decline. Given the widespread availability and cultural acceptance of matcha green tea, incorporating it into the daily routine may offer a simple yet effective strategy for cognitive enhancement and dementia prevention., Competing Interests: Authors with competing interests Enter competing interest details beginning with this statement: I have read the journal’s policy and the authors of this manuscript have the following competing interests: [Kazuhiko Uchida serves as a board member of MCBI Inc. Kohji Meno, Tatsumi Korenaga, Liu Shan, and Hideaki Suzuki are employees of MCBI Inc. Yoshitake Baba, Chika Tagata, Yoshiharu Araki, Shuto Tsunemi, Kenta Aso, Shun Inagaki, Sae Nakagawa, Makoto Kobayashi, and Takanobu Takihara are employees of ITO EN, LTD. This research received no external funding.] This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Uchida 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.)

Ethnopharmacological Relevance: Rujifang (RJF) constitutes a traditional Chinese medicinal compound extensively employed in the management of triple-negative breast cancer (TNBC). However, information regarding its potential active ingredients, antitumor effects, safety, and mechanism of action remains unreported., Aim of the Study: To investigate the efficacy and safety of RJF in the context of TNBC., Materials and Methods: We employed the ultra high-performance liquid chromatography-electrospray four-pole time-of-flight mass spectrometry technique (UPLC/Q-TOF-MS/MS) to scrutinize the chemical constituents of RJF. Subcutaneously transplanted tumor models were utilized to assess the impact of RJF on TNBC in vivo. Thirty female BLAB/c mice were randomly divided into five groups: the model group, cyclophosphamide group, and RJF high-dose, medium-dose, and low-dose groups. A total of 1 × 10 6 4T1 cells were subcutaneously injected into the right shoulder of mice, and they were administered treatments for a span of 28 days. We conducted evaluations on blood parameters, encompassing white blood cell count (WBC), red blood cell count (RBC), hemoglobin (HGB), platelet count (PLT), neutrophils, lymphocytes, and monocytes, as well as hepatorenal indicators including alkaline phosphatase (ALP), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), albumin, and creatinine (CRE) to gauge the safety of RJF. Ki67 and TUNEL were detected via immunohistochemistry and immunofluorescence, respectively. We prepared RJF drug-containing serum for TNBC cell lines and assessed the in vitro inhibitory effect of RJF on tumor cell growth through the CCK8 assay and cell cycle analysis. RT-PCR was employed to detect the mRNA expression of cyclin-dependent kinase and cyclin-dependent kinase inhibitors in tumor tissues, and Western blot was carried out to ascertain the expression of cyclin and pathway-related proteins., Results: 100 compounds were identified in RJF, which consisted of 3 flavonoids, 24 glycosides, 18 alkaloids, 3 amino acids, 8 phenylpropanoids, 6 terpenes, 20 organic acids, and 18 other compounds. In animal experiments, both CTX and RJF exhibited substantial antitumor effects. RJF led to an increase in the number of neutrophils in peripheral blood, with no significant impact on other hematological indices. In contrast, CTX reduced red blood cell count, hemoglobin levels, and white blood cell count, while increasing platelet count. RJF exhibited no discernible influence on hepatorenal function, whereas Cyclophosphamide (CTX) decreased ALP, GOT, and GPT levels. Both CTX and RJF reduced the expression of Ki67 and heightened the occurrence of apoptosis in tumor tissue. RJF drug-containing serum hindered the viability of 4T1 and MD-MBA-231 cells in a time and concentration-dependent manner. In cell cycle experiments, RJF diminished the proportion of G2 phase cells and arrested the cell cycle at the S phase. RT-PCR analysis indicated that RJF down-regulated the mRNA expression of CDK2 and CDK4, while up-regulating that of P21 and P27 in tumor tissue. The trends in CDKs and CDKIs protein expression mirrored those of mRNA expression. Moreover, the PI3K/AKT pathway displayed downregulation in the tumor tissue of mice treated with RJF., Conclusion: RJF demonstrates effectiveness and safety in the context of TNBC. It exerts anti-tumor effects by arresting the cell cycle at the S phase through the PI3K-AKT pathway., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Although several potential radioprotectants have been explored, radiation esophagitis is still difficult to control. Further development of supportive therapies is required. Our purpose was to investigate the efficacy and safety of cystine and theanine for esophagitis in non-small cell lung cancer (NSCLC) patients undergoing chemoradiotherapy (CRT)., Methods: This study is a prospective observational study. The participants were recruited from unresectable locally advanced NSCLC who had scheduled to receive weekly paclitaxel or nab-paclitaxel/carboplatin plus radiation therapy (60 Gy in 30 fractions) for 6 weeks. They took an oral amino acid supplement containing 700 mg cystine and 280 mg theanine once daily regardless of CRT timing from the start of CRT until completion. The primary endpoint was the incidence of any grade esophagitis. The secondary endpoints were quality of life (QoL) and adverse events (AEs)., Results: A total of 26 patients were evaluated. All participants completed 60 Gy of RT in 30 fractions. The overall incidence of esophagitis was 73%; however, no ≥ grade 3 was reported. There were no AEs likely to be related to cystine and theanine. The mean EuroQoL 5-Dimension 5-Level health index score before and after chemoradiotherapy was 0.952 ± 0.0591 and 0.952 ± 0.0515 (P = 0.89), and the mean Visual Analogue Scale scores before and after treatment were 67.9 ± 15.4 and 79.4 ± 13.2 (P = 0.0047), respectively., Conclusion: Our study showed no severe esophagitis, any AEs, nor QoL decrease in NSCLC patients receiving CRT. Cystine and theanine are potentially effective to reduce severe CRT-induced esophagitis., Trial Registration: UMIN000052622, 26 October 2023, retrospectively registered., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder mainly affecting female individuals. Trofinetide was recently approved as the first treatment for RTT, largely on the basis of results from the phase 3 LAVENDER trial, in which trofinetide showed improvements in core symptoms of RTT compared with placebo. However, gastrointestinal (GI) symptoms such as diarrhea and vomiting were commonly reported side effects, and taste was also a reported issue. The objective of this article is to describe the perspectives of five caregivers of girls in trofinetide clinical trials as well as those of three nurse trial coordinators, with a focus on management of GI symptoms of trofinetide treatment.Audio Abstract available for this article. Audio Abstract: Jane Lane provides an overview and discusses key findings of the article titled "Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives." (MP4 83274 KB)., (© 2024. The Author(s).)

Introduction: Trofinetide was recently approved for the treatment of Rett syndrome (RTT) on the basis of the efficacy and safety findings of the phase 3 LAVENDER study, which used a body weight-based dosing regimen. Exposure-response (E-R) efficacy modeling was used to characterize relationships between trofinetide exposure measures (maximum drug concentration and area under the concentration-time curve for the dosing interval of 0-12 h [AUC 0-12 ]) and efficacy endpoints in RTT clinical studies to support the trofinetide dosing regimen., Methods: Efficacy endpoints were modeled using trofinetide exposure measures predicted from the population pharmacokinetic model and Bayesian estimates. The analysis population for each E-R model comprised individuals receiving placebo or trofinetide who had available trofinetide exposure measures. Efficacy endpoints were scores from the Rett Syndrome Behaviour Questionnaire (RSBQ), the Clinical Global Impression-Improvement, the Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite, and the Rett Syndrome Clinician Rating of Ability to Communicate Choices (RTT-COMC)., Results: Higher trofinetide exposure was associated with improvements in RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Assuming target trofinetide AUC 0-12 values of 800-1200 μg·h/mL, the reductions in RSBQ total scores at week 12 were approximately five- to seven-fold greater with trofinetide (range 3.55-4.94) versus placebo (0.76). Significant E-R relationships were also found for the CSBS-DP-IT Social Composite and RTT-COMC scores., Conclusion: E-R efficacy modeling demonstrated significant relationships between trofinetide exposure and RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Trofinetide is efficacious within the target exposure range, supporting the approved dosing regimen for trofinetide., Trial Registration: NCT01703533, NCT02715115, NCT04181723., (© 2024. The Author(s).)

