A patent review of berberine and its derivatives with various pharmacological activities (2016-2020).
TL;DR: There is a lack of research related to the biomolecular targets of BBR, which directly restricts the development of berberine in the pharmaceutical field, and the increasing number of patents involving biomolescular targets in BBR’s patent applications will be published as its related pharmacological mechanisms are further deciphered.
Abstract: Introduction Berberine (BBR), as one of the outstanding representatives of isoquinoline alkaloids, has been used as an antibacterial drug for a long time in China since ancient times. Currently, a large number of studies have been reported that berberine has a wide spectrum of pharmacological activities, such as anti-tumor, anti-inflammatory, hypoglycemic, hypolipidemic, anti-obesity, and the like. Areas covered This review systematically discussed important patents on berberine and berberine derivatives in terms of pharmacological activity between 2016 and 2020. These patents were mainly searched through the European Patent Office database and Web of Science. These berberine patents (~41) cover a wide range of applications, mainly including antitumor, anti-inflammatory, antibacterial, anti-metabolic disorder, and other newly reported pharmacological activities. Expert opinion Berberine is an important lead compound with great potential for optimization in drug development. However, there is a lack of research related to the biomolecular targets of BBR, which directly restricts the development of berberine in the pharmaceutical field. The problems involved with poor bioavailability and cytotoxicity are also worth considering in the development of berberine-based drugs. Accordingly, the increasing number of patents involving biomolecular targets in BBR's patent applications will be published as its related pharmacological mechanisms are further deciphered.
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TL;DR: Barberry fruit (BF) extract has a long history as a folk remedy due to its antimicrobial, anti-inflammatory, antioxidant, and cholagogic properties as discussed by the authors .
13 citations
TL;DR: In this article , the role of berberine (BBR) as an inhibitor of the major facilitator superfamily (MFS) efflux pump MdfA was evaluated in a recombinant E. coli reporter strain.
Abstract: In this work, we evaluated the role of berberine (BBR) as an inhibitor of the MFS efflux pump MdfA from E. coli. We demonstrated that low levels of BBR significantly increased intracellular ciprofloxacin concentrations and restored antibiotic susceptibility of the reporter strain. ABSTRACT Infections by Gram-negative pathogens are usually difficult to manage due to the drug export by efflux pumps. With the evolution and horizontal transfer of efflux pumps, there is an urgent need to discover safe and effective efflux pump inhibitors. Here, we found that the natural compound berberine (BBR), a traditional medicine for intestinal infection, is an inhibitor against the major facilitator superfamily (MFS) efflux pump MdfA in Escherichia coli. The impact of BBR on MdfA was evaluated in a recombinant E. coli reporter strain. We demonstrated that low levels of BBR significantly increased intracellular ciprofloxacin concentrations and restored antibiotic susceptibility of the reporter strain. At the same time, we conducted molecular dynamics simulations to investigate the mechanisms of BBR’s effect on MdfA. Our data indicated that BBR can aggregate to the periplasmic and cytoplasmic sides of MdfA in both of its inward and outward conformations. Protein rigidities were affected to different degrees. More importantly, two major driving forces for the conformational transition, salt bridges and hydrophilic interactions with water, were changed by BBR’s aggregation to MdfA, which affected its conformational transition. In summary, our data provide evidence for the extended application of BBR as an efflux pump inhibitor at a clinically meaningful level. We also reveal the mechanisms and provide insights into BBR’s effect on the reciprocal motion of MdfA. IMPORTANCE In this work, we evaluated the role of berberine (BBR) as an inhibitor of the MFS efflux pump MdfA from E. coli. We demonstrated that low levels of BBR significantly increased intracellular ciprofloxacin concentrations and restored antibiotic susceptibility of the reporter strain. Molecular dynamics simulations revealed the effect of BBR on the conformational transition of MdfA. Our data suggested that driving forces for MdfA’s conformational transition were affected by BBR and provided evidence for BBR’s extended application as an effective inhibitor of MdfA.
2 citations
TL;DR: The quality of the clinical trials that investigated the effects of berberine, cinnamon, or fenugreek seeds on glucose and lipid metabolism in prediabetes and diabetes was assessed and they were not efficacious enough to support their use in clinical decision making.
