Rapid biotransformation of STW 5 constituents by human gut microbiome from IBS- and non-IBS donors.

STW 5, a blend of nine medicinal plant extracts, exhibits promising efficacy in treating functional gastrointestinal disorders, notably irritable bowel syndrome (IBS). Nonetheless, its effects on the gastrointestinal microbiome and the role of microbiota on the conversion of its constituents are still largely unexplored. This study employed an experimental ex vivo model to investigate STW 5's differential effects on fecal microbial communities and metabolite production in samples from individuals with and without IBS. Using 560 fecal microcosms (IBS patients, n = 6; healthy controls, n = 10), we evaluated the influence of pre-digested STW 5 and controls on microbial and metabolite composition at time points 0, 0.5, 4, and 24 h. Our findings demonstrate the potential of this ex vivo platform to analyze herbal medicine turnover within 4 h with minimal microbiome shifts due to abiotic factors. While only minor taxonomic disparities were noted between IBS- and non-IBS samples and upon treatment with STW 5, rapid metabolic turnover of STW 5 components into specific degradation products, such as 18ß-glycyrrhetinic acid, davidigenin, herniarin, 3-(3-hydroxyphenyl)propanoic acid, and 3-(2-hydroxy-4-methoxyphenyl)propanoic acid occurred. For davidigenin, 3-(3-hydroxyphenyl)propanoic acid and 18ß-glycyrrhetinic acid, anti-inflammatory, cytoprotective, or spasmolytic activities have been previously described. Notably, the microbiome-driven metabolic transformation did not induce a global microbiome shift, and the detected metabolites were minimally linked to specific taxa. Observed biotransformations were independent of IBS diagnosis, suggesting potential benefits for IBS patients from biotransformation products of STW 5. IMPORTANCE: STW 5 is an herbal medicinal product with proven clinical efficacy in the treatment of functional gastrointestinal disorders, like functional dyspepsia and irritable bowel syndrome (IBS). The effects of STW 5 on fecal microbial communities and metabolite production effects have been studied in an experimental model with fecal samples from individuals with and without IBS. While only minor taxonomic disparities were noted between IBS- and non-IBS samples and upon treatment with STW 5, rapid metabolic turnover of STW 5 components into specific degradation products with reported anti-inflammatory, cytoprotective, or spasmolytic activities was observed, which may be relevant for the pharmacological activity of STW 5.

Vildagliptin restores cognitive function and mitigates hippocampal neuronal apoptosis in cisplatin-induced chemo-brain: Imperative roles of AMPK/Akt/CREB/ BDNF signaling cascades.

Cisplatin (CP) is a broad-spectrum antineoplastic agent used to treat many human cancers. Nonetheless, most patients receiving CP suffer from cognitive deficits, a phenomenon termed "chemo-brain". Recently, vildagliptin (Vilda), a DPP-4 inhibitor, has demonstrated promising neuroprotective properties against various neurological diseases. Therefore, the present study aims to investigate the potential neuroprotective properties of Vilda against CP-induced neurotoxicity and elucidate the underlying molecular mechanisms. Chemo-brain was induced in Sprague-Dawley rats by i.p injection of CP at a dose of 5 mg/kg once weekly for four weeks. Vilda was administered daily at a dose (10 mg/kg; P.O) for four weeks. The results revealed that Vilda restored the cognitive function impaired by CP, as assessed by the Morris water maze, Y-maze, and passive avoidance tests. Moreover, Vilda alleviated the CP-induced neurodegeneration, as shown by toluidine blue staining, besides markedly reduced amyloid plaque deposition, as evidenced by Congo red staining. Notably, Vilda boosted cholinergic neurotransmission through the downregulation of the acetylcholinesterase enzyme. In addition, the neuroprotective mechanisms of Vilda include diminishing oxidative stress by reducing MDA levels while raising GSH levels and SOD activity, repressing neuronal apoptosis as shown by elevated Bcl-2 levels together with diminished Bax and caspase-3 expressions, inhibiting neuroinflammation as shown by decreased GFAP expression, and finally boosting hippocampal neurogenesis and survival by upregulating expressions of BDNF and PCNA. These effects were mainly mediated by activating AMPK/Akt/CREB signaling cascades. In summary, Vilda can be considered a promising candidate for guarding against CP-induced chemo-brain and neurodegeneration, thus improving the quality of life of cancer patients.

Gut Microbiome-Brain Alliance: A Landscape View into Mental and Gastrointestinal Health and Disorders.

