ABSTRACT
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 × 106 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.
Subject(s)
Signal Transduction , Triple Negative Breast Neoplasms , Humans , Female , Animals , Mice , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Triple Negative Breast Neoplasms/pathology , Ki-67 Antigen/metabolism , Tandem Mass Spectrometry , Cell Line, Tumor , Cell Proliferation , Apoptosis , Cyclin-Dependent Kinases/metabolism , Cyclin-Dependent Kinases/pharmacology , Cyclin-Dependent Kinases/therapeutic use , Cyclophosphamide/pharmacology , Hemoglobins/pharmacology , Hemoglobins/therapeutic use , Transaminases , Glutamates/pharmacology , Glutamates/therapeutic use , RNA, MessengerABSTRACT
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).
Subject(s)
Gastrointestinal Diseases , Rett Syndrome , Female , Humans , Caregivers , Causality , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/drug therapy , Glutamates/therapeutic use , Rett Syndrome/complications , Rett Syndrome/drug therapy , Rett Syndrome/diagnosisABSTRACT
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 â ¡ 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-â , 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.
Subject(s)
Arthritis, Rheumatoid , Morinda , Rats , Animals , Iridoid Glycosides/chemistry , Morinda/chemistry , Chromatography, High Pressure Liquid , Aspartic Acid , Metabolomics , Arthritis, Rheumatoid/drug therapy , Edema , Alanine/therapeutic use , Glutamates/therapeutic use , BiomarkersABSTRACT
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.
Subject(s)
Epilepsy , Selenium , Rats , Animals , Pentylenetetrazole , Selenium/therapeutic use , Selenium/pharmacology , Ceftriaxone/therapeutic use , Antioxidants/pharmacology , Quality of Life , Anticonvulsants/adverse effects , Seizures/chemically induced , Seizures/drug therapy , Seizures/metabolism , Epilepsy/chemically induced , Oxidative Stress , Neurotransmitter Agents/pharmacology , Glutamates/therapeutic useABSTRACT
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.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Camellia sinensis , Glutamates , Plant Leaves , Stress, Psychological , Animals , Mice , Basic Helix-Loop-Helix Transcription Factors/metabolism , Plant Leaves/chemistry , Glutamates/pharmacology , Glutamates/therapeutic use , Camellia sinensis/chemistry , Stress, Psychological/therapyABSTRACT
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.
Subject(s)
Alcoholism , Prodrugs , Acetylcysteine/pharmacology , Acetylcysteine/therapeutic use , Alcohol Drinking/drug therapy , Alcoholism/drug therapy , Animals , Cystine , Ethanol/pharmacology , Glutamates/therapeutic use , Male , Prodrugs/therapeutic use , Rats , Rats, Wistar , Recurrence , Self AdministrationABSTRACT
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-1ß 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.
Subject(s)
Antioxidants/therapeutic use , Camellia sinensis , Dietary Supplements , Glutamates/therapeutic use , Inflammation/drug therapy , Oxidative Stress/drug effects , Animals , Antioxidants/pharmacology , Disease Models, Animal , Glutamates/pharmacology , Hot Temperature , Jejunum/drug effects , Liver/drug effects , MAP Kinase Signaling System , Male , Mice , Mice, Inbred BALB C , Phytotherapy , Signal Transduction/drug effects , Specific Pathogen-Free OrganismsABSTRACT
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.
Subject(s)
Glutamates , Neutropenia , Folic Acid , Glutamates/pharmacology , Glutamates/therapeutic use , Guanine/pharmacology , Guanine/therapeutic use , Humans , Leucovorin/adverse effects , Neutropenia/chemically induced , Neutropenia/drug therapy , Pemetrexed/adverse effectsABSTRACT
By comprehensively measuring changes in metabolites in the hippocampus of stress-loaded mice, we investigated the reasons for stress vulnerability and the effect of theanine, i.e., an abundant amino acid in tea leaves, on the metabolism. Stress sensitivity was higher in senescence-accelerated mouse prone 10 (SAMP10) mice than in normal ddY mice when these mice were loaded with stress on the basis of territorial consciousness in males. Group housing was used as the low-stress condition reference. Among the statistically altered metabolites, depression-related kynurenine and excitability-related histamine were significantly higher in SAMP10 mice than in ddY mice. In contrast, carnosine, which has antidepressant-like activity, and ornithine, which has antistress effects, were significantly lower in SAMP10 mice than in ddY mice. The ingestion of theanine, an excellent antistress amino acid, modulated the levels of kynurenine, histamine, and carnosine only in the stress-loaded SAMP10 mice and not in the group-housing mice. Depression-like behavior was suppressed in mice that had ingested theanine only under stress loading. Taken together, changes in these metabolites, such as kynurenine, histamine, carnosine, and ornithine, were suggested to be associated with the stress vulnerability and depression-like behavior of stressed SAMP10 mice. It was also shown that theanine action appears in the metabolism of mice only under stress loading.