Abstract: The prevalence of diabetes is increasing. Several antidiabetic drugs are available to treat the disease, however, none has been effective in halting the progression decline in β-cell function and insulin sensitivity. Plant-derived nutraceuticals provide therapeutic potential and are widely used in integrative medicine. However, clinical trials that evaluated the efficacy of antidiabetic nutraceuticals have been inconsistent in their findings. This study assessed the quality of the clinical trials that investigated the effects of berberine, cinnamon, or fenugreek seeds on glucose and lipid metabolism. Five databases (UB Wahlstrom, PubMed, Cochrane Library, CINAHL, and Science Direct) were systematically searched for randomized controlled studies that investigated the effects of berberine, cinnamon, or fenugreek seeds on glucose and lipid metabolism in prediabetes and diabetes. Forty-three studies (11, 20, 12 on berberine, cinnamon, and fenugreek, respectively), involving 3, 459 study participants were retrieved. The studies were appraised for trial quality using the Jadad scale and the CONSORT checklist. The included berberine, cinnamon, and fenugreek studies had a Jadad score of 3.2, 3.4, and 2.4, respectively. The studies, combined, had a Jadad score of 2.98 and only 62.7% had a score ≥3. Appraisal for reporting quality showed that 33% of the trials were identified in the title or abstract as randomized. Allocation concealment, random sequence generation, and baseline demographics and clinical characteristics were reported in 35, 44 and 74% of the trials, respectively. The included studies had suboptimal methodological and reporting qualities. The studies were not efficacious enough to support their use in clinical decision making. Further RTCs with emphasis on methodological and reporting quality and comparative effectiveness need to be conducted to determine efficacious conclusions. Disclosure I. Abdi: None.
2 citations
Patent•
30 Jan 2016
TL;DR: In this article, a statin compound and berberine are chemically synthesized into salt, and the problems that water solubility of statin medicine is poor, oral bioavailability is low, and full play of efficacy is restricted are solved.
Abstract: The invention discloses a preparation method and medical application of a statin berberine conjugate. A statin compound and berberine are chemically synthesized into salt, and the problems that water solubility of statin medicine is poor, oral bioavailability is low, and full play of efficacy is restricted are solved. The problems that water solubility of berberine hydrochloride is low, lipid solubility is low, malabsorption of the gastrointestinal tract is caused, oral bioavailability is low, and the whole-body treatment effect is influenced are also solved. The statin berberine conjugate is mainly applied to products for preventing and/or treating diseases or symptoms related to hyperlipidemia. The invention further relates to products used for preventing and/or treating the diseases or the symptoms related to hyperlipidemia.
1 citations
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TL;DR: The findings suggest that berberine and metformin showed similarity in modulating the gut microbiota, including the enrichment of SCFA-producing bacteria and reduction of microbial diversity, which may contribute to their beneficial effects to the host.
Abstract: Accumulating evidence suggests that the gut microbiota is an important factor in mediating the development of obesity-related metabolic disorders, including type 2 diabetes. Metformin and berberine, two clinically effective drugs for treating diabetes, have recently been shown to exert their actions through modulating the gut microbiota. In this study, we demonstrated that metformin and berberine similarly shifted the overall structure of the gut microbiota in rats. Both drugs showed reverting effects on the high-fat diet-induced structural changes of gut microbiota. The diversity of gut microbiota was significantly reduced by both berberine- and metformin-treatments. Nearest shrunken centroids analysis identified 134 operational taxonomic units (OTUs) responding to the treatments, which showed close associations with the changes of obese phenotypes. Sixty out of the 134 OTUs were decreased by both drugs, while those belonging to putative short-chain fatty acids (SCFA)-producing bacteria, including Allobaculum, Bacteriodes, Blautia, Butyricoccus, and Phascolarctobacterium, were markedly increased by both berberine and, to a lesser extent, metformin. Taken together, our findings suggest that berberine and metformin showed similarity in modulating the gut microbiota, including the enrichment of SCFA-producing bacteria and reduction of microbial diversity, which may contribute to their beneficial effects to the host.
490 citations
"A patent review of berberine and it..." refers background in this paper
...blood to exhibit lowering blood lipid activity [73]....
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TL;DR: The findings suggest that the prevention of obesity and insulin resistance by berberine in HFD-fed rats is at least partially mediated by structural modulation of the gut microbiota, which may help to alleviate inflammation by reducing the exogenous antigen load in the host and elevating SCFA levels in the intestine.
Abstract: Berberine, a major pharmacological component of the Chinese herb Coptis chinensis, which was originally used to treat bacterial diarrhea, has recently been demonstrated to be clinically effective in alleviating type 2 diabetes. In this study, we revealed that berberine effectively prevented the development of obesity and insulin resistance in high-fat diet (HFD)-fed rats, which showed decreased food intake. Increases in the levels of serum lipopolysaccharide-binding protein, monocyte chemoattractant protein-1, and leptin and decrease in the serum level of adiponectin corrected for body fat in HFD-fed rats were also significantly retarded by the co-administration of berberine at 100 mg/kg body weight. Bar-coded pyrosequencing of the V3 region of 16S rRNA genes revealed a significant reduction in the gut microbiota diversity of berberine-treated rats. UniFrac principal coordinates analysis revealed a marked shift of the gut microbiota structure in berberine-treated rats away from that of the controls. Redundancy analysis identified 268 berberine-responding operational taxonomic units (OTUs), most of which were essentially eliminated, whereas a few putative short-chain fatty acid (SCFA)-producing bacteria, including Blautia and Allobaculum, were selectively enriched, along with elevations of fecal SCFA concentrations. Partial least square regression models based on these 268 OTUs were established (Q2>0.6) for predicting the adiposity index, body weight, leptin and adiponectin corrected for body fat, indicating that these discrete phylotypes might have a close association with the host metabolic phenotypes. Taken together, our findings suggest that the prevention of obesity and insulin resistance by berberine in HFD-fed rats is at least partially mediated by structural modulation of the gut microbiota, which may help to alleviate inflammation by reducing the exogenous antigen load in the host and elevating SCFA levels in the intestine.