Background and Objective: Methylmalonic aciduria (MMA) and propionic aciduria (PA) are organic acidurias characterised by the accumulation of toxic metabolites and hyperammonaemia related to secondary N-acetylglutamate deficiency. Carglumic acid, a synthetic analogue of N-acetylglutamate, decreases ammonia levels by restoring the functioning of the urea cycle. However, there are limited data available on the long-term safety and effectiveness of carglumic acid. Here, we present an interim analysis of the ongoing, long-term, prospective, observational PROTECT study (NCT04176523), which is investigating the long-term use of carglumic acid in children and adults with MMA and PA., Methods: Individuals with MMA or PA from France, Germany, Italy, Norway, Spain, Sweden and the UK who have received at least 1 year of carglumic acid treatment as part of their usual care are eligible for inclusion. The primary objective is the number and duration of acute metabolic decompensation events with hyperammonaemia (ammonia level >159 µmol/L during a patient's first month of life or >60 µmol/L thereafter, with an increased lactate level [> 1.8 mmol/L] and/or acidosis [pH < 7.35]) before and after treatment with carglumic acid. Peak plasma ammonia levels during the last decompensation event before and the first decompensation event after carglumic acid initiation, and the annualised rate of decompensation events before and after treatment initiation are also being assessed. Secondary objectives include the duration of hospital stay associated with decompensation events. Data are being collected at approximately 12 months' and 18 months' follow-up., Results: Of the patients currently enrolled in the PROTECT study, data from ten available patients with MMA (n = 4) and PA (n = 6) were analysed. The patients had received carglumic acid for 14-77 (mean 36) months. Carglumic acid reduced the median peak ammonia level of the total patient population from 250 µmol/L (range 97-2569) before treatment to 103 µmol/L (range 97-171) after treatment. The annualised rate of acute metabolic decompensations with hyperammonaemia was reduced by a median of - 41% (range - 100% to + 60%) after treatment with carglumic acid. Of the five patients who experienced a decompensation event before treatment and for whom a post-treatment rate could be calculated, the annualised decompensation event rate was lower after carglumic acid treatment in four patients. The mean duration of hospital inpatient stay during decompensation events was shorter after than before carglumic acid treatment initiation in four of five patients for whom length of stay could be calculated., Conclusions: In this group of patients with MMA and PA, treatment with carglumic acid for at least 1 year reduced peak plasma ammonia levels in the total patient population and reduced the frequency of metabolic decompensation events, as well as the duration of inpatient stay due to metabolic decompensations in a subset of patients., Clinical Trial Registration: ClinicalTrials.gov, NCT04176523. Registered 25 November, 2019, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04176523 ., (© 2024. Crown.)

This study aimed to investigate the therapeutic effects of Morinda officinalis iridoid glycosides(MOIG) on paw edema and bone loss of rheumatoid arthritis(RA) rats, and analyze its potential mechanism based on ultra-high performance liguid chromatography-guadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS) serum metabolomics. RA rats were established by injecting bovin type Ⅱ collagen. The collagen-induced arthritis(CIA) rats were administered drug by gavage for 8 weeks, the arthritic score were used to evaluate the severity of paw edem, serum bone metabolism biochemical parameters were measured by ELISA kits, Masson staining was used to observe the bone microstructure of the femur in CIA rats. UPLC-Q-TOF-MS was used to analyze the alteration of serum metabolite of CIA rats, principal component analysis(PCA) and partial least squares-discriminant analysis(PLS-DA) were used to screen the potential biomarkers, KEGG database analysis were used to construct related metabolic pathways. The results demonstrated that the arthritic score, serum levels of IL-6 and parameters related with bone metabolism including OCN, CTX-Ⅰ, DPD and TRAP were significantly increased, and the ratio of OPG and RANKL was significantly decreased, the microstructure of bone tissue and cartilage were destructed in CIA rats, while MOIG treatments could significantly reduce arthritis score, mitigate the paw edema, reverse the changes of serum biochemical indicators related with bone metabolism, and improve the microstructure of bone tissue and cartilage of CIA rats. The non-targeted metabolomics results showed that 24 altered metabolites were identified in serum of CIA rats; compared with normal group, 13 significantly altered metabolites related to RA were identified in serum of CIA rats, mainly involving alanine, aspartate and glutamate metabolism; compared with CIA model group, MOIG treatment reversed the alteration of 15 differential metabolites, mainly involving into alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism, valine, leucine and isoleucine biosynthesis. Therefore, MOIG significantly alleviated paw edema, improved the destruction of microstructure of bone and cartilage in CIA rats maybe through involving into the regulation of amino acid metabolism.

Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson's disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release., Objective: We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia., Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats., Results: Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats., Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.

A library of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives was prepared from N-Boc-3-azetidinone employing the Horner-Wadsworth-Emmons reaction, rhodium(I)-catalyzed conjugate addition of arylboronic acids, and subsequent elaborations to obtain N-unprotected hydrochlorides, N-alkylated and N-acylated azetidine derivatives. The compounds were evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, revealing several derivatives to possess AChE inhibition comparable to that of the AChE inhibitor rivastigmine. The binding mode of the AChE inhibitor donepezil and selected active compounds 26 and 27 within the active site of AChE was studied using molecular docking. Furthermore, the neuroprotective activity of the prepared compounds was evaluated in models associated with Parkinson's disease (salsolinol-induced) and aspects of Alzheimer's disease (glutamate-induced oxidative damage). Compound 28 showed the highest neuroprotective effect in both salsolinol- and glutamate-induced neurodegeneration models, and its protective effect in the glutamate model was revealed to be driven by a reduction in oxidative stress and caspase-3/7 activity., (© 2023 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Aim: The main aim of this study was to investigate the additional effects of L-theanine, an amino acid in tea and an analog of glutamate with neuroprotective and anti-depressant properties, on obsessive-compulsive disorder (OCD) symptoms in combination with fluvoxamine., Methods: Patients from either sex aged between 18 and 60 years diagnosed with OCD, based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), who had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of more than 21 were enrolled in a double-blinded, parallel-group, placebo-controlled, clinical trial of 10 weeks to receive either L-theanine (100 mg twice daily) and fluvoxamine (100 mg daily initially followed by 200 mg daily after week 5) or placebo and fluvoxamine. The primary outcome of interest in this study was the Y-BOCS total score decrease from baseline., Results: From a total of 95 evaluated patients, 50 completed our study; 30 were randomly assigned to each group. Multivariate analysis (ANOVA) showed a significant effect of time × $$ \times $$ treatment for L-theanine in obsession subscale (F = 5.51, P = 0.008) of the Y-BOCS score but not in the total and compulsion scores. Our results showed significantly more improvement in obsession subscale scores in L-theanine compared to placebo group (P = 0.007, Cohen's d = 0.82). Also, total Y-BOCS scores were lower in L-theanine compared to placebo group at week 5 (P = 0.039, Cohen's d = 0.60) and 10 (P = 0.008, Cohen's d = 0.80). However, there was no significant between-group differences in compulsion subscale scores. Complete response was also more frequent in the L-theanine group (P = 0.0001)., Conclusion: Findings in this study suggest L-theanine as a relatively safe and effective adjuvant therapy for moderate to severe OCD., (© 2023 The Authors. Psychiatry and Clinical Neurosciences © 2023 Japanese Society of Psychiatry and Neurology.)

Background: As an "off-target" effect, cephalosporins can enhance glutamate transporter-1 expression in astrocytes to recycle glutamate from synaptic cleft, and exhibited analgesic properties in animals and humans with chronic pain., Methods: In the present study, we focused on making a side-by-side comparison of the analgesic potentials of cefadroxil and ceftriaxone, using rodent models of peripheral neuropathic pain, inflammatory pain and incisional pain. Microdialysis technique was adopted to validate the in vivo glutamate regulatory properties of these two drugs in central nervous system., Results: We have shown that cefadroxil and ceftriaxone are beneficial in a variety of pain scenarios, without inducing observable side effects. The two cephalosporins worked better on neuropathic pain, rather than inflammatory pain or incisional pain, suggesting nociceptive system was differentially affected. Further, microdialysis has confirmed that cephalosporins can effectively reverse the elevated levels of glutamate in brain of animals with neuropathic pain., Conclusions: The outcome of this study may guide us to identify a molecular skeleton derived from cefadroxil, based on which we could possibly develop new non-antibiotic analgesic compounds with glutamate recycling properties.

Epilepsy is one of the most serious worldwide neurological disorders that lead to the cognitive-psychosocial insults in recurrent seizures. About one third of the patients are drug-resistant, so innovative drugs are needed to manage seizures to improve the quality of life. Ceftriaxone is a cephalosporin antibiotic that increases the expression of glutamate transporters-1 and improves the neurobehavioral effects caused by increased glutamate level in the CNS. Selenium is well known antioxidant. The present study aimed to investigate ceftriaxone and selenium therapeutic effects against epilepsy in rats. Epilepsy was induced by PTZ given at a dose (50 mg/kg I.P) on alternative days for 13 days. Eighty rats were randomly divided into 8 groups: Group1-2; normal and vehicle control, Group 3; PTZ group, Group 4-8; kindled rats received selenium, ceftriaxone100, ceftriaxone200, selenium + ceftriaxone100 and selenium + ceftriaxone200 mg/kg/day respectively for a week. At the end of the study, behavioral tests were performed. Oxidative stress, inflammatory markers, neurotransmitters and GLT-1 were measured in brain tissue homogenate. Brain histopathological investigation was also done. PTZ-kindled rats exhibited increased Racine score, besides behavioral tests and histopathological changes, significant elevation in oxidative stress and inflammatory markers, with decrease in serotonin, dopamine, GABA levels and GLT-1 expressions. Selenium and Ceftriaxone alone or combined treatment decreased Racine score with remarkable improvement in behavioral and histopathological changes. The antioxidant enzymes, neurotransmitters and GLT-1 expressions were increased, along with reduced TNF-α, IL-1 levels. Current study showed that selenium + ceftriaxone100 group represents a possible approach to improve epilepsy particularly through inhibiting oxidative stress and inflammation., 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.)