Subject(s)
Depression/drug therapy , Glutamates/therapeutic use , Hippocampus/drug effects , Stress, Psychological/drug therapy , Animals , Arginase/metabolism , Camellia sinensis , Drug Evaluation, Preclinical , Glutamates/pharmacology , Hippocampus/metabolism , Histidine Decarboxylase/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Male , Mice , Phytotherapy , Stress, Psychological/metabolism , Tryptophan Oxygenase/metabolismABSTRACT
The young leaves of green tea become lighter in color than usual when protected from sunlight by a shading net for about two weeks while growing. These leaves are called "shaded white leaf tea" or SWLT. In the eluate of SWLT, the amount of amino acids (361 mg/L) was significantly higher than that in regular tea (53.5 mg/L). Since theanine and arginine, the first and second most abundant amino acids in SWLT, have significant antistress effects, we examined the antistress effect of SWLT on humans. SWLT or placebo green tea (3 g) was eluted with room-temperature water (500 mL). Participants consumed the tea for one week prior to pharmacy practice and continued for 10 days in the practice period. The state-trait anxiety inventory, an anxiety questionnaire, tended to be scored lower in the SWLT group than the placebo, but other stress markers showed no differences. The effect of the difference in SWLT components examined with mice showed that aspartic acid and asparagine, which are abundant in SWLT, counteracted the antistress effects of theanine and arginine. Large amounts of caffeine also interfered with SWLT's antistress effect. Thus, SWLT, which is high in caffeine and amino acids, suppressed depressant behavior in mice.
Subject(s)
Amino Acids/chemistry , Antidepressive Agents/therapeutic use , Caffeine/chemistry , Stress, Psychological/drug therapy , Tea/chemistry , Amino Acids/isolation & purification , Amylases/metabolism , Animals , Antidepressive Agents/chemistry , Antidepressive Agents/isolation & purification , Antidepressive Agents/pharmacology , Arginine/isolation & purification , Arginine/therapeutic use , Behavior, Animal/drug effects , Caffeine/isolation & purification , Catechin/chemistry , Catechin/isolation & purification , Female , Glutamates/isolation & purification , Glutamates/therapeutic use , Humans , Male , Mice , Placebo Effect , Plant Extracts/chemistry , Plant Leaves/chemistry , Plant Leaves/metabolism , Stress, Psychological/pathology , Tea/metabolism , Young AdultABSTRACT
Mood disorders represent one of the most prevalent and costly psychiatric diseases worldwide. The current therapies are generally characterized by several well-known side effects which limit their prolonged use. The use of herbal medicine for the management of several psychiatric conditions is becoming more established, as it is considered a safer support to conventional pharmacotherapy. The aim of this study was to investigate the possible anxiolytic and antidepressant activity of a fixed combination of L-theanine, Magnolia officinalis, and Melissa officinalis (TMM) in an attempt to evaluate how the multiple modulations of different physiological systems may contribute to reducing mood disorders. TMM showed an anxiolytic-like and antidepressant-like activity in vivo, which was related to a neuroprotective effect in an in vitro model of excitotoxicity. The effect of TMM was not altered by the presence of flumazenil, thus suggesting a non-benzodiazepine-like mechanism of action. On the contrary, a significant reduction in the effect was observed in animals and neuronal cells co-treated with AM251, a cannabinoid receptor type 1 (CB1) antagonist, suggesting that the endocannabinoid system may be involved in the TMM mechanism of action. In conclusion, TMM may represent a useful and safe candidate for the management of mood disorders with an innovative mechanism of action, particularly as an adjuvant to conventional therapies.
