Preparation and Evaluation of Berberine-Excipient Complexes in Enhancing the Dissolution Rate of Berberine Incorporated into Pellet Formulations.

Berberine is used in the treatment of metabolic syndrome and its low solubility and very poor oral bioavailability of berberine was one of the primary hurdles for its market approval. This study aimed to improve the solubility and bioavailability of berberine by preparing pellet formulations containing drug-excipient complex (obtained by solid dispersion). Berberine-excipient solid dispersion complexes were obtained with different ratios by the solvent evaporation method. The maximum saturation solubility test was performed as a key factor for choosing the optimal complex for the drug-excipient. The properties of these complexes were investigated by FTIR, DSC, XRD and dissolution tests. The obtained pellets were evaluated and compared in terms of pelletization efficiency, particle size, mechanical strength, sphericity and drug release profile in simulated media of gastric and intestine. Solid-state analysis showed complex formation between the drug and excipients used in solid dispersion. The optimal berberine-phospholipid complex showed a 2-fold increase and the optimal berberine-gelucire and berberine-citric acid complexes showed more than a 3-fold increase in the solubility of berberine compared to pure berberine powder. The evaluation of pellets from each of the optimal complexes showed that the rate and amount of drug released from all pellet formulations in the simulated gastric medium were significantly lower than in the intestine medium. The results of this study showed that the use of berberine-citric acid or berberine-gelucire complex could be considered a promising technique to increase the saturation solubility and improve the release characteristics of berberine from the pellet formulation.

Supersaturated Drug Delivery System of Oxyberberine Based on Cyclodextrin Nanoaggregates: Preparation, Characterization, and in vivo Application.

Propose: Oxyberberine (OBB), one of the main metabolites of berberine derived from intestinal and erythrocyte metabolism, exhibits appreciable anti-hyperuricemic activity. However, the low water solubility and poor plasma concentration-effect relationship of OBB hamper its development and utilization. Therefore, an OBB-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) supersaturated drug delivery system (SDDS) was prepared and characterized in this work. Methods: OBB-HP-ß-CD SDDS was prepared using the ultrasonic-solvent evaporation method and characterized. Additionally, the in vitro and in vivo release experiments were conducted to assess the release kinetics of OBB-HP-ß-CD SDDS. Subsequently, the therapeutic efficacy of OBB-HP-ß-CD SDDS on hyperuricemia (HUA) was investigated by means of histopathological examination and evaluation of relevant biomarkers. Results: The results of FT-IR, DSC, PXRD, NMR and molecular modeling showed that the crystallized form of OBB was transformed into an amorphous OBB-HP-ß-CD complex. Dynamic light scattering indicated that this system was relatively stable and maintained by formation of nanoaggregates with an average diameter of 23 nm. The dissolution rate of OBB-HP-ß-CD SDDS was about 5 times higher than that of OBB raw material. Furthermore, the AUC0-t of OBB-HP-ß-CD SDDS (10.882 µg/mL*h) was significantly higher than that of the raw OBB counterpart (0.701 µg/mL*h). The oral relative bioavailability of OBB-HP-ß-CD SDDS was also enhanced by 16 times compared to that of the raw material. Finally, in vivo pharmacodynamic assay showed the anti-hyperuricemic potency of OBB-HP-ß-CD SDDS was approximately 5-10 times higher than that of OBB raw material. Conclusion: Based on our findings above, OBB-HP-ß-CD SDDS proved to be an excellent drug delivery system for increasing the solubility, dissolution, bioavailability, and anti-hyperuricemic potency of OBB.

Intelligent berberine-loaded erythrocytes attenuated inflammatory cytokine productions in macrophages.

