Anti-CD22/CD20 Bispecific Antibody with Enhanced Trogocytosis for Treatment of Lupus

The humanized anti-CD22 antibody, epratuzumab, has demonstrated therapeutic activity in clinical trials of lymphoma, leukemia and autoimmune diseases, treating currently over 1500 cases of non-Hodgkin lymphoma, acute lymphoblastic leukemias, Waldenström’s macroglobulinemia, Sjögren’s syndrome, and systemic lupus erythematosus. Because epratuzumab reduces on average only 35% of circulating B cells in patients, and has minimal antibody-dependent cellular cytotoxicity and negligible complement-dependent cytotoxicity when evaluated in vitro, its therapeutic activity may not result completely from B-cell depletion. We reported recently that epratuzumab mediates Fc/FcR-dependent membrane transfer from B cells to effector cells via trogocytosis, resulting in a substantial reduction of multiple BCR modulators, including CD22, CD19, CD21, and CD79b, as well as key cell adhesion molecules, including CD44, CD62L, and β7 integrin, on the surface of B cells in peripheral blood mononuclear cells obtained from normal donors or SLE patients. Rituximab has clinical activity in lupus, but failed to achieve primary endpoints in a Phase III trial. This is the first study of trogocytosis mediated by bispecific antibodies targeting neighboring cell-surface proteins, CD22, CD20, and CD19, as demonstrated by flow cytometry and immunofluorescence microscopy. We show that, compared to epratuzumab, a bispecific hexavalent antibody comprising epratuzumab and veltuzumab (humanized anti-CD20 mAb) exhibits enhanced trogocytosis resulting in major reductions in B-cell surface levels of CD19, CD20, CD21, CD22, CD79b, CD44, CD62L and β7-integrin, and with considerably less immunocompromising B-cell depletion that would result with anti-CD20 mAbs such as veltuzumab or rituximab, given either alone or in combination with epratuzumab. A CD22/CD19 bispecific hexavalent antibody, which exhibited enhanced trogocytosis of some antigens and minimal B-cell depletion, may also be therapeutically useful. The bispecific antibody is a candidate for improved treatment of lupus and other autoimmune diseases, offering advantages over administration of the two parental antibodies in combination.     

Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential

CD47 is a widely expressed cell surface protein that functions as a regulator of phagocytosis mediated by cells of the innate immune system, such as macrophages and dendritic cells. CD47 serves as the ligand for a receptor on these innate immune cells, SIRP-alpha, which in turn delivers an inhibitory signal for phagocytosis. We previously found increased expression of CD47 on primary human acute myeloid leukemia (AML) stem cells, and demonstrated that blocking monoclonal antibodies directed against CD47 enabled the phagocytosis and elimination of AML, non-Hodgkin’s lymphoma (NHL), and many solid tumors in xenograft models. Here, we report the development of a humanized anti-CD47 antibody with potent efficacy and favorable toxicokinetic properties as a candidate therapeutic. A novel monoclonal anti-human CD47 antibody, 5F9, was generated, and antibody humanization was carried out by grafting its complementarity determining regions (CDRs) onto a human IgG4 format. The resulting humanized 5F9 antibody (Hu5F9-G4) bound monomeric human CD47 with an 8 nM affinity. Hu5F9-G4 induced potent macrophage-mediated phagocytosis of primary human AML cells in vitro and completely eradicated human AML in vivo, leading to long-term disease-free survival of patient-derived xenografts. Moreover, Hu5F9-G4 synergized with rituximab to eliminate NHL engraftment and cure xenografted mice. Finally, toxicokinetic studies in non-human primates showed that Hu5F9-G4 could be safely administered intravenously at doses able to achieve potentially therapeutic serum levels. Thus, Hu5F9-G4 is actively being developed for and has been entered into clinical trials in patients with AML and solid tumors (ClinicalTrials.gov identifier: NCT02216409).     