Background: Despite numerous clinical trials and decades of endeavour, there is still no effective cure for Alzheimer's disease. Computational drug repositioning approaches may be employed for the development of new treatment strategies for Alzheimer's patients since an extensive amount of omics data has been generated during pre-clinical and clinical studies. However, targeting the most critical pathophysiological mechanisms and determining drugs with proper pharmacodynamics and good efficacy are equally crucial in drug repurposing and often imbalanced in Alzheimer's studies., Methods: Here, we investigated central co-expressed genes upregulated in Alzheimer's disease to determine a proper therapeutic target. We backed our reasoning by checking the target gene's estimated non-essentiality for survival in multiple human tissues. We screened transcriptome profiles of various human cell lines perturbed by drug induction (for 6798 compounds) and gene knockout using data available in the Connectivity Map database. Then, we applied a profile-based drug repositioning approach to discover drugs targeting the target gene based on the correlations between these transcriptome profiles. We evaluated the bioavailability, functional enrichment profiles and drug-protein interactions of these repurposed agents and evidenced their cellular viability and efficacy in glial cell culture by experimental assays and Western blotting. Finally, we evaluated their pharmacokinetics to anticipate to which degree their efficacy can be improved., Results: We identified glutaminase as a promising drug target. Glutaminase overexpression may fuel the glutamate excitotoxicity in neurons, leading to mitochondrial dysfunction and other neurodegeneration hallmark processes. The computational drug repurposing revealed eight drugs: mitoxantrone, bortezomib, parbendazole, crizotinib, withaferin-a, SA-25547 and two unstudied compounds. We demonstrated that the proposed drugs could effectively suppress glutaminase and reduce glutamate production in the diseased brain through multiple neurodegeneration-associated mechanisms, including cytoskeleton and proteostasis. We also estimated the human blood-brain barrier permeability of parbendazole and SA-25547 using the SwissADME tool., Conclusions: This study method effectively identified an Alzheimer's disease marker and compounds targeting the marker and interconnected biological processes by use of multiple computational approaches. Our results highlight the importance of synaptic glutamate signalling in Alzheimer's disease progression. We suggest repurposable drugs (like parbendazole) with well-evidenced activities that we linked to glutamate synthesis hereby and novel molecules (SA-25547) with estimated mechanisms for the treatment of Alzheimer's patients., (© 2023. The Author(s).)

Background: Recent genetic evidence implicates glutamatergic-receptor variations in schizophrenia. Glutamatergic excess during early life in people with schizophrenia may cause excitotoxicity and produce structural deficits in the brain. Cortical thickness and gyrification are reduced in schizophrenia, but only a subgroup of patients exhibits such structural deficits. We delineate the structural variations among unaffected siblings and patients with schizophrenia and study the role of key glutamate-receptor polymorphisms on these variations., Methods: Gaussian Mixture Model clustering was applied to the cortical thickness and gyrification data of 114 patients, 112 healthy controls, and 42 unaffected siblings to identify subgroups. The distribution of glutamate-receptor (GRM3, GRIN2A, and GRIA1) and voltage-gated calcium channel (CACNA1C) variations across the MRI-based subgroups was studied. The comparisons in clinical symptoms and cognition between patient subgroups were conducted., Results: We observed a "hypogyric," "impoverished-thickness," and "supra-normal" subgroups of patients, with higher negative symptom burden and poorer verbal fluency in the hypogyric subgroup and notable functional deterioration in the impoverished-thickness subgroup. Compared to healthy subjects, the hypogyric subgroup had significant GRIN2A and GRM3 variations, the impoverished-thickness subgroup had CACNA1C variations while the supra-normal group had no differences., Conclusions: Disrupted gyrification and thickness can be traced to the glutamatergic receptor and voltage-gated calcium channel dysfunction respectively in schizophrenia. This raises the question of whether MRI-based multimetric subtyping may be relevant for clinical trials of agents affecting the glutamatergic system.

Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular enzyme, is a key rate-limiting enzyme of DNA biosynthesis and repair which is primarily active in proliferating and metabolically active cells. Eighty-four percent of chordoma samples had loss of TS expression which may predict response to anti-folates. Pemetrexed suppresses tumor growth by inhibiting enzymes involved in folate metabolism, resulting in decreased availability of thymidine which is necessary for DNA synthesis. Pemetrexed inhibited growth in a preclinical mouse xenograft model of human chordoma. We report three cases of metastatic chordoma that had been heavily treated previously with a variety of standard therapies with poor response. In two cases, pemetrexed was added and objective responses were observed on imaging with one patient on continuous treatment for > 2 years with continued shrinkage. One case demonstrated tumor growth after treatment with pemetrexed. The two cases which had a favorable response had a loss of TS expression, whereas the one case with progressive disease had TS present. These results demonstrate the activity of pemetrexed in recurrent chordoma and warrant a prospective clinical trial which is ongoing (NCT03955042)., (© 2023. The Author(s).)

Objective: Trichotillomania and skin-picking disorder are underrecognized and often disabling conditions in which individuals repeatedly pull at their hair or pick at their skin, leading to noticeable hair loss or tissue damage. To date there is a severe paucity of evidence-based treatments for these conditions. In this study, the authors sought to determine whether memantine, a glutamate modulator, is more effective than placebo in reducing hair-pulling and skin-picking behavior., Methods: One hundred adults with trichotillomania or skin-picking disorder (86 women; mean age, 31.4 years [SD=10.2]) were enrolled in a double-blind trial of memantine (dosing range, 10-20 mg/day) or placebo for 8 weeks. Participants were assessed with measures of pulling and picking severity. Outcomes were examined using a linear mixed-effects model. The prespecified primary outcome measure was treatment-related change on the NIMH Trichotillomania Symptom Severity Scale, modified to include skin picking., Results: Compared with placebo, memantine treatment was associated with significant improvements in scores on the NIMH scale, Sheehan Disability Scale, and Clinical Global Impressions severity scale in terms of treatment-by-time interactions. At study endpoint, 60.5% of participants in the memantine group were "much or very much improved," compared with 8.3% in the placebo group (number needed to treat=1.9). Adverse events did not differ significantly between the treatment arms., Conclusions: This study found that memantine treatment resulted in statistically significant reductions in hair pulling and skin-picking symptoms compared with placebo, with relatively high efficacy (based on number needed to treat), and was well tolerated. The glutamate system may prove to be a beneficial target in the treatment of compulsive behaviors.

Background and Aims: Fibromyalgia is a widespread chronic pain syndrome associated with several comorbid conditions that affect the quality of patients' life. Its pathogenesis is complex, and the treatment strategies are limited by partial efficacy and potential adverse effects. So, our aim was to investigate the possible ameliorative effects of ethosuximide and sodium butyrate on fibromyalgia and compare their effects to pregabalin., Materials and Methods: In a mouse model of reserpine induced fibromyalgia, the effect of ethosuximide, sodium butyrate, and pregabalin was investigated. Evaluation of mechanical allodynia, cold hypersensitivity, anxiety, cognitive impairment, and depression was performed. Also, the brain and spinal cord tissue serotonin, dopamine and glutamate in addition to the serum levels of interleukin (IL)-4 and transforming growth factor beta 1 (TGF-β1) were assayed. Moreover, the expression of nuclear factor kappa B (NF-κB) synaptophysin was immunoassayed in the hippocampal tissues., Key Findings: Ethosuximide and sodium butyrate restored the behavioral tests to the normal values except for the antidepressant effect which was evident only with ethosuximide. Both drugs elevated the levels of the anti-inflammatory cytokines IL-4 and TGF-β1, reduced the hippocampal NF-κB, and increased synaptophysin expression with superiority of sodium butyrate. Ethosuximide reduced only spinal cord and brain glutamate while improved brain dopamine while sodium butyrate elevated spinal cord dopamine and serotonin with no effect on glutamate. Also, sodium butyrate elevated brain serotonin and reduced glutamate with no effect on brain dopamine., Significance: Each of sodium butyrate and ethosuximide would serve as a promising therapeutic modality for management of fibromyalgia and its comorbid conditions., 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.)