Erythrocytes are impressive tools for drug delivery, especially to macrophages. Therefore, berberine was loaded into erythrocytes using both hypotonic pre-swelling and endocytosis methods to target macrophages. Physicochemical and kinetic parameters of the resulting carrier cells, such as drug loading/release kinetics, osmotic fragility, and hematological indices, were determined. Drug loading was optimized for the study using Taguchi experimental design and lab experiments. Loaded erythrocytes were targeted to macrophages using ZnCl2 and bis-sulfosuccinimidyl-suberate, and targeting was evaluated using flow cytometry and Wright-Giemsa staining. Differentiated macrophages were stimulated with lipopolysaccharide, and the inflammatory profiles of macrophages were evaluated using ELISA, western blotting, and real-time PCR. Findings indicated that the endocytosis method is preferred due to its low impact on the erythrocyte's structural integrity. Maximum loading achieved (1386.68 ± 22.43 µg/ml) at 1500 µg/ml berberine treatment at 37 °C for 2 h. Berberine successfully inhibited NF-κB translation in macrophages, and inflammatory response markers such as IL-1ß, IL-8, IL-23, and TNF-α were decreased by approximately ninefold, sixfold, twofold, eightfold, and twofold, respectively, compared to the LPS-treated macrophages. It was concluded that berberine-loaded erythrocytes can effectively target macrophages and modulate the inflammatory response.

Nanodiamond-based berberine aquasomes for enhancing penetration across epidermis to treat psoriasis.

The use of berberine hydrochloride (BCS class III) has limited application in psoriasis, when given as topical drug delivery systems, due to low permeability in the skin layer. Hence, berberine hydrochloride-loaded aquasome nanocarriers were developed for skin targeting, particularly epidermis (primary site of psoriasis pathophysiology) and enhance the skin permeability of berberine hydrochloride. Aquasomes were formulated using the adsorption method and characterized by structural morphology TEM, % drug adsorption, drug release profile (in-vitro and ex-vivo), in-vivo efficacy study and stability study. The reduced particle size and higher surface charge of SKF3 formulation (263.57 ± 27.78 nm and -21.0 ± 0.43 mV) showed improved stability of aquasomes because of the development of higher surface resistance to formation of aggregates. The adsorption of hydrophilic berberine and the non-lipidic nature of aquasomes resulted in % adsorption efficiency (%AE) of 94.46 ± 0.39 %. The controlled first-order release behavior of aquasomes was reported to be 52.647 ± 14.63 and 32.08 ± 12.78 % in in-vitro and ex-vivo studies, respectively. In-vivo studies demonstrated that topical application of berberine hydrochloride loaded aquasomes significantly alleviated psoriasis symptoms like hyperkeratosis, scaling and inflammation, due to the reduction in the inflammatory cytokines (IL-17 and IL-23). Therefore, aquasome formulation exhibits an innovative approach for targeted application of berberine hydrochloride in the management of psoriasis.

Berberine and hesperidin prevent the memory consolidation impairment induced by pentylenetetrazole in zebrafish.

This study verified the effects of the natural compounds berberine and hesperidin on seizure development and cognitive impairment triggered by pentylenetetrazole (PTZ) in zebrafish. Adult animals were submitted to a training session in the inhibitory avoidance test and, after 10 minutes, they received an intraperitoneal injection of 25, 50, or 100 mg/kg berberine or 100 or 200 mg/kg hesperidin. After 30 minutes, the animals were exposed to 7.5 mM PTZ for 10 minutes. Animals were submitted to the test session 24 h after the training session to verify their cognitive performance. Zebrafish larvae were exposed to 100 µM or 500 µM berberine or 10 µM or 50 µM hesperidin for 30 minutes. After, larvae were exposed to PTZ and had the seizure development evaluated by latency to reach the seizure stages I, II, and III. Adult zebrafish pretreated with 50 mg/kg berberine showed a longer latency to reach stage III. Zebrafish larvae pretreated with 500 µM berberine showed a longer latency to reach stages II and III. Hesperidin did not show any effect on seizure development both in larvae and adult zebrafish. Berberine and hesperidin pretreatments prevented the memory consolidation impairment provoked by PTZ-induced seizures. There were no changes in the distance traveled in adult zebrafish pretreated with berberine or hesperidin. In larval stage, berberine caused no changes in the distance traveled; however, hesperidin increased the locomotion. Our results reinforce the need for investigating new therapeutic alternatives for epilepsy and its comorbidities.

The Possible Synergistic Pharmacological Effect of an Oral Berberine (BBR) and Curcumin (CUR) Complementary Therapy Alleviates Symptoms of Irritable Bowel Syndrome (IBS): Results from a Real-Life, Routine Clinical Practice Settings-Based Study.