Subject(s)
Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/therapeutic use , Glutamates/therapeutic use , Magnolia , Melissa , Mood Disorders/drug therapy , Plant Extracts/therapeutic use , Animals , Behavior, Animal/drug effects , Cells, Cultured , Disease Models, Animal , Drug Combinations , Male , Mice , Phytotherapy/methods , Plants, Medicinal , Treatment OutcomeABSTRACT
The lack of effective treatment for chronic discomfort without negative side effects highlights the need for alternative treatments. Pain Bloc-R is a natural health product composed of vitamins B6, B12, D, white willow bark extract, Angelica root extract, acetyl L-carnitine HCl, caffeine, L-theanine, Benfotiamine, and L-tetrahydropalmatine. The objective of this study was to compare the effects of Pain Bloc-R, acetaminophen, and placebo on unresolved aches and discomfort as assessed by the brief pain inventory (BPI) and modified Cornell musculoskeletal discomfort questionnaires. This randomized, double-blind, placebo-controlled, crossover study consisted of three 7-day periods with Pain Bloc-R, acetaminophen, or placebo, each separated by a 7-day washout. Twenty-seven healthy adults (ages 22-63 years) were randomized to receive the three interventions in different sequences. The BPI "pain at its worst" scores were significantly lower when participants took Pain Bloc-R than when they took acetaminophen (21.8% vs. 9.8% decrease, p = 0.026) after seven days of supplementation. Pain Bloc-R achieved a significant improvement in the "pain at its least" score, significantly decreased the interference of discomfort in walking, and significantly decreased musculoskeletal discomfort total scores (34%, p = 0.040) after seven days. In a post hoc subgroup analysis based on age and gender, male participants ≤45 years taking Pain Bloc-R reported significant reductions in pain severity and pain interference vs. acetaminophen. Pain Bloc-R performed as well as acetaminophen in managing unresolved non-pathological pain in otherwise healthy individuals.
Subject(s)
Berberine Alkaloids/therapeutic use , Caffeine/therapeutic use , Chronic Pain/drug therapy , Pain Management/methods , Plant Extracts/therapeutic use , Thiamine/analogs & derivatives , Vitamins/therapeutic use , Acetylcarnitine , Adult , Angelica , Cross-Over Studies , Double-Blind Method , Drug Combinations , Female , Glutamates/therapeutic use , Humans , Hydrochloric Acid/therapeutic use , Male , Middle Aged , Plant Bark , Plant Roots , Salix , Sex Factors , Thiamine/therapeutic use , Treatment Outcome , Vitamin B 12/therapeutic use , Vitamin B 6/therapeutic use , Vitamin D/therapeutic use , Young AdultABSTRACT
L-arginine (Arg) is a semiessential amino acid with several physiological functions. N-Carbamylglutamate (NCG) can promote the synthesis of endogenous Arg in mammals. However, the roles of Arg or NCG on hepatic inflammation and apoptosis in suckling lambs suffering from intrauterine growth restriction (IUGR) are still unclear. The current work is aimed at examining the effects of dietary Arg and NCG on inflammatory and hepatocyte apoptosis in IUGR suckling lambs. On day 7 after birth, 48 newborn Hu lambs were selected from a cohort of 432 twin lambs. Normal-birthweight and IUGR Hu lambs were allocated randomly (n = 12/group) to control (CON), IUGR, IUGR+1% Arg, or IUGR+0.1% NCG groups. Lambs were fed for 21 days from 7 to 28 days old. Compared with CON lambs, relative protein 53 (P53), apoptosis antigen 1 (Fas), Bcl-2-associated X protein (Bax), caspase-3, cytochrome C, tumor necrosis factor alpha (TNF-α), nuclear factor kappa-B (NF-κB) p65, and NF-κB pp65 protein levels were higher (P < 0.05) in liver from IUGR lambs, whereas those in liver from IUGR lambs under Arg or NCG treatment were lower than those in IUGR lambs. These findings indicated that supplementing Arg or NCG reduced the contents of proinflammatory cytokines at the same time when the apoptosis-related pathway was being suppressed, thus suppressing the IUGR-induced apoptosis of hepatic cells.
