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1.
Life Sci ; 340: 122441, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38253309

ABSTRACT

Although nalbuphine, a semi-synthetic analgesic compound, is less potent than morphine in terms of alleviating severe pain, our recent findings have revealed that nalbuphine-6-glucuronide (N6G), one of the glucuronide metabolites of nalbuphine, promotes a significantly more robust analgesic effect than its parent drug. Nevertheless, despite these promising observations, the precise mechanisms underlying the analgesic effects of nalbuphine glucuronides have yet to be determined. In this study, we aim to elucidate the mechanisms associated with the analgesic effects of nalbuphine glucuronides. Pharmacokinetic and pharmacodynamic studies were conducted to investigate the relationship between the central and peripheral compartments of nalbuphine and its derivatives. The analgesic responses of these compounds were evaluated based on multiple behavioral tests involving thermal and mechanical stimuli. Radioligand binding assays were also performed to determine the binding affinity and selectivity of these compounds for different opioid receptors. The results of these tests consistently confirmed that the heightened analgesic effects of N6G are mediated through its enhanced binding affinity for both mu- and kappa-opioid receptors, even comparable to those of morphine. Notably, N6G exhibited fewer side effects and did not induce sudden death, thereby highlighting its superior safety profile. Additionally, pharmacokinetic studies indicated that N6G could cross the blood-brain barrier when administered peripherally, offering pain relief. Overall, N6G provides great analgesic efficacy and enhanced safety. These findings highlight the potential value of nalbuphine glucuronides, particularly N6G, as promising candidates for the development of novel analgesic drugs.


Subject(s)
Nalbuphine , Receptors, Opioid, kappa , Humans , Nalbuphine/adverse effects , Receptors, Opioid, mu , Glucuronides/therapeutic use , Analgesics/pharmacology , Analgesics/therapeutic use , Receptors, Opioid/metabolism , Morphine/adverse effects , Pain/drug therapy , Pain/chemically induced , Analgesics, Opioid/therapeutic use
2.
J Org Chem ; 88(14): 9946-9958, 2023 07 21.
Article in English | MEDLINE | ID: mdl-37410072

ABSTRACT

3-O-ß-Glucuronide triterpenes are plant-derived compounds. Some of them have been used as herbal medicine and in pharmaceuticals, such as chikusetsu saponins and Quillaja saponins. However, the demand for these materials has remained largely a challenge owing to their natural scarcity and low-yielding purification process. Therefore, a chemical triterpene 3-O-glucuronidation was conducted in this study to alleviate the surging demand on natural source. Various glucuronyl imidate donors and oleanane-type triterpene acceptors were synthesized, and the relative reactivity values (RRV) and acceptor nucleophilic constants (Aka) were systematically measured to study their influence on glucuronidation yield. As a result, applying donors in higher RRV value generally improved the production of 3-O-glucuronide triterpenes. Meanwhile, a bulky pivaloyl group was an ideal 2-O-protection to provide ß-selectivity and prevented side reactions, including orthoester formation and acyl-transfer reaction. Collectively, a positive correlation was observed between reactive donors/acceptors and improved glucuronidation yields. These findings offered insights on the influence of donors' and acceptors' reactivities on 3-O-ß-glucuronide triterpenes synthesis, and this knowledge would help to access saponins of interest to address future needs.


Subject(s)
Plants, Medicinal , Saponins , Triterpenes , Triterpenes/chemistry , Glucuronides , Plants, Medicinal/chemistry , Saponins/chemistry , Plant Extracts/chemistry
4.
J Med Chem ; 64(8): 4450-4461, 2021 04 22.
Article in English | MEDLINE | ID: mdl-33819035

ABSTRACT

Overexpression of glucose transporters (GLUTs) in colorectal cancer cells is associated with 5-fluorouracil (1, 5-FU) resistance and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting drug conjugate, triggered by glutathione in the tumor microenvironment, that releases 5-FU and GLUTs inhibitor (phlorizin (2) and phloretin (3)). Using an orthotopic colorectal cancer mice model, we showed that the conjugate exhibited better antitumor efficacy than 5-FU, with much lower exposure of 5-FU during treatment and without significant side effects. Our study establishes a GLUT-targeting theranostic incorporating a disulfide linker between the targeting module and cytotoxic payload as a potential antitumor therapy.