Irritable bowel syndrome (IBS) is a prevalent chronic functional gastrointestinal disorder, characterised by recurrent abdominal discomfort and altered bowel movements. IBS cause a significantly negative impact on quality of life (QoL). Growing pharmacological evidence suggests that berberine (BBR) and curcumin (CUR) may mitigate IBS symptoms through multiple complementary synergistic mechanisms, resulting in the attenuation of intestinal inflammation and regulation of bowel motility and gut functions. In the present observational study conducted under real-life routine clinical practice settings, 146 patients diagnosed with IBS were enrolled by general practitioner clinics and pharmacies in Belgium. For the first time, this study assessed the potential synergistic pharmacological effect of a combined oral BBR/CUR supplement (Enterofytol® PLUS, containing 200 mg BBR and 49 mg CUR) (two tablets daily for 2 months), serving as complementary therapy in the management of IBS. Following the 2-month supplementation, significant improvements were observed in the patients' IBS severity index (IBSSI) (47.5%) and all the primary IBS symptoms, such as abdominal discomfort (47.2%), distension (48.0%), intestinal transit (46.8%), and QoL (48.1%) (all p < 0.0001). The improvement in the patients' IBSSI was independent of age, sex, and IBS sub-types. The patients' weekly maximum stool passage frequency decreased significantly (p < 0.0001), and the stool status normalized (p < 0.0001). The patients' need for concomitant conventional IBS treatment decreased notably: antispasmodics by 64.0% and antidiarrhoeals by 64.6%. Minor adverse effects were reported by a small proportion (7.1%) of patients, mostly gastrointestinal. The majority (93.1%) experienced symptom improvement or resolution, with a high satisfaction rate (82.6%) and willingness to continue the supplementation (79.0%). These findings support the potential synergistic pharmacological role of BBR and CUR in IBS, and their co-supplementation may alleviate IBS symptoms and improve QoL.

Bone-Targeted Supramolecular Nanoagonist Assembled by Accurate Ratiometric Herbal-Derived Therapeutics for Osteoporosis Reversal.

Developing novel strategies for defeating osteoporosis has become a world-wide challenge with the aging of the population. In this work, novel supramolecular nanoagonists (NAs), constructed from alkaloids and phenolic acids, emerge as a carrier-free nanotherapy for efficacious osteoporosis treatment. These precision nanoagonists are formed through the self-assembly of berberine (BER) and chlorogenic acid (CGA), utilizing noncovalent electrostatic, π-π, and hydrophobic interactions. This assembly results in a 100% drug loading capacity and stable nanostructure. Furthermore, the resulting weights and proportions of CGA and BER within the NAs are meticulously controlled with strong consistency when the CGA/BER assembly feed ratio is altered from 1:1 to 1:4. As anticipated, our NAs themselves could passively target osteoporotic bone tissues following prolonged blood circulation, modulate Wnt signaling, regulate osteogenic differentiation, and ameliorate bone loss in ovariectomy-induced osteoporotic mice. We hope this work will open a new strategy to design efficient herbal-derived Wnt NAs for dealing with intractable osteoporosis.

Lack of berberine effect on bone mechanical properties in rats with experimentally induced diabetes.

Multidirectional health-promoting activities of some plant-derived substances make them candidates for drugs used in diabetes and its complications such as osteoporosis. Berberine is a compound for which both antidiabetic and antiosteoporotic effects have been documented. The aim of the study was to investigate the effects of berberine on the skeletal disorders induced by experimental type 1 diabetes in rats. The experiments were performed on 3-month-old female rats, divided into three groups: I - healthy control rats, II - diabetic control rats, III - diabetic rats receiving berberine. Diabetes was induced by a single streptozotocin injection. Berberine administration (50 mg/kg/day p.o.) started two weeks later and lasted four weeks. Serum bone turnover markers and other biochemical parameters, bone mass and mineralization, histomorphometric parameters and mechanical properties were studied. Diabetes induced strong disorders of bone turnover, bone microarchitecture, and strength of cancellous bone. Berberine counteracted the effect of diabetes on the bone formation marker (osteocalcin) concentration, the growth plate, and some parameters of cancellous bone microarchitecture, but did not improve bone mineralization and bone mechanical properties in the diabetic rats. The lack of effect of berberine on bone quality does not support its use in the prevention of diabetes-induced bone damage.