Subject(s)
Arginine/therapeutic use , Fetal Growth Retardation/drug therapy , Fetal Growth Retardation/metabolism , Glutamates/therapeutic use , Animals , Apoptosis/drug effects , Blotting, Western , Body Weight/drug effects , Caspase 3/metabolism , Caspase 8/metabolism , Caspase 9/metabolism , Cytochromes c/metabolism , Female , Hepatocytes/drug effects , Hepatocytes/metabolism , In Situ Nick-End Labeling , Liver/drug effects , Liver/metabolism , NF-kappa B/metabolism , Pregnancy , Radioimmunoassay , Reverse Transcriptase Polymerase Chain Reaction , Sheep , Tumor Necrosis Factor-alpha/metabolismABSTRACT
PURPOSE: Capecitabine-based adjuvant chemotherapy for colorectal cancer patients often causes adverse events (AEs), such as diarrhea, stomatitis, anorexia, and hand-foot syndrome (HFS). Cystine and theanine were reported to attenuate some chemotherapy-associated AEs, and hence are also expected to attenuate capecitabine-induced AEs. Therefore, we aimed to investigate the safety and efficacy of cystine/theanine treatment in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery. METHODS: A total of 100 colorectal cancer patients treated with capecitabine as an adjuvant chemotherapy after surgery were randomly allocated into the cystine/theanine group (n = 52) or the placebo group (n = 48). The primary endpoint was incidence rate of diarrhea of grade 1 or higher in accordance with the Common Terminology Criteria for AEs (CTCAE) v.4.0, Japanese Clinical Oncology Group (JCOG) version. The secondary endpoints included incidence rates of other AEs (CTCAE v.4.0-JCOG), as well as the incidence rate of HFS according to the HFS grading scale. RESULTS: There were no significant differences in capecitabine-induced AEs between the two groups. However, the incidence rate of diarrhea of grade 1 or higher tended to be lower in the cystine/theanine group than the placebo group (18.4% vs. 28.9%, p = 0.169) as well as the incidence rate of HFS of grade 1 or higher (CTCAE v.4.0-JCOG or HFS grading scale) (67.4% vs. 77.8%, p = 0.185, 67.3% vs. 80.0%, p = 0.124, respectively). CONCLUSION: This trial demonstrated that cystine/theanine treatment of colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery is safe and has the tendency to reduce the incidence rate of diarrhea or HFS. TRIAL REGISTRATION: UMIN000024784.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/drug therapy , Cystine/therapeutic use , Glutamates/therapeutic use , Administration, Oral , Adult , Aged , Aged, 80 and over , Anorexia/chemically induced , Anorexia/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine/administration & dosage , Capecitabine/adverse effects , Chemotherapy, Adjuvant , Colorectal Neoplasms/surgery , Cystine/adverse effects , Diarrhea/chemically induced , Diarrhea/drug therapy , Double-Blind Method , Drug-Related Side Effects and Adverse Reactions/drug therapy , Female , Glutamates/adverse effects , Hand-Foot Syndrome/drug therapy , Hand-Foot Syndrome/etiology , Humans , Male , Middle Aged , Stomatitis/chemically induced , Stomatitis/drug therapyABSTRACT
BACKGROUND/PURPOSE: Spinal cord injury (SCI) is a devastating medical condition for which no effective pharmacological interventions exist. l-Theanine (LT), a major amino acid component of green tea, exhibits potent antioxidative and anti-inflammatory activities and protects against various neural injuries. Here, we evaluated the potential therapeutic effects of LT on the recovery of behavioral motor functions after SCI in rats and the underlying neuroprotective mechanisms. METHODS: SCI was induced by applying vascular clips to the dura through a four-level T5-T8 laminectomy, and saline or LT (10/30 mg/kg) was intrathecally administered at 1-, 6-, and 24-h post-SCI. At 72-h post-SCI, half of the rats from each group for each parameter were sacrificed, and their spinal cord was excised for measurement of malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase, catalase, tumor necrosis factor-α, interleukin-1ß/-6, myeloperoxidase, and caspase-3. The remaining rats from each group were subjected to Bresnahan locomotor-rating scale (BBB), inclined-plane, toe-spread, and hindfoot bar-grab tests at 1-, 4-, 7-, 10-, and 14-days post-SCI. RESULTS: LT treatment reduced NO and MDA levels, increased antioxidative strength, and markedly suppressed the levels of neuroinflammatory and apoptotic markers in the spinal cord after SCI. Moreover, LT treatment drastically promoted the recovery of behavioral motor functions post-SCI. CONCLUSION: Our findings revealed that LT can enhance the recovery of behavioral motor functions after SCI in rats, which related to the suppression of post-traumatic oxidative response, neural inflammation, and apoptosis. This evidence indicates that LT holds considerable potential for use in the clinical treatment/prevention of SCI-induced motor dysfunction.