Programming Stem Cells for Therapeutic Angiogenesis Using Biodegradable Polymeric Nanoparticles

Controlled vascular growth is critical for successful tissue regeneration and wound healing, as well as for treating ischemic diseases such as stroke, heart attack or peripheral arterial diseases. Direct delivery of angiogenic growth factors has the potential to stimulate new blood vessel growth, but is often associated with limitations such as lack of targeting and short half-life in vivo. Gene therapy offers an alternative approach by delivering genes encoding angiogenic factors, but often requires using virus, and is limited by safety concerns. Here we describe a recently developed strategy for stimulating vascular growth by programming stem cells to overexpress angiogenic factors in situ using biodegradable polymeric nanoparticles. Specifically our strategy utilized stem cells as delivery vehicles by taking advantage of their ability to migrate toward ischemic tissues in vivo. Using the optimized polymeric vectors, adipose-derived stem cells were modified to overexpress an angiogenic gene encoding vascular endothelial growth factor (VEGF). We described the processes for polymer synthesis, nanoparticle formation, transfecting stem cells in vitro, as well as methods for validating the efficacy of VEGF-expressing stem cells for promoting angiogenesis in a murine hindlimb ischemia model.     

Inducing Controlled Release and Increased Tumor-Targeted Delivery of Chlorambucil via Albumin/Liposome Hybrid Nanoparticles

Liposomes possess good biocompatibility and excellent tumor-targeting capacity. However, the rapid premature release of lipophilic drugs from the lipid bilayer of liposomes has negative effect on the tumor-targeted drug delivery of liposomes. In this study, a lipophilic antitumor drug—chlorambucil (CHL)—was encapsulated into the aqueous interior of liposomes with the aid of albumin to obtain the CHL-loaded liposomes/albumin hybrid nanoparticles (CHL-Hybrids). The in vitro accumulative release rate of CHL from CHL-Hybrids was less than 50% within 48 h, while the accumulative CHL release was more than 80% for CHL-loaded liposomes (CHL-Lip). After intravenous injection into rats, the half-life (t _1/2β = 5.68 h) and maximum blood concentration (C _max = 4.58 μg/mL) of CHL-Hybrids were respectively 1.1 times and 3.5 times higher than that of CHL-Lip. In addition, CHL-Hybrids had better tumor-targeting capacity for it significantly increased the drug accumulation in B16F10 tumors, which contributed to the significantly control of tumor growth compared with CHL-Lip. Furthermore, CHL-Hybrid-treated B16F10 melanoma-bearing mice displayed the longest median survival time of 30.0 days among all the treated groups. Our results illustrated that the proposed hybrids drug delivery system would be a promising strategy to maintain the controlled release of lipophilic antitumor drugs from liposomes and simultaneously facilitate the tumor-targeted drug delivery.     

Molecular Docking Analysis of 120 Potential HPV Therapeutic Epitopes Using a New Analytical Method

International Journal of Peptide Research and Therapeutics - The accurate modelling and scoring of protein–peptide (Pr–Pe) complexes are determining factors in the drug discovery...     

Potential Therapeutic Value of a Novel FAAH Inhibitor for the Treatment of Anxiety

Anxiety disorders are among the most prevalent psychiatric diseases with high personal costs and a remarkable socio-economic burden. However, current treatment of anxiety is far from satisfactory. Novel pharmacological targets have emerged in the recent years, and attention has focused on the endocannabinoid (eCB) system, given the increasing evidence that supports its central role in emotion, coping with stress and anxiety. In the management of anxiety disorders, drug development strategies have left apart the direct activation of type-1 cannabinoid receptors to indirectly enhance eCB signalling through the inhibition of eCB deactivation, that is, the inhibition of the fatty acid amide hydrolase (FAAH) enzyme. In the present study, we provide evidence for the anxiolytic-like properties of a novel, potent and selective reversible inhibitor of FAAH, ST4070, orally administered to rodents. ST4070 (3 to 30 mg/kg per os) administered to CD1 male mice induced an increase of time spent in the exploration of the open arms of the elevated-plus maze. A partial reduction of anxiety-related behaviour by ST4070 was also obtained in Wistar male rats, which moderately intensified the time spent in the illuminated compartment of the light-dark box. ST4070 clearly inhibited FAAH activity and augmented the levels of two of its substrates, N-arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine, in anxiety-relevant brain regions. Altogether, ST4070 offers a promising anxiolytic-like profile in preclinical studies, although further studies are warranted to clearly demonstrate its efficacy in the clinic management of anxiety disorders.     