Despite the large arsenal of analgesic medications, neuropathic pain (NP) management is not solved yet. Angiotensin II receptor type 1 (AT1) has been identified as a potential target in NP therapy. Here, we investigate the antiallodynic effect of AT1 blockers telmisartan and losartan, and particularly their combination with morphine on rat mononeuropathic pain following acute or chronic oral administration. The impact of telmisartan on morphine analgesic tolerance was also assessed using the rat tail-flick assay. Morphine potency and efficacy in spinal cord samples of treated neuropathic animals were assessed by [ 35 S]GTPγS-binding assay. Finally, the glutamate content of the cerebrospinal fluid (CSF) was measured by capillary electrophoresis. Oral telmisartan or losartan in higher doses showed an acute antiallodynic effect. In the chronic treatment study, the combination of subanalgesic doses of telmisartan and morphine ameliorated allodynia and resulted in a leftward shift in the dose-response curve of morphine in the [ 35 S]GTPγS binding assay and increased CSF glutamate content. Telmisartan delayed morphine analgesic-tolerance development. Our study has identified a promising combination therapy composed of telmisartan and morphine for NP and opioid tolerance. Since telmisartan is an inhibitor of AT1 and activator of PPAR-γ, future studies are needed to analyze the effect of each component.

Background: Only a fraction of patients with malignant pleural mesothelioma (MPM) will respond to chemo- or immunotherapy. For the majority, the condition will irremediably relapse after 13 to 18 months. In this study, we hypothesized that patients' outcome could be correlated to their immune cell profile. Focus was given to peripheral blood eosinophils that, paradoxically, can both promote or inhibit tumor growth depending on the cancer type., Methods: The characteristics of 242 patients with histologically proven MPM were retrospectively collected in three centers. Characteristics included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR). The mean absolute eosinophil counts (AEC) were determined by averaging AEC data sets of the last month preceding the administration of chemo- or immunotherapy., Results: An optimal cutoff of 220 eosinophils/µL of blood segregated the cohort into two groups with significantly different median OS after chemotherapy (14 and 29 months above and below the threshold, p = 0.0001). The corresponding two-year OS rates were 28% and 55% in the AEC ≥ 220/µL and AEC < 220/µL groups, respectively. Based on shorter median PFS (8 vs 17 months, p < 0.0001) and reduced DCR (55.9% vs 35.2% at 6 months), the response to standard chemotherapy was significantly affected in the AEC ≥ 220/µL subset. Similar conclusions were also drawn from data sets of patients receiving immune checkpoint-based immunotherapy., Conclusion: In conclusion, baseline AEC ≥ 220/µL preceding therapy is associated with worse outcome and quicker relapse in MPM., Competing Interests: Beyond the scope of this study, AS participated to clinical trials and expert boards with Amphera, AstraZeneca, BMS, MSD, Regeneron/Sanofi, Roche and Trizell. VH declares consultancy fees from AstraZeneca and Chiesi. The remaining 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 © 2023 Willems, Scherpereel, Wasielewski, Raskin, Brossel, Fontaine, Grégoire, Halkin, Jamakhani, Heinen, Louis, Duysinx, Hamaidia and Willems.)

Group rearing is a common housing condition, but group-housed older mice show increased adrenal hypertrophy, a marker of stress. However, the ingestion of theanine, an amino acid unique to tea leaves, suppressed stress. We aimed to elucidate the mechanism of theanine's stress-reducing effects using group-reared older mice. The expression of repressor element 1 silencing transcription factor (REST), which represses excitability-related genes, was increased in the hippocampus of group-reared older mice, whereas the expression of neuronal PAS domain protein 4 (Npas4), which is involved in the regulation of excitation and inhibition in the brain, was lower in the hippocampus of older group-reared mice than in same-aged two-to-a-house mice. That is, the expression patterns of REST and Npas4 were found to be just inversely correlated. On the other hand, the expression levels of the glucocorticoid receptor and DNA methyltransferase, which suppress Npas4 transcription, were higher in the older group-housed mice. In mice fed theanine, the stress response was reduced and Npas4 expression tended to be increased. These results suggest that Npas4 expression was suppressed by the increased expression of REST and Npas4 downregulators in the group-fed older mice, but that theanine avoids the decrease in Npas4 expression by suppressing the expression of Npas4 transcriptional repressors.

Background: Gulf War Illness is a multi-symptom condition affecting veterans of the 1990 to 1991 Gulf War, which often presents with comorbid hypertension. The purpose of this study was to analyze the effects of the low glutamate diet, as well as an acute challenge of monosodium glutamate (MSG)/placebo, on resting heart rate, blood oxygenation level, and blood pressure (BP) in this population., Methods: These data were measured at 4 time points: baseline, after 1 month on the low glutamate diet, and during each challenge week, where subjects were randomized into a double-blind, placebo-controlled, crossover challenge with MSG/placebo over 3 days each week. Pre-post diet changes were analyzed using paired t tests, change in the percentage of veterans meeting the criteria for hypertension was compared using chi-square or Fisher exact tests, and crossover challenge results were analyzed using general linear modeling in SAS® 9.4., Results: There was a significant reduction in systolic BP (sitting and recumbent; both P < .001) and diastolic BP (sitting; P = .02) after 1 month on the diet. The percentage meeting the criteria for hypertension was also significantly reduced (P < .05). Challenge with MSG/placebo did not demonstrate an acute effect of glutamate on blood pressure., Conclusion: Overall, these findings suggest that the low glutamate diet may be an effective treatment for lowering blood pressure in veterans with Gulf War Illness. This dietary effect does not appear to be driven by reduced consumption of free glutamate, but rather, by an increase in consumption of non-processed foods., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Increasing evidence suggests that individuals with alcohol use disorder (AUD) present with a disrupted glutamatergic system that underlies core components of addictive disorders, including drug relapse and low impulse control. N-acetylcysteine (NAC) is a cystine prodrug that has been found to promote glutamate homeostasis and drug abstinence. However, no studies to date have evaluated NAC's effect on impulsivity in substance use disorders. Here we determined whether NAC would decrease alcohol-intake behaviors, in addition to improving impulse control, in long-term alcohol drinking male Wistar-Han rats. Before the start of the experiments, all rats were exposed to long-term intermittent access to 20% ethanol for at least seven weeks. Next, in different groups of rats, the effect of NAC (60 and/or 90 mg/kg) was evaluated on (i) voluntary alcohol drinking using a two-bottle free choice paradigm, (ii) the motivation to self-administer alcohol under a progressive ratio schedule of reinforcement, and (iii) relapse-like drinking using the alcohol deprivation effect model. Finally, (iv) NAC's effect on impulse control was evaluated using the five-choice serial reaction time task. Results showed that NAC administration at 90 mg/kg significantly reduced relapse-like drinking and improved impulse control. In contrast, NAC had no effect on levels of alcohol drinking or motivation to drink alcohol. In conclusion, our findings continue to support the use of NAC as an adjuvant treatment for the maintenance of abstinence in AUD. Moreover, we provide evidence for NAC's efficacy in improving impulse control following drinking, which warrants further investigation in substance use settings., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Gabapentin and pregabalin are drugs to treat neuropathic pain. Several studies highlighted effects on presynaptic terminals of nociceptors. Via binding to α2δ subunits of voltage-gated calcium channels, gabapentinoids modulate the synaptic transmission of nociceptive information. However, recent studies revealed further properties of these substances. Treatment with gabapentin or pregabalin in animal models of neuropathic pain resulted not only in reduced symptoms of hyperalgesia but also in an attenuated activation of glial cells and decreased production of pro-inflammatory mediators in the spinal dorsal horn., Methods: In the present study, we aimed to investigate the impact of gabapentinoids on the inflammatory response of spinal dorsal horn cells, applying the established model of neuro-glial primary cell cultures of the superficial dorsal horn (SDH). We studied effects of gabapentin and pregabalin on lipopolysaccharide (LPS)-induced cytokine release (bioassays), expression of inflammatory marker genes (RT-qPCR), activation of transcription factors (immunocytochemistry), and Ca2+ responses of SDH neurons to stimulation with substance P and glutamate (Ca2+-imaging)., Results: We detected an attenuated LPS-induced expression and release of interleukin-6 by SDH cultures in the presence of gabapentinoids. In addition, a significant main effect of drug treatment was observed for mRNA expression of microsomal prostaglandin E synthase 1 and the inhibitor of nuclear factor kappa B. Nuclear translocation of inflammatory transcription factors in glial cells was not significantly affected by gabapentinoid treatment. Moreover, both substances did not modulate neuronal responses upon stimulation with substance P or glutamate., Conclusion: Our results provide evidence for anti-inflammatory capacities of gabapentinoids on the acute inflammatory response of SDH primary cultures upon LPS stimulation. Such effects may contribute to the pain-relieving effects of gabapentinoids., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Riluzole, approved to manage amyotrophic lateral sclerosis, is mechanistically unique among glutamate-based therapeutics because it reduces glutamate transmission through a dual mechanism (i.e., reduces glutamate release and enhances glutamate reuptake). The profile of riluzole is favorable for normalizing glutamatergic dysregulation that perpetuates methamphetamine (METH) dependence, but pharmacokinetic and metabolic liabilities hinder repurposing. To mitigate these limitations, we synthesized troriluzole (TRLZ), a third-generation prodrug of riluzole, and tested the hypothesis that TRLZ inhibits METH hyperlocomotion and conditioned place preference (CPP) and normalizes METH-induced changes in mesolimbic glutamate biomarkers. TRLZ (8, 16 mg/kg) reduced hyperlocomotion caused by METH (1 mg/kg) without affecting spontaneous activity. TRLZ (1, 4, 8, 16 mg/kg) administered during METH conditioning (0.5 mg/kg x 4 d) inhibited development of METH place preference, and TRLZ (16 mg/kg) administered after METH conditioning reduced expression of CPP. In rats with established METH place preference, TRLZ (16 mg/kg) accelerated extinction of CPP. In cellular studies, chronic METH enhanced mRNA levels of glutamate carboxypeptidase II (GCPII) in the ventral tegmental area (VTA) and prefrontal cortex (PFC). Repeated METH also caused enhancement of GCPII protein levels in the VTA that was prevented by TRLZ (16 mg/kg). TRLZ (16 mg/kg) administered during chronic METH did not affect brain or plasma levels of METH. These results indicate that TRLZ, already in clinical trials for cerebellar ataxia, reduces development, expression and maintenance of METH CPP. Moreover, normalization of METH-induced GCPII levels in mesolimbic substrates by TRLZ points toward studying GCPII as a therapeutic target of TRLZ., Competing Interests: Conflict of Interest Authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: A rare yet severe neoplasia called malignant pleural mesothelioma (MPM) typically manifests itself in advanced stages. Despite some improvements in the treatment of patients with MPM, this malignancy continues to have a detrimental prognosis . The primary goal of the present study was to assess the associatin between ERCC1, RRM1, and thymidylate synthase (TS) expression and disease outcome in patients with malignant pleural mesothelioma (MPM) treated with either pemetrexed plus cisplatin or gemcitabine plus cisplatin., Methods: This prospective cohort study was done on ninety-one advanced MPM patients. The patients received either pemetrexed plus platinum (55 of 91) or gemcitabine plus platinum chemotherapy (36 of 91). Tissue biopsy was taken at time of diagnosis. Immunohistochemistry was used to assess the levels of ERCC1, RRM1, and TS transcription in tissue biopsies (paraffin embedded)., Results: Based on the findings, 70% of patients with low expression of TS had low expression of ERCC1, and 68% of patients with high expression of TS had high expression of ERCC1, suggesting  a significat association between ERCC1 expression and TS expression (p=0.005). However, there was no relation between ERCC1 and RRM1 expression patterns (p= 0.296). In patients underwen platinum-based theraphy (n 91), a significant correlation was detected between low ERCC1 median High-scoring and longer progression time (TTP;9.6 v 5.3 months;P< .001) or overall survival (OS) (OS;18.1 v 9.1 months; P<0.001). A significant correlation was found between low TS protein expression and longer time progression (TTP; 11.8 v 5.4 months; P< .001) or OS (OS; 19.8 v 8.5 months; P <0.001) in patients undergoing pemetrexed plus platinum chemotherapy (n 55). Low RRM1 expression was accompanied by high progression free survival (TTP; 10.6 v 3.8 months) and OS (OS; 20.6 v 8.6 months) in patients receiving gemcitabine plus platinum chemotherapy. Based on the multivariate test results, the independent variables significantly affecting OS were tumor stage (HR: 2.3; 95% CI: 1.1-4.9; p= 0.021) and ERCC1 (HR: 2.7; 95% CI: 1.7-4.3; p < 0.001)., Conclusion: Decreased TS protein expression can be indicative of greater responsivness to pemtrexed and of longer TTP and OS in individuals with advanced MPM (locally progressed or metastatic) who are receiving pemetrexed-based chemotheraphy. Low ERCC1 expressions in individuals with advanced MPM can predict increased PFS and OS, as well as a better responsivness to platinum-based chemotherapy. In patients with progressed MPM receiving gemcitabine plus cisplatin chemotherapy, lower RRM1 expression was associated with a better prognosis, longer PFS, and longer OS.