Subject(s)
Glutamates/therapeutic use , Neuroprotective Agents/therapeutic use , Oxidative Stress , Spinal Cord Injuries , Animals , Rats , Rats, Sprague-Dawley , Recovery of Function , Spinal Cord Injuries/drug therapyABSTRACT
Anxiety disorders are highly prevalent in modern societies, and are ranked the sixth most important contributor of non-fatal negative health outcomes. L-theanine is an amino acid naturally found in green tea (Camellia sinensis) and some other plant extracts, and recent clinical studies have proposed promising adjuvant effects of L-theanine for the negative impact of anxiety and psychological stress on health. In this integrative narrative review, we aimed to appraise and further discuss the effects of L-theanine administration on anxiety disorders and psychological stress. Published data suggests that L-theanine administered at daily doses ranging from 200 to 400 mg for up to 8 weeks are safe and induce anxiolytic and anti-stress effects in acute and chronic conditions. L-theanine at doses lower and higher than these may also show promising therapeutic potential; however, a more thorough investigation through randomized double-blind placebo-controlled crossover clinical trials are necessary to elucidate its effects for longer periods, providing further insights for meta-analyses and the development of recommendation guidelines. Additionally, animal studies investigating a higher dosage, its combination with other pharmacological compounds and associated metabolic comorbidities are recommended, as cases of hepatotoxicity associated with the consumption of green tea extract have been reported.
Subject(s)
Antihypertensive Agents/therapeutic use , Glutamates/therapeutic use , Psychotropic Drugs/therapeutic use , Sleep Aids, Pharmaceutical/therapeutic use , Animals , Anxiety/drug therapy , Blood Pressure/drug effects , Depressive Disorder, Major/drug therapy , Humans , Schizophrenia/drug therapy , Stress, Psychological/drug therapyABSTRACT
The green tea amino acid theanine is abundant in green tea rather than black and oolong teas, which are all made of the identical tea plant "Chanoki" (Camellia sinensis). Theanine has a molecular structure close to glutamine (GLN) compared to glutamic acid (Glu), in terms of the absence of a free carboxylic acid moiety from the gamma carbon position. Theanine efficiently inhibits [3H]GLN uptake without affecting [3H]Glu uptake in rat brain synaptosomes. In contrast to GLN, however, theanine markedly stimulates the abilities to replicate and to commit to a neuronal lineage following prolonged exposure in cultured neural progenitor cells (NPCs) prepared from embryonic and adult rodent brains. Upregulation of transcript expression is found for one of the GLN transporter isoforms, Slc38a1, besides the promotion of both proliferation and neuronal commitment along with acceleration of the phosphorylation of mechanistic target of rapamycin (mTOR) and relevant downstream proteins, in murine NPCs cultured with theanine. Stable overexpression of Slc38a1 similarly facilitates both cellular replication and neuronal commitment in pluripotent embryonic carcinoma P19â¯cells. In P19â¯cells with stable overexpression of Slc38a1, marked phosphorylation is seen for mTOR and downstream proteins in a manner insensitive to further additional phosphorylation by theanine. Taken together, theanine would exhibit a novel pharmacological property to up-regulate Slc38a1 expression for activation of the intracellular mTOR signaling pathway required for neurogenesis after sustained exposure in undifferentiated NPCs in the brain. In this review, a novel neurogenic property of the green tea amino acid theanine is summarized for embryonic and adult neurogenesis with a focus on the endogenous amino acid GLN on the basis of our accumulating evidence to date.
