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Abstract Durian (Durio zibethinus L.) fruit pulp is a rich source of γ-glutamylcysteine (γ-EC), a direct precursor to the antioxidant glutathione (GSH). This study elucidated the in vitro neuroprotective potential of unripe durian fruit pulp extract (UDE) against H2O2-induced neurotoxicity in SH-SY5Y cells and neuroinflammation in lipopolysaccharide (LPS)-stimulated BV-2 cells. Treatments with γ-EC, GSH standards, or UDE exhibited no cytotoxicity in SH-SY5Y and BV-2 cells, except at high concentrations. A 4-h pretreatment with 100 µM γ-EC or UDE containing 100 µM γ-EC significantly increased SH-SY5Y cell viability post H2O2 induction. Moreover, a similar pretreatment reduced LPS-stimulated production of proinflammatory cytokines in BV-2 cells. The neuroprotective effect of UDE is primarily attributed to γ-EC provision and the promotion of GSH synthesis, which in turn elevates intracellular GSH levels and reduces proinflammatory cytokines. This study identifies γ-EC in UDE as a potential neuroprotective biomarker boosting intracellular GSH levels, providing insights into UDE's therapeutic potential.

IntroductionBenign prostatic hyperplasia (BPH) is the enlargement of the prostate gland, primarily occurring in aging men, in which transforming growth factor-beta (TGF-β) plays a critical role in prostate cell hyperproliferation and leads to uncomfortable urinary symptoms in BPH patients. Pterocarpus indicus Willd. is well known for its ethnopharmacological applications for treating ailments such as diuresis and bladder stones.MethodsThis study aimed to examine the effect of P. indicus extract (PI extract) on TGF-β-induced WPMY-1 cell proliferation, followed by bioassay-guided fractionation to isolate the active metabolites. Angolensin (Ang) and maackiain (Mac) were isolated from bioassay-guided fractionation. Network analysis was performed to investigate the potential mechanisms. Furthermore, network analysis of the Ang-Mac combination in BPH highlighted the potential top ten pathways, including PI3K/AKT signaling pathway. Accordingly, subsequent investigation focused on evaluating the effect of PI extract, Ang, Mac, and Ang-Mac combination on the expression of PCNA, p53, and PI3K/AKT protein localization and expression.Results and discussionResults revealed inhibition of cell proliferation in TGF-β-induced WPMY-1 cells, correlating with downregulated PCNA expression. While PI extract and Mac induced apoptosis via p53 upregulation, Ang and Ang-Mac combination did not significantly affect apoptosis through the p53 pathway. Additionally, both metabolites exhibited potent inhibition of p-PI3K and p-AKT protein localization and expression in the nucleus of TGF-β-induced WPMY-1 cells. This study suggests that PI extract, Ang, and Mac are promising compounds for treating BPH, as evidenced by in silico and in vitro studies. Additionally, Ang and Mac could be used to standardize PI extract in future investigations.

Neurodegenerative diseases (NDDs) are marked by progressive degeneration of neurons within the central nervous system. A notable rise in the prevalence of NDDs has been noticed in the recent past. There is an undeniable requirement for the discovery of innovative therapies aimed at treating NDDs, as current medications predominantly address symptoms rather than provide cures. Approved therapies often experience a decline in therapeutic efficacy over time and are associated with significant side effects. The current investigation explores the potential of spilanthol, the major bioactive compound isolated from Acmella paniculata, in attenuating NDDs through a multi-faceted approach combining in silico, and in vitro methodologies. In silico pharmacokinetic and toxicity screening of spilanthol indicated favorable characteristics for oral delivery, blood–brain barrier permeability, and minimal toxicity. Network pharmacology predicts that spilanthol attenuates neuroinflammation in NDDs by suppressing the toll-like receptor signaling pathway. Molecular docking and dynamics simulations demonstrate robust binding affinities between spilanthol and key proteins in the TLR4 pathway. In vitro experiments conducted using BV-2 microglial cells demonstrate the potential of spilanthol to reduce the production of proinflammatory cytokines and mediators such as NO, TNF-α, and IL-6 induced by lipopolysaccharide. The cumulative findings of the present study indicate that spilanthol mitigates neurodegeneration by alleviating neuroinflammation.

Background: Clerodendrum petasites, an herbal plant in Thailand, has been used for many years in folk medicine. However, scientific evidence regarding CNS safety pharmacology and antinociceptive activity of C. petasites (CP) has not yet been well characterized. Purpose: The present study aimed to assess the CNS safety pharmacology and antinociceptive and antiinflammatory effects of CP extract. Methods: The effect of CP extract on CNS safety pharmacology was assessed using LABORAS automated home cage monitoring and rotarod test. Its pharmacological activity was evaluated both in-vitro, and in-vivo using hot-plate, acetic acid-induced writhing, formalin, and carrageenan-induced paw edema models. Results and conclusion: CP extract significantly improved thermal and chemical nociceptive behaviors and acute inflammatory pain at all doses: 300, 600, and 1200 mg/kg, p.o. The antiinflammatory effect of CP extract in inflammatory pain models was comparable to the effect of positive control: indomethacin 10 mg/kg at all dose levels tested. Further, the CP extract at 600 mg/kg dose significantly inhibited 82.3% of carrageenan-induced total edema. In-vitro, CP extract at 12.5, 25, and 50 μg/mL concentrations significantly reduced the expression of LPS-induced nitric oxide, IL-6, and TNF-α expression in both RAW 264.7 macrophage and BV-2 microglial cell lines. In addition, CP extract did not show any potential effects on the CNS, indicated by no significant effects on motor coordination, spontaneous locomotor activity, general behaviors, and well-being compared to vehicle-treated mice (p > 0.05). Overall, the present study evidences the potential antinociceptive, antiinflammatory efficacies of CP extract with a favorable CNS safety profile.