Huntington disease (HD) is a neurodegenerative disorder caused by polyglutamine-encoding CAG repeat expansion in the huntingtin (HTT) gene. HTT is involved in the axonal transport of vesicles containing brain-derived neurotrophic factor (BDNF). In HD, diminished BDNF transport leads to reduced BDNF delivery to the striatum, contributing to striatal and cortical neuronal death. Pridopidine is a selective and potent sigma-1 receptor (S1R) agonist currently in clinical development for HD. The S1R is located at the endoplasmic reticulum (ER)-mitochondria interface, where it regulates key cellular pathways commonly impaired in neurodegenerative diseases. We used a microfluidic device that reconstitutes the corticostriatal network, allowing the investigation of presynaptic dynamics, synaptic morphology and transmission, and postsynaptic signaling. Culturing primary neurons from the HD mouse model Hdh CAG140/+ provides a "disease-on-a-chip" platform ideal for investigating pathogenic mechanisms and drug activity. Pridopidine rescued the trafficking of BDNF and TrkB resulting in an increased neurotrophin signaling at the synapse. This increased the capacity of HD neurons to release glutamate and restored homeostasis at the corticostriatal synapse. These data suggest that pridopidine enhances the availability of corticostriatal BDNF via S1R activation, leading to neuroprotective effects., Competing Interests: Declaration of Competing Interest Michael R. Hayden is CEO of Prilenia Therapeutics. Michal Geva and Noga-Gershoni Emek are employees of Prilenia Therapeutics. Frédéric Saudou received a research grant from Teva Pharmaceutical and then from Prilenia during the study. The remaining 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. All additional authors have declared that no conflict of interest exists., (Copyright © 2022. Published by Elsevier Inc.)

Importance: Dysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models., Objective: To compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo)., Design, Setting, and Participants: CANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021., Interventions: Patients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity., Main Outcomes and Measures: The primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review., Results: A total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo., Conclusions and Relevance: In this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents., Trial Registration: ClinicalTrials.gov Identifier: NCT03428217.

Targeted drug delivery, often referred to as "smart" drug delivery, is a process whereby a therapeutic drug is delivered to specific parts of the body in a manner that increases its concentration at the desired sites relative to others. This approach is poised to revolutionize medicine as exemplified by the recent FDA approval of Cytalux (FDA approves pioneering drug for ovarian cancer surgery - Purdue University News) which is a folate-receptor targeted intraoperative near infrared (NIR) imaging agent that was developed in our laboratories. Fracture-associated morbidities and mortality affect a significant portion of world population. United states, Canada and Europe alone spent $48 billion in treating osteoporosis related fractures although this number doesn't count the economic burden due to loss in productivity. It is estimated that by 2050 ca 21 million hip fractures would occur globally which will be leading cause of premature death and disability. Despite the need for improvement in the treatment for fracture repair, methods for treating fractures have changed little in recent decades. Systemic delivery of fracture-homing bone anabolics holds great promise as a therapeutic strategy in this regard. Here we report the design of a fracture-targeted peptide comprised of a payload that binds and activates the parathyroid hormone receptor (PTHR1) and is linked to a targeting ligand comprised of 20 D-glutamic acids (D-Glu 20 ) that directs accumulation of the payload specifically at fracture sites. This targeted delivery results in reduction of fracture healing times to <1/2 while creating repaired bones that are >2-fold stronger than saline-treated controls in mice. Moreover, this hydroxyapatite-targeted peptide can be administered without detectable toxicity to healthy tissues or modification of healthy bones in dogs. Additionally, since similar results are obtained upon treatment of osteoporotic and diabetic fractures in mice, and pain resolution is simultaneously accelerated by this approach, we conclude that this fracture-targeted anabolic peptide displays significant potential to revolutionize the treatment of bone fractures., Competing Interests: Declaration of Competing Interest P.S.L and S.A.L own stock in Quince Tx. S.A.L, C.M.C, M.T. and J.J.N are employees of Quince Tx., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Ferroptosis is a type of iron-dependent cell death pertaining to an excess of lipid peroxidation. It has been suggested that sorafenib-an anti-angiogenic medication for hepatocellular carcinoma (HCC)-induces ferroptosis, but the underlying mechanism for this remains largely unknown. We employed siRNA-mediated gene silencing to investigate the role of Src homology region 2 domain-containing phosphatase-1 (SHP-1), following sorafenib treatment, in cystine/glutamate-antiporter-system-Xc - -regulated cystine uptake. Co-immunoprecipitation was also performed to examine the interactions between MCL1, beclin 1 (BECN1), and solute carrier family 7 member 11 (SLC7A11), which functions as the catalytic subunit of system Xc - . The results of this study showed that sorafenib enhanced the activity of SHP-1, dephosphorylated STAT3, downregulated the expression of MCL1 and, consequently, reduced the association between MCL1 and BECN1. In contrast, increased binding between BECN1 and SLC7A11 was observed following sorafenib treatment. The elevated interaction between BECN1 and SLC7A11 inhibited the activity of system Xc - , whereas BECN1 silencing restored cystine intake and protected cells from ferroptosis. Notably, ectopic expression of MCL1 uncoupled BECN1 from SLC7A11 and rescued cell viability by attenuating lipid peroxidation. The results revealed that ferroptosis could be induced in HCC via SHP-1/STAT3-mediated downregulation of MCL1 and subsequent inhibition of SLC7A11 by increased BECN1 binding.