Targeting lipophagy as a potential therapeutic strategy for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is becoming an increasingly serious disease worldwide. Unfortunately, no specific drug has been approved to treat NAFLD. Accumulating evidence suggests that lipotoxicity, which is induced by an excess of intracellular triacylglycerols (TAGs), is a potential mechanism underlying the ill-defined progression of NAFLD. Under physiological conditions, a balance is maintained between TAGs and free fatty acids (FFAs) in the liver. TAGs are catabolized to FFAs through neutral lipolysis and/or lipophagy, while FFAs can be anabolized to TAGs through an esterification reaction. However, in the livers of patients with NAFLD, lipophagy appears to fail. Reversing this abnormal state through several lipophagic molecules (mTORC1, AMPK, PLIN, etc.) facilitates NAFLD amelioration; therefore, restoring failed lipophagy may be a highly efficient therapeutic strategy for NAFLD. Here, we outline the lipophagy phases with the relevant important proteins and discuss the roles of lipophagy in the progression of NAFLD. Additionally, the potential candidate drugs with therapeutic value targeting these proteins are discussed to show novel strategies for future treatment of NAFLD.

Berberine-loaded nanostructured lipid carriers mitigate warm hepatic ischemia/reperfusion-induced lesion through modulation of HMGB1/TLR4/NF-κB signaling and autophagy.

OBJECTIVE: Berberine (BBR) is a known alkaloid that has verified its protective effects against ischemia/reperfusion (I/RN) lesion in multiple organs but its poor oral bioavailability limited its use. Despite the previous works, its possible impact on the warm hepatic I/RN-induced lesion is not clear. Accordingly, a nanostructured lipid carrier of BBR (NLC BBR) was developed for enhancing its efficiency and to inspect its protective mechanistic against warm hepatic I/RN. METHODS: NLC BBR formula was evaluated pharmaceutically. Wistar rats were orally pre-treated with either BBR or NLC BBR (100 mg/kg) for 2 weeks followed by hepatic I/RN (30 min/24 h). Biochemical, ELISA, qPCR, western blot, histopathological, and immunohistochemical studies were performed. KEY FINDINGS: Optimized NLC BBR was prepared with a particle size of 130 ± 8.3 nm. NLC BBR divulged its aptitude to safeguard the hepatic tissues partly due to anti-inflammatory capacity through downsizing the HMGB1/TLR4/NF-κB trajectory with concomitant rebating of TNF-α, iNOS, COX-2, and MPO content. Furthermore, NLC BBR antiapoptotic trait was confirmed by boosting the prosurvival protein (Bcl-2) and cutting down the pro-apoptotic marker (Bax). Moreover, its antioxidant nature was confirmed by TAC uplifting besides MDA subsiding. On the other hand, NLC BBR action embroiled autophagy flux spiking merit exemplified in Beclin-1 and LC3-II enhancement. Finally, NLC BBR administration ascertained its hepatocyte guarding action by recovering the histopathological ailment and diminishing serum transaminases. CONCLUSION: NLC BBR purveyed reasonable shielding mechanisms and subsided incidents contemporaneous to warm hepatic I/RN lesion in part, by moderating HMGB1/TLR4/NF-κB inflammatory signaling, autophagy, and apoptosis.

Oral administration of berberine limits post-traumatic osteoarthritis development and associated pain via AMP-activated protein kinase (AMPK) in mice.

OBJECTIVE: We investigated the effect of berberine, a natural plant product that can activate AMP-activated protein kinase (AMPK), on Osteoarthritis (OA) development and associated pain in mice. DESIGN: Human primary knee chondrocytes were utilized to investigate how AMPK is activated by berberine. Both global knockout (KO) of AMPKα1 and congenic wild type (WT) mice were subjected to the post-traumatic OA through destabilization of medial meniscus (DMM) surgery. Two weeks after surgery, the mice were randomly divided into two groups with one group receiving berberine chloride daily via drinking water and were sacrificed at 6 and 12 weeks after surgery. OA severity was assessed by histological and histomorphometric analyses of cartilage degradation, synovitis, and osteophyte formation. OA-associated pain behavior was also determined. Immunohistochemistry (IHC) analyses were carried out to examine changes in AMPK signaling. RESULTS: Berberine induced phosphorylation of AMPKα (Thr172) via liver kinase B1 (LKB1), the major upstream kinase of AMPK, in chondrocytes in vitro. Both WT and AMPKα1KO developed OA and associated pain post DMM surgery. However, treatment with berberine significantly reduced severity of OA and associated pain in WT but not AMPKα1KO mice. IHC analysis of WT DMM knee cartilage further revealed that berberine inhibited concomitant loss of expression and phosphorylation of AMPKα and expression of SIRT1 and SIRT3, suggesting an important role of activation of AMPK signaling in mediating beneficial effect of berberine. CONCLUSIONS: Berberine acts through AMPK to reduce joint structural damage and pain associated with post-traumatic OA in mice in vivo.