Abstract Background Curcumin and piperine are major bioactive compounds of Curcuma longa and Piper nigrum, widely consumed as spices and flock medicine. The combinational use of these plants is a common practice in Southeast Asia. Synergism between curcumin and piperine has been found in several animal models but not in periodontal disease and diabetes, and the antinociceptive interaction is still unknown. Hence, the present study aimed to assess the interaction between curcumin and piperine in pain and its potential CNS side effect profile. Methods Formalin test and in vitro LPS-stimulated RAW 264.7 macrophage cells were used to assess the synergistic interaction of curcumin and piperine in a mouse model of inflammatory pain. Tail-flick and cold plate tests were applied to determine the antinociceptive synergism between piperine and curcumin. The interaction was determined by applying isobolographic analysis. The potential CNS-side effects of the curcumin and piperine combination were also assessed using LABORAS automated home-cage behavioral analysis. Results Curcumin alone dose-dependently improved pain-like behaviors in the formalin, tail-flick, and cold plate tests with the ED50 of 71.4, 34.4, and 31.9 mg/kg, respectively. Additionally, piperine exhibited efficacy in the formalin, tail-flick, and cold plate tests with the ED50 of 18.4, 8.1, and 28.1 mg/kg, respectively. The combination of curcumin and piperine (1:1 ED50 ratio) produced synergistic interaction in the formalin, tail-flick, and cold plate tests as assessed significantly lower experimental ED50 values (5.9, 5.2, and 5.5 mg/kg) compared to theoretical ED50 values (44.9, 21.3, and 30.0 mg/kg), isobologram analysis, and interaction index values of 0.13, 0.24 and 0.18, respectively. The synergistic interaction of curcumin and piperine was further confirmed by the efficacy of the combination in LPS-stimulated RAW 264.7 macrophage cells. Curcumin and piperine interacted synergistically, reducing proinflammatory mediators. The combination also demonstrated better compatibility profiles with neuronal cells. Furthermore, the curcumin-piperine combination had no effects on mouse spontaneous locomotor behaviors in LABORAS automated home cage monitoring. Conclusion Overall, the present study demonstrates strong antinociceptive synergism between curcumin and piperine in mouse models with no potential CNS side effects, suggesting its possible use in clinical trials.

Abstract Metformin is a well-tolerated antidiabetic drug and has recently been repurposed for numerous diseases, including pain. However, a higher dose of metformin is required for effective analgesia, which can potentiate its dose-dependent gastrointestinal side effects. Curcumin is a natural polyphenol and has beneficial therapeutic effects on pain. Curcumin has been used as an analgesic adjuvant with several analgesic drugs, allowing synergistic antinociceptive effects. Nevertheless, whether curcumin can exert synergistic analgesia with metformin is still unknown. In the present study, the nature of curcumin-metformin anti-inflammatory interaction was evaluated in in vitro using lipopolysaccharide-induced RAW 264.7 macrophage and BV-2 microglia cells. In both macrophage and microglia, curcumin effectively potentiates the anti-inflammatory effects of metformin, indicating potential synergistic effects in both peripheral and central pathways of pain. The nature of the interaction between curcumin and metformin was further recapitulated using a mouse model of formalin-induced pain. Coadministration of curcumin and metformin at a 1:1 fixed ratio of their ED50 doses significantly reduced the dose required to produce a 50% effect compared to the theoretically required dose in phase II of the formalin test with a combination index value of 0.24. Besides, the synergistic interaction does not appear to involve severe CNS side effects indicated by no motor alterations, no alterations in short-term and long-term locomotive behaviors, and the general well-being of mice. Our findings suggest that curcumin exerts synergistic anti-inflammation with metformin with no potential CNS adverse effects.

Abstract Background Crinum latifolium L. (Amaryllidaceae) has been used in Southeast Asian traditional medicine to alleviate the symptoms of benign prostatic hyperplasia (BPH). The pathological mechanism of BPH is associated with the induction of prostate stromal cell proliferation through transforming growth factor-beta (TGF-β). Standardization as well as investigation of the potential anti-BPH activity of C. latifolium extract could benefit the further development of BPH-related analyses and provide evidence to support the application of this extract for BPH treatment. This study aimed to standardize and investigate the antiproliferative activity of the ethanolic extract of C. latifolium leaves. The major alkaloids isolated from C. latifolium were also explored for their potential use as bioactive markers. Methods Two major alkaloids were isolated from the ethanolic extract of C. latifolium leaves by chromatographic techniques, identified by NMR and MS, and quantified by a validated UHPLC method. Their antiproliferative activity was studied in human prostate stromal cells (WPMY-1) induced by TGF-β. The synergistic effect of combining the two major isolated alkaloids was analyzed by the zero interaction potency (ZIP) model. Results Two alkaloids, lycorine (1) and 6α-hydroxybuphanidrine (2), were isolated from the ethanolic leaf extract of C. latifolium. A UHPLC method for the quantification of (1) and (2) was developed and validated in terms of linearity, precision, and accuracy. The C. latifolium leaf extract contained 0.279 ± 0.003% (1) and 0.232 ± 0.004% (2). The crude extract was more potent than either (1) and (2) alone against TGF-β-treated WPMY-1 cell proliferation. The drug combination study revealed that the greatest synergistic effect of (1) and (2) was achieved at a 1:1 ratio. Conclusions The results of this study support the anti-BPH activity of C. latifolium in traditional medicine and suggest that these the two isolated alkaloids may promote the efficacy of the C. latifolium extract. Additionally, major alkaloids (1) and (2) can be used as bioactive markers for the standardization of C. latifolium extracts.