Headaches are a very common condition that most people will experience many times during their lives. This article presents the primary headaches, which are a large group of diseases where the headache is not a symptom of another known disease. Tension-type headache affects approximately 80% of the general population, and the prevalence of migraine is estimated at 10-12%. Clinical data and experience to date have demonstrated that botulinum toxin may be an effective prophylactic treatment for chronic headache types. It has been used in neurology for the treatment of dystonia and blepharospasm. Now it has been approved to treat chronic migraine and has been shown to confer significant benefit in refractory cases. Based on clinical experience botulinum toxin has also been tried in other headache disorders. While it is intuitively attractive to think that due to its effect on pain by sensory modulation, there may also be efficacy in its use in chronic tension-type headache and cluster headache, so far, there is little evidence to support this. Botulinum toxin is effective in pain control through its interaction with the SNARE complex, which inhibits the release of neurotransmitters, such as glutamate, substance P and calcitonin gene-related peptide. OnabotulinumtoxinA is effective not only in headache frequency and pain intensity but in other parameters, including quality of life.

Proline, glutamate, and leucine-rich protein 1 (PELP1) are involved in several cancers, but little is known about PELP1 in lung cancer. In this study, PELP1 expression was evaluated in 305 lung cancer (NSCLC) specimens to explore the role of PELP1 in lung cancer. After silencing PELP1, the proliferation, migration, invasion of tumor cells, PELP1 in relation to cell cycle and signaling pathways were evaluated, and whole-genome exons were analyzed. PELP1 is overexpressed in lung cancer, PELP1 expression correlated with squamous carcinoma, smoking, and wild-type EGFR status (all Ps<0.001) but associated with lung cancer-specific survival (P > 0.05). Silencing significantly inhibited lung cancer cell proliferation, migration, and invasion (P < 0.05) and promoted high sensitivity of lung cancer cells to tyrosine kinase inhibitor (TKI) gefitinib. PELP1-silenced cells showed downregulated phosphorylated MAPK, cyclinD1, CDK2, and upregulated RB (P < 0.05) but no change in AKT. In PELP1-silenced lung cancer cells, 140 genes were upregulated, and 143 genes were downregulated. Furthermore, the number of T regulatory cell was higher in lung adenocarcinoma with pelp1 high-expression and pelp1 expression was negatively correlated with CD274 (PDL-1) and CTLA4. Therefore, PELP1 plays an important role in the malignant behavior of NSCLC and could be a potential therapeutic target., Competing Interests: Declaration of Competing Interest All authors declare that there is no conflict of interest relate to the work of this paper., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

The accumulation of alpha-synuclein (α-Syn) into Lewy bodies in cortical and subcortical regions has been linked to the pathogenesis of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While there is a strong link between synuclein aggregates and the reduction in dopamine function in the emergence of PD, less is known about the consequences of α-Syn accumulation in glutamatergic neurons and how this could be exploited as a therapeutic target. Transgenic h-α-synL62 (L62) mice, in which synuclein aggregation is achieved through the expression of full-length human α-Syn fused with a signal sequence peptide, were used to characterise glutamatergic transmission using a combination of behavioural, immunoblotting, and histopathological approaches. The protein aggregation inhibitor hydromethylthionine mesylate (HMTM) alone, or in combination with the glutamatergic compounds 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine hydrochloride (MTEP) and memantine, was used to target α-Syn aggregation. We show that accumulation of α-Syn aggregates in glutamatergic synapses affected synaptic protein expression including metabotropic glutamate receptor 5 (mGLUR5) levels and ratio of N-methyl-d-aspartate (NMDA) receptor subunits GluN1/GluN2A. The ratio of NMDA receptor subunits and levels of mGLUR5 were both normalised by HMTM in L62 mice. These alterations, however, did not affect glutamate release in synaptosomes derived from L62 mice or behavioural endpoints following pharmacological manipulations of glutamate functions. Our results confirm that HMTM acts in the L62 mouse model of PD as an inhibitor of pathological aggregation of synuclein and show that HMTM treatment normalises both the ratio of NMDA receptor subunits and mGLUR5 levels. These findings support the potential utility of HMTM as a disease-modifying treatment for PD aiming to reduce synuclein aggregation pathology., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Pharmacological modulation of glutamate has long been considered to be of immense therapeutic utility. The metabotropic glutamate receptors (mGluRs) are potential targets for safely altering glutamate-driven excitation. Data support the potential therapeutic use of mGluR modulators in the treatment of anxiety, depression, schizophrenia, and other psychiatric disorders, pain, epilepsy, as well as neurodegenerative and neurodevelopmental disorders. For each of the three mGluR groups, compounds have been constructed that produce either potentiation or functional blockade. PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059. Efficacy with mGlu5R antagonists has been reported in trials with patients with gastroesophageal reflux disease; data from patients with Parkinson's disease or Fragile X syndrome have not been as robust as hoped. Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression. The Group III mGluRs are the least developed of the mGluR receptor targets. The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Organic acidurias (OAs) are a group of rare metabolic disorders that disrupt the regular amino acid metabolism. OAs are characterized by recurrent episodes of acidemia, ketonuria and hyperammonemia which can result in brain/liver damage and renal failure, and despite the life-long protein-restricted diet, impaired growth and long-term complications can occur. Consequently, a long-term management of OAs patients is required, aimed principally at reducing the frequency and duration of metabolic decompensation/hyperammonemia episodes. Nevertheless, unlike the acute phase, evidence on the chronic management of OAs patients is less consolidated., Subjects and Methods: To expand the knowledge on this field, 13 Italian referral centers for the management of OAs were involved in a survey focused on the long-term use of carglumic acid (Carbaglu®, Recordati Rare Diseases)., Results: Participating centers reported a reduction between 69% and 81% in the annual number of metabolic decompensations with the chronic use of carglumic acid and an improvement in protein intake. Most centers reported no difficulty using carglumic acid as a long-term therapy, along with a great compliance., Conclusions: Taken together, obtained data align with the available literature and support a positive clinical experience with the long-term carglumic acid administration. Additional studies aimed at better defining a proper dosage for the chronic administration of carglumic acid and the clinical and biochemical characteristics of patients treated chronically are needed. In addition, the potential impact of this treatment regimen on the neurological development and growth of patients should be elucidated.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficit and repetitive behaviour. In the past few years, increasing clinical evidence has shown that the cerebellum may contribute to the neuropathology of ASD. However, studies in the mechanism for the involvement of the cerebellum in autism remained speculative. Although some have suggested the possibility of a change of glutamate decarboxylases in the cerebellum of autistic patients, this remains controversial and is limited to the alteration in transcriptional level. This study aimed to investigate the cerebellar structure and determine the expression of rate-limiting GABAergic enzymes in GABA signalling of the autism cerebellum. Pregnant C57BL/6 J mice were intraperitoneally injected with a dosage of 500 mg/kg valproic acid (VPA) on embryonic day 10.5 for autistic behavioural induction. This study found that early prenatal exposure to VPA led to tail deformation and decreased cerebellar weight and size. Early adult mouse models with autistic behaviour showed reduced expression of both isoforms of glutamate decarboxylases (GAD) 65 and 67 in the cerebellum. Also, protein expressions of cerebellar type 1 GABA transporter (GAT-1) and GABA transaminase (GABAT) were reduced in VPA mice. It indicated that abnormal GABA production, recycling, and metabolism could alter the excitatory-inhibitory balance in the autistic cerebellum. Thus, our findings provide supporting evidence that cerebellum impairment could be an etiology of environmentally induced autism. Changes in cerebellar structure and the altered GABAergic enzymes in the cerebellum provide targets for future therapeutic studies in idiopathic autism., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Once considered only scaffolding proteins at glutamatergic postsynaptic density (PSD), Homer1 proteins are increasingly emerging as multimodal adaptors that integrate different signal transduction pathways within PSD, involved in motor and cognitive functions, with putative implications in psychiatric disorders. Regulation of type I metabotropic glutamate receptor trafficking, modulation of calcium signaling, tuning of long-term potentiation, organization of dendritic spines' growth, as well as meta- and homeostatic plasticity control are only a few of the multiple endocellular and synaptic functions that have been linked to Homer1. Findings from preclinical studies, as well as genetic studies conducted in humans, suggest that both constitutive (Homer1b/c) and inducible (Homer1a) isoforms of Homer1 play a role in the neurobiology of several psychiatric disorders, including psychosis, mood disorders, neurodevelopmental disorders, and addiction. On this background, Homer1 has been proposed as a putative novel target in psychopharmacological treatments. The aim of this review is to summarize and systematize the growing body of evidence on Homer proteins, highlighting the role of Homer1 in the pathophysiology and therapy of mental diseases., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To investigate the metabolic changes in rats with minimal hepatic encephalopathy (MHE) treated with oral magnesium sulphate administration., Materials and Methods: A total of 30 Sprague-Dawley rats were divided into a control group and MHE group (further divided into an MHE group and an MHE-Mg group treated with oral administration of 124 mg/kg/day magnesium sulphate). Morris water maze (MWM), Y maze and narrow beam walking (NBW) were used to evaluate cognitive and motor functions. Brain manganese and magnesium content were measured. The metabolic changes in rats with MHE were investigated using hydrogen-nuclear magnetic resonance. Metabolomic signatures were identified with enrichment and pathway analysis., Results: A significantly decreased number of entries into the MWM within the range of interest, longer latency and total time during NBW, and higher brain manganese content were found in rats with MHE. After magnesium sulphate treatment, the rats with MHE had better behavioural performance and lower brain manganese content. The 25 and 26 metabolomic signatures were identified in the cortex and striatum of rats with MHE. The pathway analysis revealed alanine, aspartate and glutamate metabolism as the major abnormal metabolic pathways associated with these metabolomic signatures., Conclusion: Alanine, aspartate and glutamate metabolism are major abnormal metabolic pathways in rats with MHE, which could be restored by magnesium sulphate treatment.