Gut microbiota includes a vast collection of microorganisms residing within the gastrointestinal tract. It is broadly recognized that the gut and brain are in constant bidirectional communication, of which gut microbiota and its metabolic production are a major component, and form the so-called gut microbiome-brain axis. Disturbances of microbiota homeostasis caused by imbalance in their functional composition and metabolic activities, known as dysbiosis, cause dysregulation of these pathways and trigger changes in the blood-brain barrier permeability, thereby causing pathological malfunctions, including neurological and functional gastrointestinal disorders. In turn, the brain can affect the structure and function of gut microbiota through the autonomic nervous system by regulating gut motility, intestinal transit and secretion, and gut permeability. Here, we examine data from the CAS Content Collection, the largest collection of published scientific information, and analyze the publication landscape of recent research. We review the advances in knowledge related to the human gut microbiome, its complexity and functionality, its communication with the central nervous system, and the effect of the gut microbiome-brain axis on mental and gut health. We discuss correlations between gut microbiota composition and various diseases, specifically gastrointestinal and mental disorders. We also explore gut microbiota metabolites with regard to their impact on the brain and gut function and associated diseases. Finally, we assess clinical applications of gut-microbiota-related substances and metabolites with their development pipelines. We hope this review can serve as a useful resource in understanding the current knowledge on this emerging field in an effort to further solving of the remaining challenges and fulfilling its potential.

Synthesis of some azoles incorporating a sulfonamide moiety as anticonvulsant agents.

Many derivatives of heterocyclic compounds containing a sulfonamide thiazole moiety were synthesized through the reaction of 2-(cyano or chloro)-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide with isocyanate followed by halogenated compounds, arylidene, 2-hydroxy benzaldehydes, active methylene compounds, and heterocyclic amines. The anticonvulsant activity for 15 of the synthesized compounds was evaluated and 6 compounds showed protection against picrotoxin-induced convulsion. 4-(6-Amino-3,5-dicyano-4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-N-(thiazol-2-yl)benzenesulfonamide (11b) exhibited significant anticonvulsive effects, abolished the tonic extensor phase and offered 100% protection.

Role of PI3K/Akt axis in mitigating hippocampal ischemia-reperfusion injury via CB1 receptor stimulation by paracetamol and FAAH inhibitor in rat.

AIMS: Acetaminophen or paracetamol (PAR), the recommended antipyretic in COVID-19 and clinically used to alleviate stroke-associated hyperthermia interestingly activates cannabinoid receptor (CB1) through its AM404 metabolite, however, to date, no study reports the in vivo activation of PAR/AM404/CB1 axis in stroke. The current study deciphers the neuroprotective effect off PAR in cerebral ischemia/reperfusion (IR) rat model and unmasks its link with AM404/CB1/PI3K/Akt axis. MATERIALS AND METHODS: Animals were allocated into 5 groups: (I) sham-operated (SO), (II) IR, (III) IR + PAR (100 mg/kg), (IV) IR + PAR (100 mg/kg) + URB597; anandamide degradation inhibitor (0.3 mg/kg) and (V) IR + PAR (100 mg/kg) + AM4113; CB1 Blocker (5 mg/kg). All drugs were intraperitoneally administered at the inception of the reperfusion period. KEY FINDINGS: PAR administration alleviated the cognitive impairment in the Morris Water Maze as well as hippocampal histopathological and immunohistochemical examination of GFAP. The PAR signaling was associated with elevation of anandamide level, CB1 receptor expression and survival proteins as pS473-Akt. P(tyr202/thr204)-ERK1/2 and pS9-GSK3ß. Simultaneously, PAR increased hippocampal BDNF and ß-arrestin1 levels and decreased glutamate level. PAR restores the deranged redox milieu induced by IR Injury, by reducing lipid peroxides, myeloperoxidase activity and NF-κB and increasing NPSH, total antioxidant capacity, nitric oxide and Nrf2 levels. The pre-administration of AM4113 reversed PAR effects, while URB597 potentiated them. SIGNIFICANCE: PAR poses a significant neuroprotective effect which may be mediated, at least in part, via activation of anandamide/CB1/PI3K/Akt pathway in the IR rat model.

Modulation of Intestinal Corticotropin-Releasing Hormone Signaling by the Herbal Preparation STW 5-II: Possible Mechanisms for Irritable Bowel Syndrome Management.