Abstract The failure to develop analgesic drugs is attributed not only to the complex and diverse pathophysiology of pain in humans but also to the poor experimental design and poor preclinical assessment of pain. Although considerable efforts have been devoted to overcoming the relevant problems, many features of the behavioral pain assessment remain to be characterized. For example, a decreased locomotor activity as a common presentation of pain-like behavior has yet to be described. Studies on mice experimentally induced with carrageenan have provided opportunities to explore pain-related behaviors in automated home-cage monitoring. Through this approach, the locomotor activities of mice with carrageenan-induced inflammatory pain can be precisely and objectively captured. Here, we found that the mobile behaviors of mice reduced, and their immobility increased, indicating that carrageenan induction in mice caused a significant decrease in locomotor activity. These non-reflexive pain behaviors were strongly correlated with the reflexive pain behaviors measured via von Frey and plantar tests. Furthermore, the pharmacological intervention using indomethacin improved the locomotor activity of mice with carrageenan-induced pain. Thus, the analysis of the locomotor activity in automated home-cage monitoring is useful for studying the behavioral analgesia and the pharmacological screening of analgesic drugs. The combined evaluation of reflexive and non-reflexive pain behaviors enhances the translational utility of preclinical pain research in rodents.

Bacterial meningitis remains one of the most prevalent infectious diseases worldwide. Although advances in medical care have improved mortality and morbidity, neurological complications remain high. Therefore, aside from antibiotics, therapeutic adjuvants targeting neuroinflammation are essential to combat the long-term neuronal sequelae of bacterial meningitis. In the present study, we propose (−)-dendroparishiol as a potential add-on therapy to improve neuroinflammation associated with bacterial meningitis. The biological activity of (−)-dendroparishiol was first predicted by computational analysis and further confirmed in vitro using a cell-based assay with LPS-induced BV-2 microglial cells. Biological pathways involved with (−)-dendroparishiol were identified by applying network pharmacology. Computational predictions of biological activity indicated possible attenuation of several inflammatory processes by (−)-dendroparishiol. In LPS-induced BV-2 microglial cells, (−)-dendroparishiol significantly reduced the expression of inflammatory mediators: iNOS, NO, COX-2, IL-6, and TNF-α. Molecular docking results demonstrated the potential iNOS and COX-2 inhibitory activity of (−)-dendroparishiol. Network pharmacological analysis indicated the plausible role of (−)-dendroparishiol in biological processes involved in oxidative stress and neuroinflammation with enrichment in neuroinflammatory pathways. Overall, this study provides scientific evidence for the potential application of (−)-dendroparishiol in the management of bacterial meningitis-associated neuroinflammation.

Abstract Background To report on prevalence of gout flare in emergency departments and to report the quality of gout care in emergency departments and causes of admission at emergency departments. Methods A retrospective chart review of visits that had a primary diagnosis in gout by the International Classification of Diseases, the tenth revision, at emergency departments from 6 universities in Thailand over a 5 year period from 1 January 2012 to 31 December 2016. Results Six hundred thirty-two visits were included to the study. Prevalence of gout flare in emergency departments was 0.04. Only 29.3% of the visits had arthrocentesis. 628/632 (99.4%) and 519/585 (88.7%) of the visits were prescribed medications in emergency departments and had home medications, respectively. Although all visits that were prescribed colchicine in emergency departments received adequate doses of colchicine, it was also found that more than 2.4 mg/day of colchicine was prescribed (3/394, 0.8%) for home medications. In addition, 183/343 (53.4%) of the visits with normal renal function were prescribed non-steroidal anti-inflammatory drugs (NSAIDs). However, prescribed NSAIDs in abnormal renal function (42/343, 12.2%) was also found. The interruption of dosing, including increase, decrease, addition or discontinuance of urate lowing therapy in a gout flare period was 42/632 (6.6%). The most common cause of admission was acute gouty arthritis (31/47, 66.0%). Conclusions Quality of gout care in the emergency departments was not good. Inappropriate management of gout flare in emergency departments was demonstrated in our study, particularly with regard to investigations and pharmacological management. Gaps between clinicians and guidelines, the knowledge of clinicians, and overcrowding in emergency departments were hypothesized in the results.

Curcumin is a polyphenol compound that alleviates several neuroinflammation-related diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and cerebral injury. However, the therapeutic efficacy of curcumin is limited by its poor physicochemical properties. The present study aimed to develop a new carrier-linked curcumin prodrug, curcumin diethyl γ-aminobutyrate (CUR-2GE), with improved physicochemical and anti-neuroinflammatory properties. CUR-2GE was designed and synthesized by conjugating curcumin with gamma-aminobutyric acid ethyl ester (GE) via a carbamate linkage. The carbamate linkage was selected to increase stability at acidic pH while GE served as a promoiety for lipophilic enhancement. The synthesized CUR-2GE was investigated for solubility, partition coefficient, stability, and bioconversion. The solubility of CUR-2GE was less than 0.05 μg/mL similar to that of curcumin, while the lipophilicity with log P of 3.57 was significantly increased. CUR-2GE was resistant to chemical hydrolysis at acidic pH (pH 1.2 and 4.5) as anticipated but rapidly hydrolyzed at pH 6.8 and 7.4. The incomplete hydrolysis of CUR-2GE was observed in simulated gastrointestinal fluids which liberated the intermediate curcumin monoethyl γ-aminobutyric acid (CUR-1GE) and the parent curcumin. In plasma, CUR-2GE was sequentially converted to CUR-1GE and curcumin within 1 h. In lipopolysaccharide (LPS)-stimulated BV-2 microglial cells, CUR-2GE effectively attenuated the pro-inflammatory mediators by decreasing the secretion of nitric oxide and cytokines (TNF-α and IL-6) to a greater extent than curcumin due to an increase in cellular uptake. Altogether, the newly developed acid-stable CUR-2GE prodrug is a potential pre-clinical and clinical candidate for further evaluation on neuroprotective and anti-neuroinflammatory effects.