The natural product berberine synergizes with osimertinib preferentially against MET-amplified osimertinib-resistant lung cancer via direct MET inhibition.

Berberine is a natural product that has long been used in traditional Chinese medicine due to its antimicrobial, anti-inflammatory and metabolism-regulatory properties. Osimertinib is the first third-generation EGFR-tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations and those resistant to earlier generation EGFR-TKIs due to a T790M mutation. However, emergence of acquired resistance to osimertinib limits its long-term efficacy in the clinic. One known mechanism of acquired resistance to osimertinib and other EGFR-TKIs is MET (c-MET) gene amplification. Here, we report that berberine, when combined with osimertinib, synergistically and selectively decreased the survival of several MET-amplified osimertinib-resistant EGFR mutant NSCLC cell lines with enhanced induction of apoptosis likely through Bim elevation and Mcl-1 reduction. Importantly, this combination effectively enhanced suppressive effect on the growth of MET-amplified osimertinib-resistant xenografts in nude mice and was well tolerated. Molecular modeling showed that berberine was able to bind to the kinase domain of non-phosphorylated MET, occupy the front of the binding pocket, and interact with the activation loop, in a similar way as other known MET inhibitors do. MET kinase assay showed clear concentration-dependent inhibitory effects of berberine against MET activity, confirming its kinase inhibitory activity. These findings collectively suggest that berberine can act as a naturally-existing MET inhibitor to synergize with osimertinib in overcoming osimertinib acquired resistance caused by MET amplification.

Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study.

Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal Bifidobacterium breve level responding to BBR alone or Prob+BBR treatment. Four fadD genes encoding long-chain acyl-CoA synthetase were identified in the genome of this B. breve strain, and transcriptionally activated by BBR. In vitro BBR treatment further decreased the concentration of FFA in the culture medium of B. breve compared to vehicle. Thus, the activation of fadD by BBR could enhance FFA import and mobilization in B. breve and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (B. breve) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.

Berberine and lycopene as alternative or add-on therapy to metformin and statins, a review.

Nutraceuticals are principally extracted from natural products that are frequently safe and well-tolerated. Lycopene and berberine are natural plants with a wide range of beneficial effects including protective activities against metabolic disorders such as diabetes and cardiovascular diseases. These compounds might be considered technically more as a drug than a nutraceutical and could be prescribed as a product. However, further studies are needed to understand if these supplements could affect metabolic syndrome outcomes. Even if nutraceuticals exert a prophylactic activity within the body, their bioactivity and bioavailability have high interindividual variation, and precise assessment of biological function of these bioactive compounds in randomized clinical trials is critical. However, these reports must be interpreted with more considerations due to the low quality of the trials. The aim of this paper is to bring evidence about the management of cardiovascular diseases and diabetes through the use of nutraceuticals with particular attention to lycopene and berberine effectiveness.

Berberine inhibited carotid atherosclerosis through PI3K/AKTmTOR signaling pathway.

Atherosclerosis, a multifactorial vascular disease resulting from lipid metabolism disorders, features chronic inflammatory damage resulting from endothelial dysfunction, which usually affects multiple arteries. The carotid artery is a common site for clinical atherosclerosis evaluation. The aortic root is the standard site for quantifying atherosclerosis in mice. Due to the adverse reactions of first-line drugs, it is necessary to discover new drugs to prevent and treat atherosclerosis. Berberine (BBR) is one of the most promising natural products derived from herbal medicine Coptidis Rhizoma (Huanglian) that features significant anti-atherosclerosis properties. However, overall BBR mechanism against carotid atherosclerosis has not been clearly discovered. Our work aimed to investigate potential BBR mechanism in improving carotid atherosclerosis in ApoE knockout mice. Here, we proved that in ApoE -/- mice receiving high-fat diet for 12 weeks, BBR can reduce serum lipid levels, improve intimal hyperplasia, and antagonize carotid lipid accumulation, which may be achieved through regulating the PI3K/AKT/mTOR signaling pathway, regulating autophagy, promoting cell proliferation and inhibiting cell apoptosis. In summary, these data indicate that BBR can ameliorate carotid atherosclerosis. Therefore, it could be a promisingly therapeutic alternative for atherosclerosis.