475 citations
TL;DR: This study indicated that absolute bioavailability of BBR was 0.68% in rats, and TPGS was a good absorption enhancer capable of enhancing intestinal absorption of B BR significantly.
Abstract: Berberine chloride (BBR) is a natural isoquinoline alkaloid extracted from medicinal herbs. It has been reported that the intestinal absorption of BBR is very low. In this study, the absolute bioavailability of BBR was studied, and the enhancing effects of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) on intestinal absorption were investigated in rats. BBR injection was administrated via the femoral vein at a dose of 1.0 mg kg−1 in intravenous group, and BBR oral formulations were administrated by oral gavage at a dose of 100 mg kg−1 in BBR control (control) group and BBR-TPGS (test) group, respectively. The result showed that BBR had a very low absolute bioavailability of 0.68%, and TPGS could enhance intestinal absorption of BBR significantly. TPGS at a concentration of 2.5% could improve peak concentration (Cmax) and area under the curve (AUC0–36) of BBR by 2.9 and 1.9 times, respectively. The absorption enhancing ability of TPGS may be due to its ability to affect the biological activity of P-glycoprotein and thereby reduce the excretion of absorbed BBR into the intestinal lumen. This study indicated that absolute bioavailability of BBR was 0.68% in rats, and TPGS was a good absorption enhancer capable of enhancing intestinal absorption of BBR significantly.
238 citations
"A patent review of berberine and it..." refers methods in this paper
...Currently, there are three types of methods to improve the bioavailability of berberine: (1) permeation enhancers [9], (2) P-gp inhibitors [10], and (3) microparticle...
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TL;DR: It is concluded that sodium caprate increases the absorption of drugs mainly by the paracellular route and the effects on epithelial integrity and drug transport are dependent on time and concentration and are decreased by Ca2+.
Abstract: The effects of the absorption enhancer sodium caprate on human intestinal epithelial cells were investigated using Caco-2 cell monolayers. The effects on epithelial integrity and drug transport are dependent on time and concentration and are decreased by Ca2+, most likely through the formation of Ca22+ soaps. Morphological data indicate that exposure to sodium caprate results in cytoskeletal changes and in structural alterations of the tight junctions in the form of dilatations, while the effects on the apical cell membranes are limited. We conclude that sodium caprate increases the absorption of drugs mainly by the paracellular route.
236 citations
"A patent review of berberine and it..." refers background in this paper
...Sodium caprate, an anionic surfactant, has been shown to be a safe and effective permeation enhancer [12]....
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TL;DR: It is shown that the gut microbiota converts BBR into its absorbable form of dihydroberberine (dhBBR), which has an intestinal absorption rate 5-fold that of BBR in animals.
Abstract: The gut microbiota is important in the pathogenesis of energy-metabolism related diseases. We focused on the interaction between intestinal bacteria and orally administered chemical drugs. Oral administration of berberine (BBR) effectively treats patients with metabolic disorders. However, because BBR exhibits poor solubility, its absorption mechanism remains unknown. Here, we show that the gut microbiota converts BBR into its absorbable form of dihydroberberine (dhBBR), which has an intestinal absorption rate 5-fold that of BBR in animals. The reduction of BBR to dhBBR was performed by nitroreductases of the gut microbiota. DhBBR was unstable in solution and reverted to BBR in intestine tissues via oxidization. Heat inactivation of intestinal homogenate did not inhibit dhBBR oxidization, suggesting the process a non-enzymatic reaction. The diminution of intestinal bacteria via orally treating KK-Ay mice with antibiotics decreased the BBR-to-dhBBR conversion and blood BBR; accordingly, the lipid- and glucose-lowering efficacy of BBR was reduced. Conclusively, the gut microbiota reduces BBR into its absorbable form of dhBBR, which then oxidizes back to BBR after absorption in intestine tissues and enters the blood. Thus, interaction(s) between the gut microbiota and orally administrated drugs may modify the structure and function of chemicals and be important in drug investigation.
184 citations
"A patent review of berberine and it..." refers background in this paper
...indirectly leading to the improvement the lipophilicity of BBR [74]....
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...This compound also appeared in a previous patent, which mainly protected the preparation method of BBR’s related derivatives [58]....
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...In order to investigate these patents from different perspectives, we initially categorized and discussed them according to three aspects: (1) the improvement of BBR’s bioavailability; (2) the enhancement of its pharmacological activity; (3) the discovery of new pharmacological mechanisms and indications....
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...Experiments using high-fat hamsters showed that BBR ionpair compounds have more significant inhibitory effects when compared with berberine....
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...Zhu et al. constructed self-microemulsifying drug delivery system (BBRSMEDDS), which increased the relative bioavailability by 2.42-fold when compared to berberine hydrochloride [11]....
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