Abstract Background The aim of this systematic literature review was to comprehensively describe the anatomical pathology of tissues affected by gout. Methods We searched PubMed, The Cochrane Library, Excerpta Medica Database (EMBASE), and Web of Science Core Collection for all English language articles published before March 2018. Articles were included if they described the microscopic or macroscopic appearances of gout in human tissue. Results Four hundred and seventeen articles met inclusion criteria and were included in the review. Articles describing the anatomical pathology of gout in musculoskeletal structures, including bone, tendon and ligaments, synovium and cartilage, were most common. Articles describing skin and kidney pathology in gout were also common, with pathology in other sites such as visceral organs less common. At all sites, monosodium urate crystal deposition was reported, and the tophus was also described within many different tissues. During a gout flare, diffuse acute neutrophilic synovial inflammation was evident. The tophus was described as an organised chronic giant cell granulomatous structure consisting of monosodium urate crystals, innate and adaptive immune cells, and fibrovascular tissue. Conclusions Consistent with the clinical presentation of gout, most studies describing the anatomical pathology of gout report involvement of musculoskeletal structures, with monosodium urate crystal deposition and tophus the most common lesions described. This review details the anatomical pathology features of gout at affected sites.

The use of endotoxin, such as lipopolysaccharide (LPS) as a model of sickness behavior, has attracted recent attention. To objectively investigate sickness behavior along with its pain-like behaviors in LPS-treated mice, the behavioral measurement requires accurate methods, which reflects clinical relevance. While reflexive pain response tests have been used for decades for pain assessment, its accuracy and clinical relevance remain problematic. Hence, we used automated home-cage monitoring LABORAS to evaluate spontaneous locomotive behaviors in LPS-induced mice. LPS-treated mice displayed sickness behaviors including pain-like behaviors in automated home-cage monitoring characterized by decreased mobile behaviors (climbing, locomotion, rearing) and increased immobility compared to that of the control group in both short- and long-term locomotive assessments. Here, in short-term measurement, both in the open-field test and automated home-cage monitoring, mice demonstrated impaired locomotive behaviors. We also assessed 24 h long-term locomotor activity in the home-cage system, which profiled the diurnal behaviors of LPS-stimulated mice. The results demonstrated significant behavioral impairment in LPS-stimulated mice compared to the control mice in both light and dark phases. However, the difference is more evident in the dark phase compared to the light phase owing to the nocturnal activity of mice. In addition, the administration of indomethacin as a pharmacological intervention improved sickness behaviors in the open-field test as well as automated home-cage monitoring, confirming that automated home-cage monitoring could be potentially useful in pharmacological screening. Together, our results demonstrate that automated home-cage monitoring could be a feasible alternative to conventional methods, such as the open-field test and combining several behavioral assessments may provide a better understanding of sickness behavior and pain-like behaviors in LPS-treated mice.

Chronic pain is a persistent and unremitting condition that has immense effects on patients’ quality of life. Studies have shown that neuroinflammation is associated with the induction and progression of chronic pain. The activation of microglia and astrocytes is the major hallmark of spinal neuroinflammation leading to neuronal excitability in the projection neurons. Excessive activation of microglia and astrocytes is one of the major contributing factors to the exacerbation of pain. However, the current chronic pain treatments, mainly by targeting the neuronal cells, remain ineffective and unable to meet the patients’ needs. Curcumin, a natural plant product found in the Curcuma genus, improves chronic pain by diminishing the release of inflammatory mediators from the spinal glia. This review details the role of curcumin in microglia and astrocytes both in vitro and in vivo and how it improves pain. We also describe the mechanism of curcumin by highlighting the major glia-mediated cascades in pain. Moreover, the role of curcumin on inflammasome and epigenetic regulation is discussed. Furthermore, we discuss the strategies used to improve the efficacy of curcumin. This review illustrates that curcumin modulating microglia and astrocytes could assure the treatment of chronic pain by suppressing spinal neuroinflammation.

Analgesic drugs in a combination-form can achieve greater efficacy with lesser side effects compared to either drug alone. The combination of drugs acting at different targets or mechanisms of action has been recognized as an alternative approach for achieving optimal analgesia. In this study, the analgesic effects of pregabalin (30, 60, 100, 200 mg/kg), curcumin (15, 30, 60, 100, 120 mg/kg), and 1:1 fixed-dose ratio of the pregabalin-curcumin combination were assessed using two acute nociceptive pain models, the acetic acid-induced writhing and tail-flick tests in mice. The pregabalin-curcumin combination produced a dose-dependent decrease in mean of writhes and an increase in the percentage of antinociception by the acetic acid-induced writhing test. In the tail-flick test, the combination also showed an improvement in antinociception indicated by the tail-flick latency, % antinociception, and area under the curve (AUC). Isobolographic analysis of interactions demonstrated a significant synergistic interaction effect between pregabalin and curcumin in both acute nociceptive pain models with the experimental ED50 below the predicted additive line and the combination index < 1. These findings demonstrate that the combination of pregabalin and curcumin exhibits a synergistic interaction in mouse models of acute nociceptive pain.

Curcumin diglutaric acid (CurDG), an ester prodrug of curcumin, has the potential to be developed as an anti-inflammatory agent due to its improved solubility and stability. In this study, the anti-inflammatory effects of CurDG were evaluated. The effects of CurDG on inflammatory mediators were evaluated in LPS-stimulated RAW 264.7 macrophage cells. CurDG reduced the increased levels of NO, IL-6, and TNF- α, as well as iNOS and COX-2 expression in cells to a greater extent than those of curcumin, along with the potent inhibition of MAPK (ERK1/2, JNK, and p38) activity. The anti-inflammatory effects were assessed in vivo by employing a carrageenan-induced mouse paw edema model. Oral administration of CurDG demonstrated significant anti-inflammatory effects in a dose-dependent manner in mice. The effects were significantly higher compared to those of curcumin at the corresponding doses (p < 0.05). Moreover, 25 mg/kg curcumin did not exert a significant anti-inflammatory effect for the overall time course as indicated by the area under the curve data, while the equimolar dose of CurDG produced significant anti-inflammatory effects comparable with 50, 100, and 200 mg/kg curcumin (p < 0.05). Similarly, CurDG significantly reduced the proinflammatory cytokine expression in paw edema tissues compared to curcumin (p < 0.05). These results provide the first experimental evidence for CurDG as a promising anti-inflammatory agent.