单克隆抗体药物与血液系统恶性肿瘤的治疗

单克隆抗体凭借其特异性强、副作用较小的优点,越来越广泛地应用于疾病的诊断与治疗。单克隆抗体药物在血液系统恶性肿瘤的治疗中也发挥了重要作用。目前,经美国食品与药品管理局(FDA)批准用于治疗血液系统恶性肿瘤的单克隆抗体药物已有六种,在临床取得良好的治疗效果。单克隆抗体药物主要通过对肿瘤细胞的直接杀伤作用、抗体依赖性细胞介导的细胞毒性反应(ADCC)、补体依赖性细胞毒性反应(CDC)和改变信号通路等机制达到治疗肿瘤的效果。另外,将单克隆抗体与放射性核素、化疗药物和毒素等偶联,用于肿瘤等疾病的靶向治疗研究,成为生物治疗领域的热点。该文对近年来国际上用于血液系统恶性肿瘤治疗的单克隆抗体药物进行了概括和总结,讨论了治疗性单克隆抗体药物存在的问题和应用前景。     

Development and Characterization of Nisin Nanoparticles as Potential Alternative for the Recurrent Vaginal Candidiasis Treatment

The aim of this work was the development and characterization of nisin-loaded nanoparticles and the evaluation of its potential antifungal activity. Candidiasis is a fungal infection caused by Candida sp. considered as one of the major public health problem currently. The discovery of antifungal agents that present a reduced or null resistance of Candida sp. and the development of more efficient drug release mechanisms are necessary for the improvement of candidiasis treatment. Nisin, a bacteriocin commercially available for more than 50 years, exhibits antibacterial action in food products with potential antifungal activity. Among several alternatives used to modulate antifungal activity of bacteriocins, polymeric nanoparticles have received great attention due to an effective drug release control and reduction of therapeutic dose, besides the minimization of adverse effects by the preferential accumulation in specific tissues. The nisin nanoparticles were prepared by double emulsification and solvent evaporation methods. Nanoparticles were characterized by dynamic light scattering, zeta potential, Fourier transform infrared, X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy. Antifungal activity was accessed by pour plate method and cell counting using Candida albicans strains. The in vitro release profile and in vitro permeation studies were performed using dialysis bag method and pig vaginal mucosa in Franz diffusion cell, respectively. The results revealed nisin nanoparticles (300 nm) with spherical shape and high loading efficiency (93.88?±?3.26%). In vitro test results suggest a promising application of these nanosystems as a prophylactic agent in recurrent vulvovaginal candidiasis and other gynecological diseases.     

L1 Cell Adhesion Molecule as a Potential Therapeutic Target in Murine Models of Endometriosis Using a Monoclonal Antibody Approach

Background/Aims

The neural cell adhesion molecule L1CAM is a transmembrane glycoprotein abnormally expressed in tumors and previously associated with cell proliferation, adhesion and invasion, as well as neurite outgrowth in endometriosis. Being an attractive target molecule for antibody-based therapy, the present study assessed the ability of the monoclonal anti-L1 antibody (anti-L1 mAb) to impair the development of endometriotic lesions in vivo and endometriosis-associated nerve fiber growth.

Methods and Results

Endometriosis was experimentally induced in sexually mature B6C3F1 (n=34) and CD-1 nude (n=21) mice by autologous and heterologous transplantation, respectively, of endometrial fragments into the peritoneal cavity. Transplantation was confirmed four weeks post-surgery by in vivo magnetic resonance imaging and laparotomy, respectively. Mice were then intraperitoneally injected with anti-L1 mAb or an IgG isotype control antibody twice weekly, over a period of four weeks. Upon treatment completion, mice were sacrificed and endometrial implants were excised, measured and fixed. Endometriosis was histologically confirmed and L1CAM was detected by immunohistochemistry. Endometriotic lesion size was significantly reduced in anti-L1-treated B6C3F1 and CD-1 nude mice compared to mice treated with control antibody (P<0.05). Accordingly, a decreased number of PCNA positive epithelial and stromal cells was detected in autologously and heterologously induced endometriotic lesions exposed to anti-L1 mAb treatment. Anti-L1-treated mice also presented a diminished number of intraperitoneal adhesions at implantation sites compared with controls. Furthermore, a double-blind counting of anti-neurofilament L stained nerves revealed significantly reduced nerve density within peritoneal lesions in anti-L1 treated B6C3F1 mice (P=0.0039).