The National Institutes of Health Stroke Scale (NIHSS) is commonly used to evaluate stroke neurological deficits and to predict the patient's outcome. Neurological instability (NI), defined as the variation of the NIHSS in the first 48 h, is a simple clinical metric that reflects dynamic changes in the area of the brain affected by the ischemia. We hypothesize that NI may represent areas of cerebral instability known as penumbra, which could expand or reduce brain injury and its associated neurological sequels. In this work, our aim was to analyze the association of NI with the functional outcome at 3 months and to study clinical biomarkers associated to NI as surrogate biomarkers of ischemic and inflammatory penumbrae in ischemic stroke (IS) patients. We included 663 IS patients in a retrospective observational study. Neutral NI was defined as a variation in the NI scale between - 5 and 5% (37.1%). Positive NI is attributed to patients with an improvement of > 5% NI after 48 h (48.9%), while negative NI is assigned to patients values lower than - 5% (14.0%). Poor outcome was assigned to patients with mRS ≥ 3 at 3 months. We observed an inverse association of poor outcome with positive NI (OR, 0.35; 95%CI, 0.18-0.67; p = 0.002) and a direct association with negative NI (OR, 6.30; 95%CI, 2.12-18.65; p = 0.001). Negative NI showed a higher association with poor outcome than most clinical markers. Regarding good functional outcome, positive NI was the marker with the higher association (19.31; CI 95%, 9.03-41.28; p < 0.0001) and with the highest percentage of identified patients with good functional outcome (17.6%). Patients with negative NI have higher glutamate levels compared with patients with neutral and positive NI (p < 0.0001). IL6 levels are significantly lower in patients with positive NI compared with neutral NI (p < 0.0001), while patients with negative NI showed the highest IL6 values (p < 0.0001). High glutamate levels were associated with negative NI at short latency times, decreasing at higher latency times. An opposite trend was observed for inflammation, and IL6 levels were similar in patients with positive and negative NI in the first 6 h and then higher in patients with negative NI. These results support NI as a prognosis factor in IS and the hypothesis of the existence of a delayed inflammatory penumbra, opening up the possibility of extending the therapeutic window for IS., (© 2021. The Author(s).)

This study aims to investigate the effect of resveratrol on intrahepatic cholestasis of pregnancy (ICP) and its effect on the gut microbiome profiles, thus contributing to the potential therapeutic strategies for ICP. ICP rat models were established by injecting 17α-ethinylestradiol (EE) subcutaneously from the thirteenth day of gestation for four days and then treated with EE (D group, n=5), resveratrol (R group, n=5), or ursodeoxycholic acid (UDCA; U group, n=5) from the seventeenth to the twentieth day of gestation. Fecal samples were analyzed with 16S ribosomal RNA (rRNA) sequencing. In results: the gut microbiota of pregnant rats was characterized with reduced alpha diversity (Chao1 index), and significant variation in the microbiota structure (ANOSIM) was also observed after being treated with EE. The richness of four phyla and ten genera was upregulated, and five phyla and ten genera were downregulated by EE treatment. The dysbiosis of Bilophila, Ruminococcus, and Actinobacteria caused by EE treatment was reversed by resveratrol administration. There was a correlation between total bile acid and alanine aminotransferase in ICP rats. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results suggested that the secondary bile acid biosynthesis was decreased, and the alanine, aspartate, and glutamate metabolism was increased after being treated with EE in pregnant rats. In conclusion, EE treatment could lead to gut microbiome dysbiosis and bile acid metabolism dysregulation in pregnant rats. Resveratrol could partially rescue gut microbiota dysbiosis and improve the biochemical characteristics caused by EE treatment.

L-Theanine, an active ingredient in the tea plant ( Camellia sinensis ) associated with calming, is widely used as a functional ingredient and dietary supplement. In this study, a heat stress mouse model was used to evaluate the anti-heat stress effect of L-theanine and its possible mechanism of action. Mice subjected to heat stress (40 °C) that were administered L-theanine at various doses (100, 200, and 400 mg kg -1 d -1 ) had reduced oxidative stress and inflammatory factors when L-theanine was administered both long-term and as a preventative treatment. Our L-theanine intervention countered the reduction in growth and feed intake of mice under heat stress and reversed liver and jejunum tissue damage. Moreover, L-theanine countered the increase in inflammatory factors TNF-α, IL-6, and IL-1β and antioxidant enzymes SOD and CAT; it also counteracted GSH-Px inactivation, the upregulation of AST and ALT enzyme activity, and MDA production. The mechanism of action may involve mediation of the P38 signaling pathway, inhibition of MK2 overexpression, and downregulation of p-P65/P65 caused by the overexpression of downstream HSP27. This would inhibit the heat stress-induced imbalance in oxidative stress and inflammatory responses.