The drug treatment for neuropathic pain remains a challenge due to poor efficacy and patient satisfaction. Curcumin has been reported to alleviate neuropathic pain, but its clinical application is hindered by its low solubility and poor oral bioavailability. Curcumin diglutaric acid (CurDG) is a curcumin prodrug with improved water solubility and in vivo antinociceptive effects. In this study, we investigated the anti-inflammatory mechanisms underlying the analgesic effect of CurDG in the chronic constriction injury (CCI)-induced neuropathy mouse model. Repeated oral administration of CurDG at a low dose equivalent to 25 mg/kg/day produced a significant analgesic effect in this model, both anti-allodynic activity and anti-hyperalgesic activity appearing at day 3 and persisting until day 14 post-CCI surgery (p < 0.001) while having no significant effect on the motor performance. Moreover, the repeated administration of CurDG diminished the increased levels of the pro-inflammatory cytokines: TNF-α and IL-6 in the sciatic nerve and the spinal cord at the lowest tested dose (equimolar to 25 mg/kg curcumin). This study provided pre-clinical evidence to substantiate the potential of pursuing the development of CurDG as an analgesic agent for the treatment of neuropathic pain.

In this work, a curcumin-diglutaric acid (CurDG) prodrug was synthesized by conjugation of curcumin with glutaric acid via an ester linkage. The water solubility, partition coefficient, release characteristics, and antinociceptive activity of CurDG were compared to those of curcumin. The aqueous solubility of CurDG (7.48 μg/mL) is significantly greater than that of curcumin (0.068 μg/mL). A study in human plasma showed that the CurDG completely releases curcumin within 2 h, suggesting the ability of CurDG to serve as a prodrug of curcumin. A hot plate test in mice showed the highest antinociceptive effect dose of curcumin at 200 mg/kg p.o., whereas CurDG showed the same effect at an effective dose of 100 mg/kg p.o., indicating that CurDG significantly enhanced the antinociceptive effect compared to curcumin. The enhanced antinociceptive effect of CurDG may be due to improved water solubility and increased oral bioavailability compared to curcumin. [ABSTRACT FROM AUTHOR]

The roots of Cymbidium ensifolium yielded a total of 17 compounds, comprising two new compounds (1-2), one new natural product (3), and 14 known compounds (4-17). The structures of new compounds were determined through the analysis of their spectroscopic data, including NMR, MS, UV, FT-IR, optical rotation, and CD. The anti-inflammatory activity of the isolated pure compounds was assessed using lipopolysaccharide-activated BV2 microglial cells. Compounds 1, 3, 6, 12, 14, and 16 showed the ability to reduce LPS induced NO release in BV2 microglial cells, with IC 50 values of 9.95 ± 2.13, 8.77 ± 3.78, 2.39 ± 0.91, 6.69 ± 2.94, 2.96 ± 1.38, 8.42 ± 2.99 μM, respectively and reduced the secretion of proinflammatory mediators (TNF-α, IL-6, MCP-1) in a concentration-dependent manner. Furthermore, the mechanistic role of the compound 3 was determined, which demonstrated its ability to inhibit the nuclear factor-κB (NF-κB) pathway through decreasing phosphorylation of p65 subunits., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Ethnopharmacological Relevance: Curcuma latifolia Roscoe, a plant in the Curcuma genus, has been used as a food additive and folk medicine in Thailand to treat pelvic pain and improve premenstrual syndrome. Although it has been used for centuries, no scientific studies have proved its potential effects on inflammatory pain and central nervous system (CNS) safety profiles., Aim of the Study: This study aimed to evaluate the potential effects of the ethanolic extract of C. latifolia rhizome on inflammatory pain in mice, together with its CNS safety profiles., Materials and Methods: First, network pharmacology was employed to identify the role of bioactive constituents in C. latifolia on inflammatory pain. In addition, in vitro pharmacology was also evaluated to confirm the anti-inflammatory activity of C. latifolia extract at cellular levels in activated macrophages and microglia. Furthermore, the efficacy of the plant extract in attenuating formalin-induced pain-like behaviors in mice was evaluated. Mice were orally administered the extract (125, 250, 500 mg/kg) followed by the measurement of formalin-induced pain-like behaviors. The LABORAS automated behavioral analysis and rotarod test were used to assess potential CNS side effects of C. latifolia extract (500 mg/kg) in mice., Results: The results demonstrated that major bioactive constituents present in C. latifolia have the ability to regulate multiple targets, biological processes and pathways associated with inflammatory pain as assessed by network pharmacology. C. latifolia modulated peripheral and central immune cells via reducing proinflammatory mediators (NO, TNF-α, and IL-6). C. latifolia extract improved formalin-induced pain-like behaviors in a dose-dependent manner during phase II of the formalin test. The efficacy of the plant extract at doses of 250 and 500 mg/kg was comparable to that of the positive control (indomethacin 10 mg/kg). Furthermore, the highest therapeutic dose of the extract did not affect motor coordination, exploratory behaviors, general behaviors, and overall well-being of mice, indicating no development of potential CNS adverse effects after administration of the extract., Conclusion: These findings provide novel perspectives on using C. latifolia extract for pain management, considering its therapeutic efficacy and CNS safety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Nanotechnology plays an integral role in multimodal analgesia. In this study, we co-encapsulated metformin (Met) and curcumin (Cur) into chitosan/alginate (CTS/ALG) nanoparticles (NPs) at their synergistic drug ratio by applying response surface methodology. The optimized Met-Cur-CTS/ALG-NPs were achieved with Pluronic® F-127 2.33 % (w/v), Met 5.91 mg, and CTS:ALG mass ratio 0.05:1. The prepared Met-Cur-CTS/ALG-NPs had 243 nm particle size, -21.6 mV zeta potential, 32.6 and 44.2 % Met and Cur encapsulations, 19.6 and 6.8 % Met and Cur loading, respectively, and 2.9:1 Met:Cur mass ratio. Met-Cur-CTS/ALG-NPs displayed stability under simulated gastrointestinal (GI) fluid conditions and during storage. In vitro release study of Met-Cur-CTS/ALG-NPs in simulated GI fluids showed sustained release, with Met exhibiting Fickian diffusion and Cur demonstrating non-Fickian diffusion following the Korsmeyer-Peppas model. Met-Cur-CTS/ALG-NPs exhibited increased mucoadhesion and improved cellular uptake in Caco-2 cells. Additionally, Met-Cur-CTS/ALG-NPs exhibited better anti-inflammatory effects in lipopolysaccharide-stimulated RAW 264.7 macrophage and BV-2 microglial cells than the equivalent amount of the Met-Cur physical mixture, indicating a greater ability to modulate peripheral and central immune mechanisms of pain. In the mouse formalin-induced pain model, Met-Cur-CTS/ALG-NPs administered orally exhibited better attenuation of pain-like behaviors and proinflammatory cytokine release compared to the Met-Cur physical mixture. Furthermore, Met-Cur-CTS/ALG-NPs did not induce significant side effects in mice at therapeutic doses. Altogether, the present study establishes a CTS/ALG nano-delivery system for Met-Cur combination against pain with improved efficacy and safety., 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.)