Subject(s)
Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemistry , Glucose Transport Proteins, Facilitative/antagonists & inhibitors , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Disease Models, Animal , Drug Stability , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Fluorouracil/therapeutic use , Glucose Transport Proteins, Facilitative/metabolism , Half-Life , Humans , Mice , Mice, Inbred BALB C , Phloretin/chemistry , Phloretin/metabolism , Phloretin/therapeutic use , Phlorhizin/chemistry , Phlorhizin/metabolism , Phlorhizin/therapeutic use , Structure-Activity Relationship , Tissue Distribution
5.
Arch Gerontol Geriatr ; 95: 104338, 2021.
Article in English | MEDLINE | ID: mdl-33652335

ABSTRACT

BACKGROUND: The association between type 2 diabetes mellitus (T2DM) and sarcopenia has been reported before, but little was known regarding associations between albuminuria status in the development of sarcopenia. This study aimed to explore the associations between albuminuria status and sarcopenia among older patients with T2DM. METHODS: This cross-sectional study recruited T2DM patients aged 65 years and older from the DM shared care center in a regional hospital who were grossly absent from functional impairment. Demographic characteristics were collected and functional assessments were performed for all participants. Urinary albumin-to-creatinine ratio (UACR) was obtained by spot urine exams, whereas UACR ≥ 30 mg/g was defined as microalbuminuria, and UACR > 300 mg/g as macroalbuminuria. Appendicular lean mass (ASM) was measured by the dual X-ray absorptiometry, and the relative appendicular muscle mass (RASM) was calculated as the ASM divided by height square (kg/m2).The definition of sarcopenia was made according to the Asian Working Group for Sarcopenia and muscle quality was defined as handgrip strength (kg) divided by RASM. RESULTS: Overall, 180 participants (mean age: 72.5±5.3 years, 53.3% males) were enrolled for study. Higher HbA1c levels and poorer renal function were significantly associated with more severe albuminuria status.Besides, sarcopenia and low handgrip strength also showed dose-responsive associations with albuminuria status, which was similar in muscle quality.The receiver operating characteristic curve determine that the UACR of 13.7 mg/g was the optimal cutoff for sarcopenia diagnosis, which was lower than the conventionally definition of microalbuminuria (<30 mg/g). CONCLUSIONS: Albuminuria status was dose-responsively associated with sarcopenia among older persons with T2DM, and the risk started to escalate from minimal albuminuria (UACR 9.18 mg/g in men and 18.4 mg/g in women). Further intervention studies are needed to evaluate potential benefits of better diabetes control in preventing sarcopenia and its outcomes.


Subject(s)
Diabetes Mellitus, Type 2 , Sarcopenia , Aged , Aged, 80 and over , Albuminuria , Cross-Sectional Studies , Female , Hand Strength , Humans , Male
6.
Nutrients ; 11(12)2019 Nov 28.
Article in English | MEDLINE | ID: mdl-31795130

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic disorders, including hepatic lipid accumulation and lipotoxicity. Plant-derived polyphenols have attracted considerable attention in the prevention of NAFLD. Lotus seedpod, rich in polyphenols, is a traditional Chinese herbal medicine. Previous studies have showed that lotus seedpod possess radioprotective, antioxidant, anti-cancer, and anti-inflammatory activities. In this study, the in vitro hepatoprotective effect of lotus seedpod extract (LSE) and its main component epigallocatechin (EGC) was examined. Firstly, oleic acid (OA), an unsaturated fatty acid, was used to induce the phenotype of NAFLD in human hepatocytes, HepG2 cells. LSE dose-dependently improved the OA-induced viability loss of HepG2 cells. Non-cytotoxic concentrations of LSE or EGC abolished intracellular lipid accumulation and oxidative stress in the OA-treated cells. In addition, LSE and EGC showed a minor effect on autophagy, and potential in reducing OA-induced occurrence of apoptosis confirmed by morphological and biochemical features, including an increase in the formation of apoptotic bodies, the exposure of phosphatidylserine, and activation of caspases. Molecular data showed the anti-apoptotic effect of LSE might be mediated via downregulation of the mitochondrial pathway. Our data imply that EGC-enriched LSE potentially could be developed as an anti-NAFLD agent.