Rotenone (RO)-induced neurotoxicity exhibits pathophysiological features similar to those reported in patients with Parkinson's disease (PD), such as nitrosative and oxidative stress, mitochondrial dysfunction, and neural cytoarchitecture alterations in the substantia nigra pars compacta (SNpc)/striatum (ST), which has been used for decades as an animal model of PD in humans. L -Theanine (LT), a major amino acid component of green tea, exhibits potent antioxidant and anti-inflammatory activities and protects against various neural injuries. We investigated the potential therapeutic effects of LT on RO-induced behavioral and neurochemical dysfunction in rats and the neuroprotective mechanisms underlying these effects. Unilateral stereotaxic intranigral infusion of RO into the SNpc to induce PD-like manifestations induced significant behavioral impairment as evaluated using an open field test, rotarod test, grip strength measurement, and beam-crossing task in rats. LT treatment (300 mg/kg i.p., 21 days) ameliorated most RO-induced behavioral impairments. In addition, LT treatment reduced nitric oxide level and lipid peroxidation production, increased mitochondrial function and integrity, as well as the activities of mitochondrial complexes I, II, IV, and V, and reduced the levels of neuroinflammatory and apoptotic markers in the SNpc and ameliorated the levels of catecholamines, GABA and glutamate in the ST induced by RO. These results demonstrate the possible therapeutic effects of LT against RO-induced behavioral impairments, including antioxidative effects, prevention of mitochondrial dysfunction, prevention of neurochemical deficiency, anti-neuroinflammatory effects, and anti-apoptotic effects. This is the first report on the neuroprotective effect of LT against RO-induced behavioral impairments, and the above evidence provides a potential clinically relevant role for LT in the management of human PD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Septic acute kidney injury (AKI) always accounts for high mortality of septic patients in ICU. Due to its not well understood mechanism for infection and immune-regulation in kidney dysfunction, there is a lack of effective therapy without side effects. Dimethyl fumarate (DMF) as an immunomodulatory molecule has been approved for treatment to multiple sclerosis. However, the therapeutic effect and immunomodulatory role underlying DMF action in septic AKI is unclear. This study aimed to elucidate the role of DMF in lipopolysaccharide (LPS)-induced septic AKI involving macrophage regulation. In current study, we administered DMF by oral gavage to mice with LPS-induced AKI, then harvested serum and kidney at three different time points. We further isolated Bone marrow-derived macrophages (BMDMs) from mice and stimulated them with LPS followed by DMF treatment. To explore immunomodulatory role of DMF in macrophages, we depleted macrophages in mice using liposomal clodronate after DMF treatment upon LPS-induced septic AKI. Then we observed that DMF attenuated renal dysfunction and murine pathological kidney injury after LPS injection. DMF could inhibit translocation of phosphorylated NF-κB p65 and suppress macrophage activation in LPS-induced AKI. DMF reduced the secretion of TNF-α and IL-6 whereas increased the secretion of IL-10 and Arg-1 in BMDMs after LPS stimulation. DMF also inhibited NF-κB p65 phosphorylation in BMDMs after LPS stimulation. Importantly, the effect of DMF against LPS-induced AKI, macrophage activation, and translocation of phosphorylated NF-κB p65 was impaired upon macrophage depletion. Thus, DMF could attenuate LPS-induced septic AKI by suppression of NF-κB p65 phosphorylation and macrophage activation. This work suggested the potential therapeutic role of DMF for patients in ICU threatened by septic AKI., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Lamotrigine owing to its excellent inhibitory property of neurotransmitter release especially glutamate is used in the treatment of epilepsy as a second-line antiepileptic drug. It differs from other antiepileptic drugs chemically and pharmacologically and is used as both monotherapy and adjunct therapy in the treatment of epilepsy. The present review focuses on two aspects (a) various analytical methods used in quantification of Lamotrigine in pharmaceutical formulations and (b) various analytical methods used to determine Lamotrigine in biological matrices. Here the various analytical methods are developed using different parameters and validation of employed methods is discussed. Estimated parameters like the linearity, LOD (Limit of detection) and LOQ (Limit of quantification) of validation are discussed for the individual method. The critical quality attributes like the wavelength of detection, mobile phase, columns, flow rate, retention time, and the sample preparation methods for the estimation of Lamotrigine by bioanalytical methods are also discussed.

Diacerein (DCN), an analogue of rhein (a glycosidal compound of natural origin), is currently used in the treatment of osteoarthritis and is given a fast-track designation for development to treat epidermolysis bullosa (EB). It is a nonsteroidal anti-inflammatory drug having disease-modifying properties in osteoarthritis and anti-inflammatory effects for the treatment of EB. Diacerein has a beneficial effect on pain relief and demonstrated antioxidant and anti-apoptotic effects, which are useful in renal disease, diabetes, and other disorders. This review discusses the possible mechanism of diacerein in the management of pain. The potential role of rhein and diacerein in the treatment of neuropathic, inflammatory and nociceptive pain is also reviewed. The effect of diacerein and rhein on mediators of pain, such as transient receptor potential cation channel subfamily V (TRPV1), Substance P, glutamate, inflammatory cytokines, nitric oxide, matrix metalloproteinases, histamine, palmitoylethanolamide, nuclear factor-kappa B (NFkB), and prostaglandin, has also been discussed. The data highlights the role of diacerein in neuropathic, nociceptive and inflammatory pain. Clinical trials and mechanism of action studies are needed to ascertain the role of diacerein, rhein or their analogues in the management of pain, alone or in combination with other approved therapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The management of Alzheimer's disease is challenging due to its complexity. However, the currently approved and marketed treatments for this neurodegenerative disorder revolves around cholinesterase inhibitors, glutamate regulators, or the combination of these agents. Despite the prompt assurance of many new drugs, several agents were unsuccessful, especially in phase II or III trials, not meeting efficacy endpoints., Objective: The execution of effective treatment approaches through further trials investigating a rational combination of agents is necessitude for Alzheimer's disease., Methods: For this review, more than 248 relevant scientific papers were considered from a variety of databases (Scopus, Web of Science, Google Scholar, ScienceDirect, and PubMed) using the keywords Alzheimer's disease, amyloid-β, combination therapies, cholinesterase inhibitors, dementia, glutamate regulators, AD hypothesis., Result and Discussion: The researcher's intent is to either develop a disease-modifying therapeutic means for aiming in the early phases of dementia and/or optimize the available symptomatic treatments principally committed to the more advanced stages of Alzheimer's. Since Alzheimer's possesses multifactorial pathogenesis, designing a multimodal therapeutic intervention for targeting different pathological processes of dementia may appear to be the most practical method to alter the course of disease progression., Conclusion: The combination approach may even allow for providing individual agents in lower doses, with reducible costs and side effects. Numerous studies on combination therapy predicted better clinical efficacy than monotherapy. The literature review highlights the major clinical studies (both symptomatic and disease-modifying) conducted in the past decade on combination therapy to combat cognitive disorder., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Pemetrexed is a cytostatic antifolate drug and a cornerstone in the treatment of lung cancer. Although generally well tolerated, a substantial part of the patient population experiences dose-limiting or even treatment-limiting toxicities. These include mucositis, skin problems, fatigue, renal toxicity, and neutropenia. Several studies confirmed that pemetrexed pharmacokinetics can serve as a prognostic factor for the development of toxicity, especially for neutropenia. Preventing and managing toxicity of pemetrexed can help to ensure durable treatment. Several evidence-based strategies are already implemented in clinical care. With the introduction of standard vitamin supplementation and dexamethasone, the incidence of hematological toxicity and skin reactions substantially decreased. In the case of high risk for toxicity, granulocyte colony-stimulating factor can be used to prevent severe hematological toxicity. Moreover, high-dose folinic acid can resolve severe pemetrexed-induced toxicity. There are several experimental options to prevent or manage pemetrexed-related toxicity, such as the use of standard folinic acid, hemodialysis, antidotes such as thymidine, hypoxanthine, and glucarpidase, and the use of therapeutic drug monitoring. These strategies still need clinical evaluation before implementation, but could enable treatment with pemetrexed for patients who are at risk for toxicity, such as in renal impairment., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The present study revealed the phylactic effects of l-theanine on a DSS-induced colitis mice model. The results showed that 3% DSS treatment significantly induced intestinal damage as reflected by DAI, histopathological feature, and colon length, while l-theanine pretreatment markedly prevented these trends to exert protective effects. Meanwhile, l-theanine pretreatment decreased the levels of TNF-α, IL-1β, IL-6, iNOS, and COX2 on DSS-induced colitis. Notably, DSS inhibited the proliferation and promoted the apoptosis of intestinal epithelial cells, thereby damaging the integrity of the intestinal epithelial barrier, whereas l-theanine also played a protective role by attenuating these deteriorated effects. It was also observed that l-theanine treatment downregulated the levels of p-p65, p65, p-p53, p53, and p-AKT protein expression in acute DSS-induced colitis, which showed the protective function of l-theanine, mainly via the NF-κB signaling pathway. Furthermore, the results of lipid analysis and transcriptome analysis show that l-theanine reversed transcriptional profiles and lipid profiles of colitis models, mainly via the inflammatory reactivity-related pathway. Interestingly, the correlation analysis between transcriptional profiles and lipid profiles showed that inflammatory response-related genes were almost significantly correlated with differential lipid metabolites. In summary, l-theanine plays a protective role in DSS-induced colitis via downregulating the NF-κB signaling pathway and regulating lipid metabolism disorders.

Patients with advanced non-small-cell lung cancer who are treated with pemetrexed display a wide variation in clinical response and toxicity. In this prospective, multicentre cohort study, we investigated the association with treatment effectiveness and toxicity of 10 polymorphisms in nine candidate genes, covering the folate pathway ( MTHFR ), cell transport ( SLC19A1/ABCC2/ABCC4 ), intracellular metabolism ( FPGS/GGH ) and target enzymes ( TYMS/DHFR/ATIC ) of pemetrexed. Adjusted for sex, ECOG performance score and disease stage, the association between ATIC (rs12995526) and overall survival (HR 1.59, 95% CI 1.06 to 2.39) was significant. Regarding toxicity, this ATIC polymorphism was significantly associated with severe laboratory (p=0.014) and clinical (p=0.016) chemotherapy-related adverse events, severe neutropenia (p=0.007) and all-grade diarrhoea (p=0.034) in multivariable analyses., Competing Interests: Competing interests: JA reports personal fees and non-financial support from Eli Lilly, outside the submitted work. In addition, JA has a patent allogenic tumor cell lysate licensed to Amphera pending, and a patent for combination immunotherapy in cancer and biomarker for immunotherapy pending; BHS reports grants from ZonMw during the conduct of the study., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)