Bacterial meningitis remains one of the most prevalent infectious diseases worldwide. Although advances in medical care have improved mortality and morbidity, neurological complications remain high. Therefore, aside from antibiotics, therapeutic adjuvants targeting neuroinflammation are essential to combat the long-term neuronal sequelae of bacterial meningitis. In the present study, we propose (-)-dendroparishiol as a potential add-on therapy to improve neuroinflammation associated with bacterial meningitis. The biological activity of (-)-dendroparishiol was first predicted by computational analysis and further confirmed in vitro using a cell-based assay with LPS-induced BV-2 microglial cells. Biological pathways involved with (-)-dendroparishiol were identified by applying network pharmacology. Computational predictions of biological activity indicated possible attenuation of several inflammatory processes by (-)-dendroparishiol. In LPS-induced BV-2 microglial cells, (-)-dendroparishiol significantly reduced the expression of inflammatory mediators: iNOS, NO, COX-2, IL-6, and TNF-α. Molecular docking results demonstrated the potential iNOS and COX-2 inhibitory activity of (-)-dendroparishiol. Network pharmacological analysis indicated the plausible role of (-)-dendroparishiol in biological processes involved in oxidative stress and neuroinflammation with enrichment in neuroinflammatory pathways. Overall, this study provides scientific evidence for the potential application of (-)-dendroparishiol in the management of bacterial meningitis-associated neuroinflammation.