Anti-inflammatory efficacy of Berberine Nanomicelle for improvement of cerebral ischemia: formulation, characterization and evaluation in bilateral common carotid artery occlusion rat model.

BACKGROUND: Berberine (BBR) is a plant alkaloid that possesses anti-inflammatory and anti-oxidant effects with low oral bioavailability. In this study, micelle formulation of BBR was investigated to improve therapeutic efficacy and examined its effect on the secretion of inflammatory cytokines in cerebral ischemia in the animal model. MATERIAL AND METHODS: Nano formulation was prepared by thin-film hydration method, and characterized by particle size, zeta potential, morphology, encapsulation efficacy, and drug release in Simulated Gastric Fluid (SGF) and Simulated Intestine Fluid (SIF). Then, Wistar rats were pretreated with the drug (100 mg/kg) and nano-drug (25, 50, 75, 100 mg/kg) for 14 days. Then, on the fourteenth day, stroke induction was accomplished by Bilateral Common Carotid Artery Occlusion (BCCAO); after that, Tumor Necrosis Factor - Alpha (TNF-α), Interleukin - 1 Beta (IL-1ß), and Malondialdehyde (MDA) levels were measured in the supernatant of the whole brain, then the anti-inflammatory effect of BBR formulations was examined. RESULT AND DISCUSSION: Micelles were successfully formed with appropriate characteristics and smaller sizes than 20 nm. The Poly Dispersity Index (PDI), zeta potential, encapsulation efficacy of micelles was 0.227, - 22 mV, 81%, respectively. Also, the stability of nano micelles was higher in SGF as compared to SIF. Our outcomes of TNF-a, IL-1B, and MDA evaluation show a significant ameliorating effect of the Berberine (BBR) and BBR-loaded micelles in pretreated groups. CONCLUSION: Our experimental data show that pretreated groups in different doses (nano BBR 100, 75, 50 mg/kg, and BBR 100 mg/kg) successfully showed decreased levels of the inflammatory factors in cerebral ischemia compared with the stroke group and pretreated group with nano BBR in the dose of 25 mg/kg. Nano BBR formulation with a lower dose can be a better candidate than conventional BBR formulation to reduce oxidative and inflammatory factors in cerebral ischemia. Therefore, BBR-loaded micelle formulation could be a promising protective agent on cerebral ischemia.

Berberine loaded nanostructured lipid carrier for Alzheimer's disease: Design, statistical optimization and enhanced in vivo performance.

Berberine, an isoquinoline alkaloid, is reported for the treatment of Alzheimer's disease. Despite having substantial therapeutic potential, it exhibits poor absorption, low oral bioavailability and limited penetration in the brain. In this study, berberine-loaded nanostructured lipid carriers (Berb-NLCs) were developed by melt-emulsification and ultrasonication using Geleol, Miglyol 812 N, Solutol HS 15 as a solid lipid, liquid lipid and surfactant, respectively. The Berb-NLC formulation was statistically optimized by a 32 factorial design in which the effect of surfactant and berberine concentration was assessed on particle size and entrapment efficiency of Berb-NLCs. Optimized Berb-NLCs (Trial-5) exhibited particle size of 186 nm, polydispersity index of 0.108, the zeta potential of -36.86 mV and 88% entrapment efficiency. The in vitro release of berberine from Batch-B5 was 82% in phosphate buffer at the end of 24 h. The comparative results of pharmacodynamic studies involving behavioral assessment by locomotor activity, passive avoidance test, elevated plus maze test and spatial memory assessment by Morris water maze demonstrated improved behavioral parameters in vivo by Berb-NLCs compared to pure berberine in Albino Wistar rats. Thus, berberine-loaded nanostructured lipid carriers have the potential of brain targeting and were effective in an animal model of Alzheimer's disease.

Berberine elevates cardiolipin in heart of offspring from mouse dams with high fat diet-induced gestational diabetes mellitus.