Corticotropin-releasing factor (CRF) mediates stress responses and alters the gut-brain axis, contributing to the pathogenesis of irritable bowel syndrome (IBS), which is recognized by abdominal pain accompanied by bowel habit disturbance. STW 5-II, a mixture of six herbal extracts, is clinically effective in functional dyspepsia and IBS. Here we aimed to establish an organoid-based stress-induced IBS-like model to investigate the mechanisms of action of STW 5-II. STW 5-II (10, 20, and 30 g/mL) was applied to intestinal organoids for 24 h before being treated with CRF (100 nM) for 48 h. The effects of STW 5-II on CRF signaling were investigated using several in vitro and in silico approaches. STW 5-II activities were further explored by in silico PyRx screening followed by molecular docking of the main 52 identified compounds in STW 5-II with both CRF receptors CRFR1 and CRFR2. CRF exposure stimulated inflammation and increased proinflammatory mediators, while STW 5-II dose-dependently counteracted these effects. STW 5-II inhibited CRF-induced claudin-2 overexpression and serotonin release. Docking of the STW 5-II constituents oleanolic acid and licorice saponin G2 to CRFR1 and CRFR2, respectively, showed a good affinity. These multi-target activities support and elucidate the clinically proven efficacy of STW 5-II in disorders of gut-brain interaction.

Medicinal Plants and Their Impact on the Gut Microbiome in Mental Health: A Systematic Review.

BACKGROUND: Various neurocognitive and mental health-related conditions have been associated with the gut microbiome, implicating a microbiome-gut-brain axis (MGBA). The aim of this systematic review was to identify, categorize, and review clinical evidence supporting medicinal plants for the treatment of mental disorders and studies on their interactions with the gut microbiota. METHODS: This review included medicinal plants for which clinical studies on depression, sleeping disorders, anxiety, or cognitive dysfunction as well as scientific evidence of interaction with the gut microbiome were available. The studies were reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Eighty-five studies met the inclusion criteria and covered thirty mental health-related medicinal plants with data on interaction with the gut microbiome. CONCLUSION: Only a few studies have been specifically designed to assess how herbal preparations affect MGBA-related targets or pathways. However, many studies provide hints of a possible interaction with the MGBA, such as an increased abundance of health-beneficial microorganisms, anti-inflammatory effects, or MGBA-related pathway effects by gut microbial metabolites. Data for Panax ginseng, Schisandra chinensis, and Salvia rosmarinus indicate that the interaction of their constituents with the gut microbiota could mediate mental health benefits. Studies specifically assessing the effects on MGBA-related pathways are still required for most medicinal plants.

Effects of the herbal preparation STW 5-II on in vitro muscle activity in the guinea pig stomach.

BACKGROUND: STW 5 is a combination of nine medicinal herbal extracts and used to treat functional gastrointestinal disorders including functional dyspepsia. It has a region-specific effect by relaxing the proximal and contracting the distal stomach. The research combination STW 5-II (Iberogast® Advance) lacks three herbal extracts but seems clinically as effective as STW 5. However, the action of STW 5-II on gastric motility is unknown. METHODS: In vitro circular and longitudinal muscle tone and contractility were recorded from guinea pig gastric fundus and antrum with isometric force transducers. KEY RESULTS: STW 5-II decreased concentration-dependently (64-512 µg/ml) the tone of circular and longitudinal muscle strips from the fundus. In contrast, STW 5-II increased concentration-dependently contraction amplitude in antral circular and longitudinal muscle. The effects were region-dependent but comparable in the two muscle layers. Application of 512 µg STW 5 or STW 5-II revealed comparable effects in the fundus and antrum circular and longitudinal muscle strips. CONCLUSIONS AND INTERFERENCES: STW 5-II had a region-specific effect and relaxed the proximal stomach but increased the contractility in the antrum. It was as effective as STW 5 which may explain its comparable clinical effects in treating functional dyspepsia. Impaired accommodation may be normalized through relaxation of the fundus, while the motility-promoting effects leading to an increase in antral motility may activate the gastric pump.

Effect of the standard herbal preparation, STW5, treatment on dysbiosis induced by dextran sodium sulfate in experimental colitis.

BACKGROUND: The standardized herbal preparation, STW 5, is effective clinically in functional gastrointestinal disorders and experimentally in ulcerative colitis (UC). The present study explores whether the beneficial effect of STW 5 involves influencing the intestinal microbiota. METHODS: UC was induced in Wistar rats by feeding them 5% dextran sodium sulfate (DSS) in drinking water for 7 days. Rats were treated concurrently with STW 5 and sacrificed 24 h after last drug administration. Fecal samples were used to determine changes in the abundance of selected microbial phyla and genera using real-time PCR. RESULTS: Induction of UC led to dysbiosis and changes in the gut microbiota. The changes included an increase in some genera of the Firmicutes, namely Enterococcus, and a decrease in others, namely Blautia, Clostridium, and Lactobacillus. DSS further induced a marked increase in the abundance of Bacteroidetes and Proteobacteria as well as in the relative abundance of Actinobacteria and its genus Bifidobacterium. Methanobrevibacter levels (phylum Euryarchaeota) were also increased. Microbial dysbiosis was associated with changes in various parameters of colonic inflammation. STW 5 effectively guarded against those changes and significantly affected the indices of edema and inflammation in the UC model. Changes in colon length, colon mass index, inflammatory and apoptotic markers, and histological changes induced by DSS were also prevented. CONCLUSIONS: Dysbiosis plays a contributing role in the development of DSS-induced UC. Derangements in the microbial flora and associated inflammatory processes were largely prevented by STW 5, suggesting that this effect might contribute towards its beneficial usefulness in this condition.