Central nervous system (CNS) diseases are a significant health burden globally, with the development of novel drugs lagging behind clinical needs. Orchidaceae plants have been traditionally used to treat CNS diseases, leading to the identification of therapeutic leads against CNS diseases from the Aerides falcata orchid plant in the present study. The study isolated and characterized ten compounds, including a previously undescribed biphenanthrene derivative, Aerifalcatin (1), for the first time from the A. falcata extract. The novel compound 1 and known compounds, such as 2,7-dihydroxy-3,4,6-trimethoxyphenanthrene (5), agrostonin (7), and syringaresinol (9), showed potential activity in CNS-associated disease models. Notably, compounds 1, 5, 7, and 9 demonstrated the ability to alleviate LPS-induced NO release in BV-2 microglial cells, with IC 50 values of 0.9, 2.5, 2.6, and 1.4 μM, respectively. These compounds also significantly inhibited the release of pro-inflammatory cytokines, IL-6 and TNF-α, reflecting their potential anti-neuroinflammatory effects. Additionally, compounds 1, 7, and 9 were found to reduce cell growth and migration of glioblastoma and neuroblastoma cells, indicating their potential use as anticancer agents in the CNS. In summary, the bioactive agents isolated from the A. falcata extract offer plausible therapeutic options for CNS diseases., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Background: Clerodendrum petasites , an herbal plant in Thailand, has been used for many years in folk medicine. However, scientific evidence regarding CNS safety pharmacology and antinociceptive activity of C. petasites (CP) has not yet been well characterized., Purpose: The present study aimed to assess the CNS safety pharmacology and antinociceptive and antiinflammatory effects of CP extract., Methods: The effect of CP extract on CNS safety pharmacology was assessed using LABORAS automated home cage monitoring and rotarod test. Its pharmacological activity was evaluated both in-vitro, and in-vivo using hot-plate, acetic acid-induced writhing, formalin, and carrageenan-induced paw edema models., Results and Conclusion: CP extract significantly improved thermal and chemical nociceptive behaviors and acute inflammatory pain at all doses: 300, 600, and 1200 mg/kg, p.o. The antiinflammatory effect of CP extract in inflammatory pain models was comparable to the effect of positive control: indomethacin 10 mg/kg at all dose levels tested. Further, the CP extract at 600 mg/kg dose significantly inhibited 82.3% of carrageenan-induced total edema. In-vitro, CP extract at 12.5, 25, and 50 μg/mL concentrations significantly reduced the expression of LPS-induced nitric oxide, IL-6, and TNF-α expression in both RAW 264.7 macrophage and BV-2 microglial cell lines. In addition, CP extract did not show any potential effects on the CNS, indicated by no significant effects on motor coordination, spontaneous locomotor activity, general behaviors, and well-being compared to vehicle-treated mice (p > 0.05). Overall, the present study evidences the potential antinociceptive, antiinflammatory efficacies of CP extract with a favorable CNS safety profile., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Background/aim: Fine particulate matter (PM 2.5 ) in air pollution causes skin damage through the induction of oxidative stress in the epidermis. Antioxidants help counteract cellular oxidant species and maintain cell homeostasis. This study aimed to examine the protective effect of standardized ethanolic extract of Thunbergia laurifolia leaves on PM 2.5 -mediated oxidative stress in epidermal keratinocytes., Materials and Methods: The extract was standardized with rosmarinic acid. Effects of standardized T. laurifolia extract (STLE) (0-400 μg/ml) and PM 2.5 (0-32 μg/ml) on cell viability after 24 h of treatment were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. PM 2.5 (0-32 μg/ml) induction of intracellular reactive oxygen species (ROS) at 6 h was monitored using 2',7'-dichlorodihydrofluorescein diacetate. Cells were co-treated for 6 h with PM 2.5 (32 μg/ml) and STLE (25-100 μg/ml) and monitored for oxidative stress inhibition. Proteins related to cellular antioxidant defense system were examined by western blot analysis, after co-treatment and STLE treatment for 6 h and 24 h, respectively. Nuclear expression of nuclear factor erythroid 2-related factor (NRF2) and p62 were determined by immunofluorescence after co-treatment of 6 h., Results: PM 2.5 (32 μg/ml) remarkably induced ROS production within 6 h. The co-treatment dramatically inhibited PM 2.5 -induced oxidative stress at 6 h. In addition, STLE enhanced cellular defense system by increasing the levels of p62, NRF2 and superoxide dismutase 1 proteins. STLE stimulated nuclear localization and function of NRF2 and p62 proteins, while suppressing Kelch-like ECH-associated protein 1., Conclusion: STLE exhibits promising natural antioxidant activity against oxidative stress induced by PM 2.5 in keratinocytes., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Ethnopharmacological Relevance: Ben-Cha-Moon-Yai (BMY) remedy used in Thai traditional medicine as an anti-inflammatory, analgesic, and antipyretic agent compromises five herbal root extracts of equal weights: Aegle marmelos (L.) Corrêa (AM), Oroxylum indicum (L.) Kurz (OI), Dimocarpus longan Lour. (DL), Dolichandrone serrulata (Wall. ex DC.) Seem. (DS), and Walsura trichostemon Miq. (WT)., Aim of the Study: To assess the anti-nociceptive and anti-inflammatory effects of the root extracts of all five species of BMY in experimental animal (mouse) models to ensure the rational use of herbal products in Thai traditional medicine., Materials and Methods: Root extracts prepared by ethanol and water extraction were used for the biological assays in animal models at five dose levels: 25, 50,100,200 & 400 mg/kg. The anti-nociceptive activity was evaluated based on hot-plate latency, duration of paw licking induced by formalin, and abdominal writhing induced by acetic acid. Carrageenan- and prostaglandin-induced paw oedema models were used to determine the anti-inflammatory activity., Results: The oral administration of AM, DS and WT root extracts displayed significant analgesic effects in the hot-plate test, both phases (early and late) of formalin test and acetic-acid induced writhing test at different dose levels. OI and DL only produced significant analgesia in the late phase of the formalin test and writhing test. The pretreatment of animals with the non-selective opioid receptor antagonist naloxone, reverse AM, DS and WT induced-antinociceptive activity. In both carrageenan and prostaglandin-induced paw oedema tests, all five herbal plant root extracts significantly reduced paw oedema at 3 h or more at different dose levels. Rotarod test results showed no effects of five herbal plant root extracts on the balance and the motor coordination at the highest dose level evaluated (400 mg/kg)., Conclusion: The root extracts of AM, DS, and WT possess both central and peripheral anti-nociceptive properties, while OI and DL possess only peripheral analgesic properties. All five root extracts own anti-inflammatory properties, which might be due to their activity on the prostaglandin system. Altogether these findings ensure the rational use of BMY remedy in Thai traditional medicine., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: To develop and validate a gout flare risk stratification tool for people with gout hospitalized for non-gout conditions., Methods: The prediction rule for inpatient gout flare was derived from a cohort of 625 hospitalized people with comorbid gout from New Zealand. The rule had four items: no pre-admission gout flare prophylaxis, no pre-admission urate-lowering therapy, tophus and pre-admission serum urate >0.36 mmol/l within the previous year (GOUT-36 rule). Two or more items are required for the classification of high risk for developing inpatient gout flares. The GOUT-36 rule was validated in a prospective cohort of 284 hospitalized people with comorbid gout from Thailand and China., Results: The GOUT-36 rule had a sensitivity of 75%, specificity of 67% and area under the curve of 0.71 for classifying people at high risk for developing inpatient gout flares. Four risk groups were developed: low (no items), moderate (one item), high (two items) and very high risk (three or four items). In a population with frequent (overall 34%) in-hospital gout flares, 80% of people with very high risk developed inpatient flares while 11% with low risk had inpatient flares., Conclusion: The GOUT-36 rule is simple and sensitive for classifying people with high risk for inpatient gout flares. The rule may help inform clinical decisions and future research on the prevention of inpatient gout flares., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Curcumin is a polyphenol compound that alleviates several neuroinflammation-related diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and cerebral injury. However, the therapeutic efficacy of curcumin is limited by its poor physicochemical properties. The present study aimed to develop a new carrier-linked curcumin prodrug, curcumin diethyl γ-aminobutyrate (CUR-2GE), with improved physicochemical and anti-neuroinflammatory properties. CUR-2GE was designed and synthesized by conjugating curcumin with gamma-aminobutyric acid ethyl ester (GE) via a carbamate linkage. The carbamate linkage was selected to increase stability at acidic pH while GE served as a promoiety for lipophilic enhancement. The synthesized CUR-2GE was investigated for solubility, partition coefficient, stability, and bioconversion. The solubility of CUR-2GE was less than 0.05 μg/mL similar to that of curcumin, while the lipophilicity with log P of 3.57 was significantly increased. CUR-2GE was resistant to chemical hydrolysis at acidic pH (pH 1.2 and 4.5) as anticipated but rapidly hydrolyzed at pH 6.8 and 7.4. The incomplete hydrolysis of CUR-2GE was observed in simulated gastrointestinal fluids which liberated the intermediate curcumin monoethyl γ-aminobutyric acid (CUR-1GE) and the parent curcumin. In plasma, CUR-2GE was sequentially converted to CUR-1GE and curcumin within 1 h. In lipopolysaccharide (LPS)-stimulated BV-2 microglial cells, CUR-2GE effectively attenuated the pro-inflammatory mediators by decreasing the secretion of nitric oxide and cytokines (TNF-α and IL-6) to a greater extent than curcumin due to an increase in cellular uptake. Altogether, the newly developed acid-stable CUR-2GE prodrug is a potential pre-clinical and clinical candidate for further evaluation on neuroprotective and anti-neuroinflammatory effects., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The effect of coffee on serum uric acid (SUA) has shown conflicting results. This study was to determine the effects of caffeinated coffee (CC) and decaffeinated coffee (DC) on SUA, serum xanthine oxidase activity (sXOA) and urine uric acid clearance (UAC)., Methods: This was a prospective randomised within-subject experimental study design of 51 healthy male participants. Each study period consisted of 3 periods, including a control, an intervention, and washout period for 1, 3 and 1 week, respectively. During the intervention period, the participants received 2, 4 or 6 gram/day of coffee, either CC or DC., Results: For DC groups, SUA significantly decreased by 6.5 (±1.1) mg/dL to 6.2 (±1.1) mg/dL during the intervention period (p=0.014). sXOA significantly increased by 0.05 (±0.07) nmol/min/mL to 0.20 (±0.38) nmol/min/mL during the intervention period (p=0.010) of CC. For UAC, there was no significant change with CC or DC. In hyperuricaemic participants, SUA significantly decreased by 7.7 (±0.7) mg/dL to 7.2 (±0.7) mg/dL during the intervention period (p=0.028) of DC. For non-hyperuricaemic, CC significantly increased SUA by 5.9 (±0.7) mg/dL to 6.2 (±0.9) mg/dL during the intervention period (p=0.008) and significantly decreased SUA to 6.0 (±0.8) mg/dL (p=0.049) during the withdrawal period. A significant increase of sXOA according with SUA in CC groups from 0.05 (±0.07) nmol/min/mL to 0.25 (±0.44) nmol/min/mL during the intervention period (p=0.040) was presented in non-hyperuricaemic participants., Conclusions: DC had a significant decrease of SUA during the intervention period. However, in non-HUS participants, SUA significantly increased in CC.