Subject(s)
Brain/drug effects , Glutamates/pharmacology , Glutamine/physiology , Neural Stem Cells/drug effects , Neurogenesis/drug effects , Neuroprotective Agents/pharmacology , Amino Acid Transport System A/physiology , Animals , Cognition Disorders/drug therapy , Cognition Disorders/prevention & control , Double-Blind Method , Forecasting , Glutamates/chemistry , Glutamates/therapeutic use , Glutamine/chemistry , Hippocampus/drug effects , Humans , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Mice, Transgenic , Mood Disorders/drug therapy , Neural Stem Cells/physiology , Neurogenesis/physiology , Phosphorylation/drug effects , Phytotherapy , Protein Processing, Post-Translational/drug effects , Randomized Controlled Trials as Topic , Rats , Sleep Wake Disorders/drug therapy , TOR Serine-Threonine Kinases/metabolism , Tea/chemistryABSTRACT
l-Theanine (l-THE) is a nonproteinogenic amino acid derived from green tea (Camellia sinensis), which exhibits strong antioxidant-like properties and contributes to the favourable umami taste sensation. Several studies have reported that the consumption of this amino acid has many therapeutic effects, including improvements in brain and gastrointestinal function, cancer drug therapeutic efficacies, antihypertensive effects, and improved immune function. Considering the recent Western commercialisation and popularity of green tea consumption as a nootropic agent in humans, the aims of this review were to consolidate the existing knowledge from ex vivo and in vitro animal models and attempt to highlight the applicability of l-THE towards the human clinical trials. Considering the anti-inflammatory and antioxidants effects of l-THE presented in the current review, further research must translate the existing knowledge gained from animal and cell models to exploring the potential metabolic health benefits and moderating effects on the pathogenesis of conditions such as obesity, arthritis, depression, and type 2 diabetes in human trials. This will bridge the gap in literature and provide more insights into the mechanisms driving pathologies characterised by the inflammatory response and oxidative stress.
Subject(s)
Glutamates/pharmacology , Tea/chemistry , Animals , Antihypertensive Agents/pharmacology , Antioxidants/pharmacology , Brain/drug effects , Camellia sinensis/chemistry , Clinical Trials as Topic/statistics & numerical data , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Glutamates/therapeutic use , Humans , Oxidative Stress/drug effects , Treatment OutcomeABSTRACT
Reserpine (RES)-induced orofacial dyskinesia (OD) has been used as an animal model for human tardive dyskinesia (TD) for decades, due to its strong pathophysiological association with striatal oxidative stress and neural cytoarchitecture alteration. L-Theanine (LT), one of the major amino acid components in green tea, has potent antioxidative, anti-inflammatory, and neuroprotective effects. In this study, we examined the potential protective effects of LT on RES-induced behavioral and neurochemical dysfunction in rats. RES treatment (1 mg/kg s.c., 3 injections 1 day apart) induced significant increases (p < 0.001) in the frequency of vacuous chewing movements (VCM), tongue protrusion (TP), as well as the duration of facial twitching (FT). LT treatment (100, 300 mg/kg orally for 14 days, starting 10 days before RES injection) was able to prevent most of the RES-induced OD. Moreover, LT treatment reduced the RES-induced lipid peroxidation (LPO) production, increased the antioxidation power and catecholamines in the striatum, and significantly reduced the levels of neuroinflammatory and apoptotic markers. Our results indicated that LT was able to counteract the increased oxidative damage, neurotransmitter deficiency, neuroinflammation, and apoptosis induced by RES, and these results have demonstrated the possible neuroprotective effects of LT against RES-induced OD, including antioxidation, neurochemical deficiency prevention, antineuroinflammation, and antiapoptosis. These findings, therefore, suggest a potential role for LT to have a clinically relevant therapeutic effect in delaying or treating human TD.
Subject(s)
Antipsychotic Agents/toxicity , Dyskinesias/drug therapy , Dyskinesias/etiology , Glutamates/therapeutic use , Reserpine/toxicity , Analysis of Variance , Animals , Caspase 3/metabolism , Cytokines/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Glutathione/metabolism , Lipid Peroxidation/drug effects , Male , Neurotransmitter Agents/metabolism , Rats , Rats, Wistar , Superoxide Dismutase/metabolismABSTRACT
Doxorubicin (DOX) is a highly potent anti-neoplastic agent widely used in clinical practice, but its dosage and duration of administration are strictly limited due to dose-related organ damage. In the present study, we examined whether theanine, an amino acid derivative found in green tea leaves, can protect against DOX-induced acute nephrotoxicity in rats. Decreases in the creatinine clearance by DOX administration were attenuated by concurrent treatment with theanine, which was consistent with the change in histological renal images assessed by microscopic examination. Theanine had no effect on the distribution of DOX to the kidney. The production of lipid peroxide in the kidney after DOX administration was suppressed by concurrent treatment with theanine. Reduced glutathione content, but not superoxide dismutase activity, was decreased following DOX administration, whereas this change was suppressed when theanine was given in combination with DOX. These results suggest that theanine prevents DOX-induced acute nephrotoxicity through its antioxidant properties.