Subject(s)
Hepatocytes/drug effects , Hepatocytes/metabolism , Lipid Metabolism/drug effects , Lipids/toxicity , Plant Extracts/pharmacology , Hep G2 Cells , Humans , Plant Extracts/chemistry , Reactive Oxygen Species
7.
Eur J Med Chem ; 178: 544-551, 2019 Sep 15.
Article in English | MEDLINE | ID: mdl-31212133

ABSTRACT

Nalbuphine, a partial agonist/antagonist opioid analgesic, is structurally related to morphine. It is equipotent to morphine and has no serious side effects. In the past few decades, studies focusing on morphine metabolism have indicated that one of its sugar-conjugated metabolites, morphine-6-glucuronide, exerts a higher analgesic effect than its parent drug. Considering that nalbuphine is a morphine analog that follows a similar metabolic scheme, nalbuphine glucuronides were synthesized in this study and their potential analgesic effects were assessed. Nalbuphine-3-glucuronide (N3G) and nalbuphine-6-glucuronide (N6G) were synthesized based on Schmidt's glycosylation with OPiv protections on the glycosyl donor. In a pharmacodynamic study, paw pressure and cold-ethanol tail-flick tests were conducted in rats to evaluate the analgesic response after intracisternal and intraperitoneal administrations of nalbuphine, N3G, or N6G. The antinociceptive response was evaluated for each compound by calculating the area under the curve and the duration spent at greater than 50% maximum possible analgesia. In conclusion, intracisternal administration of N6G exhibited a stronger analgesic response than nalbuphine in the pain tests after both cold and mechanical stimuli, but N3G had no obvious effect. Similar to that of morphine, the glucuronide metabolite of nalbuphine at the 6-O-position exerted at least three-fold higher antinociceptive potency and five-fold longer analgesic duration than nalbuphine.


Subject(s)
Analgesics, Opioid/pharmacology , Glucuronides/pharmacology , Pain Threshold/drug effects , Pain/drug therapy , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistry , Animals , Dose-Response Relationship, Drug , Glucuronides/chemical synthesis , Glucuronides/chemistry , Male , Molecular Structure , Pain Measurement , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
8.
Front Plant Sci ; 10: 1719, 2019.
Article in English | MEDLINE | ID: mdl-32038688

ABSTRACT

Flowering plants have evolved two distinct clades of chloroplast GrpE homologues (CGEs), which are the nucleotide exchange factor for Hsp70. In Arabidopsis, they are named AtCGE1 (At5g17710) and AtCGE2 (At1g36390). Characterization of their corresponding T-DNA insertion mutants revealed that there is no visible change in phenotype except a defect in protein import in an AtCGE2-knockout mutant under normal growth conditions. However, the embryo development of an AtCGE1-knockout mutant was arrested early at the globular stage. An AtCGE1-knockdown mutant, harboring a T-DNA insertion in the 5'-UTR region, exhibited growth retardation and protein import defect, and its mutant phenotypes became more severe when AtCGE2 was further knocked out. Sub-organellar distribution implied that AtCGE2 might be important for membrane biology due to its preferential association with chloroplast membranes. Biochemical studies and complementation tests showed that only AtCGE1, but not AtCGE2, can effectively rescue the heat-sensitive phenotype of Escherichia coli grpE mutant and robustly stimulate the refolding of denatured luciferase by DnaK. Interestingly, AtCGE1 and AtCGE2 are tending to form heterocomplexes, which exhibit comparable co-chaperone activity to AtCGE1 homocomplexes. Our data indicate that AtCGE1 is the principle functional homologue of GrpE. The possibility that AtCGE2 has a subsidiary or regulatory function through homo- and/or hetero-oligomerization is discussed.