Berberine (BBR) is an isoquinoline alkaloid from plants known to improve cardiac mitochondrial function in gestational diabetes mellitus (GDM) offspring but the mechanism is poorly understood. We examined the role of the mitochondrial phospholipid cardiolipin (CL) in mediating this cardiac improvement. C57BL/6 female mice were fed either a Lean-inducing low-fat diet or a GDM-inducing high-fat diet for 6 weeks prior to breeding. Lean and GDM-exposed male offspring were randomly assigned a low-fat, high-fat, or high-fat diet containing BBR at weaning for 12 weeks. The content of CL was elevated in the heart of GDM offspring fed a high fat diet containing BBR. The increase in total cardiac CL was due to significant increases in the most abundant and functionally important CL species, tetralinoleoyl-CL and this correlated with an increase in the expression of the CL remodeling enzyme tafazzin. Additionally, BBR treatment increased expression of cardiac enzymes involved in fatty acid uptake and oxidation and electron transport chain subunits in high fat diet fed GDM offspring. Thus, dietary BBR protection from cardiac dysfunction in GDM exposed offspring involves improvement in mitochondrial function mediated through increased synthesis of CL.

Oral administration of berberine represses macrophage activation-associated benign prostatic hyperplasia: a pivotal involvement of the NF-κB.

Benign prostatic hyperplasia (BPH) is one of the most common chronic diseases in men over the age of 50. Clinical studies have suggested that chronic inflammation is associated with BPH pathoprogression. Berberine (BB) is a natural compound found in Berberis vulgaris, Coptis chinensis and Phellodendron amurense. Although several studies have documented that BB may be effective for inflammation, the effects of the oral administration of BB on BPH are not fully understood. The effects of BB on chronic prostatic inflammation were evaluated in a testosterone-induced BPH animal model. Orally administered BB alleviated the pathological alterations induced by BPH and significantly suppressed the expression of inflammatory markers while enhancing the expression of antioxidant factors. Furthermore, BB regulated the activation of macrophages via NF-κB signaling pathway inhibition in the BPH rat model. The effects and underlying signaling pathway of BB in RWPE-1 cells exposed to macrophage conditioned medium (CM) were also demonstrated in vitro. While CM stimulation induced prostatic cell proliferation and upregulated the expression of inflammatory factors, BB exerted anti-proliferation and anti-inflammatory effects in RWPE-1 cells. These findings propose that BB suppresses androgen-dependent BPH development by targeting NF-κB-mediated pro-inflammatory signaling.

The protective impact of berberine against doxorubicin-induced nephrotoxicity in rats.

Doxorubicin (DOX) is a well-known anti-neoplastic agent that is widely employed to treat several types of malignancies. The current study was designed to investigate the renoprotective potential of berberine (BEB) on the doxorubicin (DOX)-induced nephrotoxicity and renal fibrosis. Rats were allocated into four groups; Negative Control, DOX nephrotoxic-induced group received a single dose of DOX (20 mg/kg, i.p.), BEB-group received (50 mg/kg, p.o.) for 14 days, and co-treatment group BEB + DOX where rats were pre-treated with BEB for 10 successive days, then received a single dose of DOX on the 11th day, followed by 4 days of receiving BEB. DOX resulted in nephrotoxicity manifested by significant increments in urea, creatinine, and kidney injury molecule (KIM-1), these biochemical findings were supported with the histopathological lesions in renal tissues. Moreover, DOX provoked oxidative stress through enhancing renal malondialdehyde (MDA) and hydrogen peroxide (H2O2) contents, and decreased renal catalase (CAT) activity. DOX triggered renal fibrosis represented by increased transforming growth factor beta-1 (TGF-ß1) and elevated collagen deposition. DOX stimulated apoptosis and inflammation in renal tissues as confirmed by increased immunoexpression of caspase-3 and NF-κB, respectively. These effects were alleviated by BEB co-treatment. Co-treatment with BEB markedly prohibited DOX-induced oxidative damage, inflammation, apoptosis, and fibrosis in renal tissue. Histopathological and immunohistochemical investigations showed the nephroprotective potential of BEB on renal injury, which was consistent with the biochemical findings. Accordingly, it could be concluded that the nephroprotective potential of BEB against DOX-induced kidney injury and fibrosis might be mediated by the anti-oxidant, anti-inflammatory and anti-fibrosis activities.