STW 5 Herbal Preparation Modulates Wnt3a and Claudin 1 Gene Expression in Zebrafish IBS-like Model.

AIM: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic abdominal pain and stool irregularities. STW 5 has proven clinical efficacy in functional gastrointestinal disorders, including IBS, targeting pathways that suppress inflammation and protect the mucosa. Wnt signaling is known to modulate NF-kß-dependent inflammatory cytokine production. This sparked the idea of evaluating the impact of STW 5 on the expression of inflammatory-response and Wnt/ß catenin-target genes in an IBS-like model. MAIN METHODS: We used zebrafish and dextran sodium sulfate (DSS) treatment to model IBS-like conditions in vivo and in vitro and examined the effects of subsequent STW 5 treatment on the intestines of DSS-treated fish and primary cultured intestinal and neuronal cells. Gross gut anatomy, histology, and the expression of Wnt-signaling and cytokine genes were analyzed in treated animals and/or cells, and in controls. KEY FINDINGS: DSS treatment up-regulated the expression of interleukin-8, tumor necrosis factor-α, wnt3a, and claudin-1 in explanted zebrafish gut. Subsequent STW 5 treatment abolished both the macroscopic signs of gut inflammation, DSS-induced mucosecretory phenotype, and normalized the DSS-induced upregulated expression of il10 and Wnt signaling genes, such as wnt3a and cldn1 in explanted zebrafish gut. Under inflammatory conditions, STW 5 downregulated the expression of the pro-inflammatory cytokine genes il1ß, il6, il8, and tnfα while it upregulated the expression of the anti-inflammatory genes il10 and wnt3a in enteric neuronal cells in vitro. SIGNIFICANCE: Wnt signaling could be a novel target for the anti-inflammatory and intestinal permeability-restoring effects of STW 5, possibly explaining its clinical efficacy in IBS.

Mechanistic insights into the protective effect of paracetamol against rotenone-induced Parkinson's disease in rats: Possible role of endocannabinoid system modulation.

Parkinson's disease (PD) is a disabling progressive neurodegenerative disease. So far, PD's treatment remains symptomatic with no curative effects. Aside from its blatant analgesic and antipyretic efficacy, recent studies highlighted the endowed neuroprotective potentials of paracetamol (PCM). To this end: the present study investigated: (1) Possible protective role of PCM against rotenone-induced PD-like neurotoxicity in rats, and (2) the mechanisms underlying its neuroprotective actions including cannabinoid receptors' modulation. A dose-response study was conducted using three doses of PCM (25, 50, and 100 mg/kg/day, i.p.) and their effects on body weight changes, spontaneous locomotor activity, rotarod test, tyrosine hydroxylase (TH) and α-synuclein expression, and striatal dopamine (DA) content were evaluated. Results revealed that PCM (100 mg/kg/day, i.p.) halted PD motor impairment, prevented rotenone-induced weight loss, restored normal histological tissue structure, reversed rotenone-induced reduction in TH expression and striatal DA content, and markedly decreased midbrain and striatal α-synuclein expression in rotenone-treated rats. Accordingly, PCM (100 mg/kg/day, i.p.) was selected for further mechanistic investigations, where it ameliorated rotenone-induced oxidative stress, neuro-inflammation, apoptosis, and disturbed cannabinoid receptors' expression. In conclusion, our findings imply a multi-target neuroprotective effect of PCM in PD which could be attributed to its antioxidant, anti-inflammatory and anti-apoptotic activities, in addition to cannabinoid receptors' modulation.