9.
J Org Chem ; 83(7): 3688-3701, 2018 04 06.
Article in English | MEDLINE | ID: mdl-29512381

ABSTRACT

This study examines the utility of the N-benzylcarbamoyl (BnCar) protecting group in glycosylation reactions of the parent O-2 protected carbohydrate donor. It was found that the BnCar group imparted exclusively ß-selectivity with primary and secondary alcohols. A mechanistic study revealed the activated intermediate to be the glycosyl triflate in a skew conformation, which results in ß-selective glycosylation via an SN2-like pathway. The BnCar group can be readily cleaved using tetrabutylammonium nitrite, without affecting ester and ether protecting groups. Taken together, these results show BnCar to be useful for the synthesis of complex oligosaccharides, an undertaking that requires delicate chemical differentiation of various protecting groups.

10.
Front Plant Sci ; 8: 2079, 2017.
Article in English | MEDLINE | ID: mdl-29259618

ABSTRACT

The proton gradient established by the pH difference across a biological membrane is essential for many physiological processes, including ATP synthesis and ion and metabolite transport. Currently, ionophores are used to study proton gradients, and determine their importance to biological functions of interest. Because of the lack of an easy method for monitoring the proton gradient across the inner envelope membrane of chloroplasts (ΔpHenv), whether the concentration of ionophores used can effectively abolish the ΔpHenv is not proven for most experiments. To overcome this hindrance, we tried to setup an easy method for real-time monitoring of the stromal pH in buffered, isolated chloroplasts by using fluorescent pH probes; using this method the ΔpHenv can be calculated by subtracting the buffer pH from the measured stromal pH. When three fluorescent dyes, BCECF-AM [2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester], CFDA-SE [5(6)-Carboxyfluorescein diacetate succinimidyl ester] and SNARF-1 carboxylic acid acetate succinimidyl ester were incubated with isolated chloroplasts, BCECF-AM and CFDA-SE, but not the ester-formed SNARF-1 were taken up by chloroplasts and digested with esterase to release high levels of fluorescence. According to its relatively higher pKa value (6.98, near the physiological pH of the stroma), BCECF was chosen for further development. Due to shielding of the excitation and emission lights by chloroplast pigments, the ratiometric fluorescence of BCECF was highly dependent on the concentration of chloroplasts. By using a fixed concentration of chloroplasts, a highly correlated standard curve of pH to the BCECF ratiometric fluorescence with an r-square value of 0.98 was obtained, indicating the reliability of this method. Consistent with previous reports, the light-dependent formation of ΔpHenv can be detected ranging from 0.15 to 0.33 pH units upon illumination. The concentration of the ionophore nigericin required to collapse the ΔpHenv was then studied. The establishment of a non-destructive method of monitoring the stromal pH will be valuable for studying the roles of the ΔpHenv in chloroplast physiology.

11.
Chem Asian J ; 8(12): 3191-9, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24039058

ABSTRACT

The total synthesis of a glycoglycerolipid isolate of Meiothermus taiwanensis and its truncated structural analogues is reported. Our synthesis employed DMF-modulated and low-concentration glycosylation reactions for the construction of α- and ß-glycosidic bonds in the absence of participating protecting groups. Further simplification of the synthesis was achieved by employing a low-concentration one-pot glycosylation procedure. Preliminary immunological studies showed that one of the truncated structural analogues suppressed the cytokine production of THP-1 monocytes.


Subject(s)
Deinococcus/chemistry , Glycolipids/chemical synthesis , Glycolipids/immunology , Cell Line , Cytokines/biosynthesis , Cytokines/drug effects , Cytokines/immunology , Dose-Response Relationship, Drug , Glycolipids/chemistry , Glycosylation , Humans , Lipopolysaccharides/pharmacology , Molecular Conformation , Structure-Activity Relationship
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