Neuropathic pain is a debilitating chronic pain condition, and its treatment remains a clinical challenge. Curcumin, a naturally occurring phenolic compound, possesses diverse biological and pharmacological effects but has not yet been approved as a drug due to its low bioavailability. In order to overcome this limitation, we synthesized a potential ester prodrug of curcumin, curcumin diethyl diglutarate (CurDDG). In this study, we evaluated the pharmacological advantages of CurDDG over curcumin in a mouse model of chronic constriction injury (CCI), and the anti-inflammatory effect of CurDDG in LPS-induced RAW 264.7 macrophage cells was accessed to clarify the underline mechanism. Mice were treated with various oral doses of curcumin (25, 50, 100 and 200 mg/kg/day, daily for 14 days) or equimolar doses of CurDDG. CurDDG at all doses tested significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia compared with the CCI-control group. CurDDG at 25, 50 and 100 mg/kg demonstrated significantly greater efficacy on both mechanical and thermal hypersensitivities compared to that of curcumin. The effect of CurDDG correlated well with the inhibition of TNF-α and IL-6 levels in both the sciatic nerve and the spinal cord, as compared to its respective control groups. Similarly, in the in vitro study, CurDDG significantly reduced the LPS-induced expression of TNF-α and IL-6. Moreover, CurDDG significantly decreased COX-2 and iNOS levels and attenuated p38, JNK, and ERK1/2 phosphorylation as compared to the curcumin-treated cells. Altogether, this study demonstrated the improved pharmacological effects of curcumin by its diglutarate conjugate, CurDDG., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Analgesic drugs in a combination-form can achieve greater efficacy with lesser side effects compared to either drug alone. The combination of drugs acting at different targets or mechanisms of action has been recognized as an alternative approach for achieving optimal analgesia. In this study, the analgesic effects of pregabalin (30, 60, 100, 200 mg/kg), curcumin (15, 30, 60, 100, 120 mg/kg), and 1:1 fixed-dose ratio of the pregabalin-curcumin combination were assessed using two acute nociceptive pain models, the acetic acid-induced writhing and tail-flick tests in mice. The pregabalin-curcumin combination produced a dose-dependent decrease in mean of writhes and an increase in the percentage of antinociception by the acetic acid-induced writhing test. In the tail-flick test, the combination also showed an improvement in antinociception indicated by the tail-flick latency, % antinociception, and area under the curve (AUC). Isobolographic analysis of interactions demonstrated a significant synergistic interaction effect between pregabalin and curcumin in both acute nociceptive pain models with the experimental ED 50 below the predicted additive line and the combination index < 1. These findings demonstrate that the combination of pregabalin and curcumin exhibits a synergistic interaction in mouse models of acute nociceptive pain.