Anti-inflammatory and tight junction protective activity of the herbal preparation STW 5-II on mouse intestinal organoids.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional bowel disorder, in which recurrent abdominal pain is associated with defecation or a change in bowel habits. STW 5-II is a combination of six medicinal herbs with a clinically proven efficacy in managing IBS. AIM: This study aims to establish an in vitro IBS model using mouse intestinal organoids and to explore the anti-inflammatory and tight junction protective activities of the multi-herbal preparation STW 5-II. METHODS: Intestinal organoids were cultured in 1:1 Matrigel™ and medium domes. Inflammation and tight junction disruption were induced by a cocktail of cytokines (TNFα, IFNγ, IL-1ß, IL-6) and bacterial proteins (LPS, flagellin). Organoids were treated with different concentrations of STW 5-II, and its multi-target activity was assessed using microarray analyses, RT-qPCR, immunofluorescence, western blot, immunohistochemistry, and a FITC permeability assay. In addition, we analyzed the expression of pNF-κB, pSTAT1, iNOS and ZO-1. In silico analyses were conducted to predict and identify the active components that may be responsible in mediating the multi-target anti-inflammatory activity of STW 5-II. RESULTS: An organoid based IBS model was successfully established. STW 5-II effectively reduced the cytokines-induced overexpression of the pro-inflammatory mediators pNF-κB, pSTAT1 and iNOS. Moreover, STW 5-II attenuated cytokine-mediated downregulation of the tight junction protein, ZO-1. This finding was confirmed by a FITC permeability assay. In silico analyses revealed a promising inhibitory activity of some isolated compounds from STW 5-II against NF-κB, STAT1 and iNOS. CONCLUSION: STW 5-II possesses multiple anti-inflammatory as well as tight junction protective activities that could explain its clinically proven efficacy in managing IBS symptoms.

Application of an in vitro digestion model to study the metabolic profile changes of an herbal extract combination by UHPLC-HRMS.

BACKGROUND: STW 5 is a fixed herbal combination containing extracts from nine medicinal plants: bitter candytuft, greater celandine, garden angelica roots, lemon balm leaves, peppermint leaves, caraway fruits, licorice roots, chamomile flowers, and milk thistle fruit. STW 5 is a clinically proven treatment for functional dyspepsia and irritable bowel syndrome. PURPOSE: Using a static in vitro method, we simulated oral, gastric, and small intestinal digestion and analyzed the metabolic profile changes by UHPLC-HRMS to determine the impact of oro-gastro-intestinal digestion on STW 5 constituents. STUDY DESIGN AND METHODS: STW 5 was incubated according to the InfoGest consensus method. Samples of each digestive phase were analyzed by UHPLC-HRMS in ESI positive and negative modes. After data processing, background subtraction, and normalization, the peak areas of detectable compounds were compared to untreated reference samples and recovery ratios were calculated to monitor the metabolic profile of STW 5 during simulated digestion. RESULTS: Although the levels of some constituents were reduced, we did not observe complete degradation of any of the constituents of STW 5 upon in vitro digestion. We did not detect any new metabolites beyond increased levels of caffeic acid and liquiritigenin due to degradation of progenitor compounds. Changes observed in intestinal bioaccessibility ratios were mainly a result of isomerization, hydrolysis, protein binding, and low water solubility. CONCLUSION: The majority of STW 5 constituents are stable towards simulated in vitro digestion and can reach the colon to interact with gut microbiota if they remain unabsorbed in the upper intestinal tract.

STW 5 is effective against nonsteroidal anti-inflammatory drugs induced gastro-duodenal lesions in rats.

BACKGROUND: Proton pump inhibitors are often used to prevent gastro-intestinal lesions induced by nonsteroidal anti-inflammatory drugs. However, they are not always effective against both gastric and duodenal lesions and their use is not devoid of side effects. AIM: To explore the mechanisms mediating the clinical efficacy of STW 5 in gastro-duodenal lesions induced by nonsteroidal anti-inflammatory drugs (NSAIDs), exemplified here by diclofenac, in a comparison to omeprazole. METHODS: Gastro-duodenal lesions were induced in rats by oral administration of diclofenac (5 mg/kg) for 6 successive days. One group was given concurrently STW 5 (5 mL/kg) while another was given omeprazole (20 mg/kg). A day later, animals were sacrificed, stomach and duodenum excised and divided into 2 segments: One for histological examination and one for measuring inflammatory mediators (tumor necrosis factor α, interleukins-1ß and 10), oxidative stress enzyme (heme oxygenase-1) and apoptosis regulator (B-cell lymphoma 2). RESULTS: Diclofenac caused overt histological damage in both tissues, associated with parallel changes in all parameters measured. STW 5 and omeprazole effectively prevented these changes, but STW 5 superseded omeprazole in protecting against histological damage, particularly in the duodenum. CONCLUSION: The findings support the therapeutic usefulness of STW 5 and its superiority over omeprazole as adjuvant therapy to NSAIDs to protect against their possible gastro-duodenal side effects.