Conclusions

Local anti-L1 mAb treatment suppressed endometriosis growth in B6C3F1 and CD-1 nude mice and exerted a potent anti-neurogenic effect on induced endometriotic lesions in vivo. The findings of this preliminary study in mice provide a strong basis for further testing in in vivo models.     

Pre-Clinical Study for the Antidiabetic Potential of Selenium Nanoparticles

This research was delineated to explore the efficacy of selenium nanoparticles delivered in liposomes (L-Se) in the mitigation of type-2 diabetes mellitus. Adult female Wistar rats were assigned into four groups: group I, the normal control group in which the rats received normal saline solution orally; group II, the diabetic control group in which the rats were injected intraperitoneally with a single dose of streptozotocin (STZ) for induction of diabetes; group III, the metformin (Met)-treated group in which the diabetic rats were treated orally with Met; and group IV, the L-Se-treated group in which the diabetic rats were treated orally with L-Se. All treatments were delivered for 21 days. Blood and pancreas tissue samples were obtained for biochemical analysis, immunohistochemical examinations, and histopathological investigation. The L-Se-treated group showed significant drop in serum glucose and pancreatic malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), and prostaglandin F2α (PGF2α) levels associated with significant rise in serum insulin and pancreatic glutathione, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) values, in addition to significant improvement in the immunohistochemical indices (insulin and glucagon). Aforementioned results are appreciated by the histopathological findings of pancreatic tissue. In conclusion, our data have brought about compelling evidence favoring the antidiabetic potency of elemental selenium nanoparticles delivered in liposomes through preservation of pancreatic β cell integrity with consequent increment of insulin secretion and in turn glucose depletion, repression of oxidative stress, potentiation of the antioxidant defense system, and inhibition of pancreatic inflammation.     

Development of Norwalk Virus-Specific Monoclonal Antibodies with Therapeutic Potential for the Treatment of Norwalk Virus Gastroenteritis

Passive immunoprophylaxis or immunotherapy with norovirus-neutralizing monoclonal antibodies (MAbs) could be a useful treatment for high-risk populations, including infants and young children, the elderly, and certain patients who are debilitated or immunocompromised. In order to obtain antinorovirus MAbs with therapeutic potential, we stimulated a strong adaptive immune response in chimpanzees to the prototype norovirus strain Norwalk virus (NV) (genogroup I.1). A combinatorial phage Fab display library derived from mRNA of the chimpanzees'' bone marrow was prepared, and four distinct Fabs reactive with Norwalk recombinant virus-like particles (rVLPs) were recovered, with estimated binding affinities in the subnanomolar range. Mapping studies showed that the four Fabs recognized three different conformational epitopes in the protruding (P) domain of NV VP1, the major capsid protein. The epitope of one of the Fabs, G4, was further mapped to a specific site involving a key amino acid residue, Gly365. One additional specific Fab (F11) was recovered months later from immortalized memory B cells and partially characterized. The anti-NV Fabs were converted into full-length IgG (MAbs) with human γ1 heavy chain constant regions. The anti-NV MAbs were tested in the two available surrogate assays for Norwalk virus neutralization, which showed that the MAbs could block carbohydrate binding and inhibit hemagglutination by NV rVLP. By mixing a single MAb with live Norwalk virus prior to challenge, MAbs D8 and B7 neutralized the virus and prevented infection in a chimpanzee. Because chimpanzee immunoglobulins are virtually identical to human immunoglobulins, these chimpanzee anticapsid MAbs may have a clinical application.     

Identification of Potential Carbonic Anhydrase Inhibitors for Glaucoma Treatment Through an In-Silico Approach

Glaucoma is a neurodegenerative disease and second leading cause of blindness in western world. The disease is characterized by an elevated intraocular pressure. Carbonic anhydrase plays a major role by forming aqueous humor and its inhibition can reduce intraocular pressure by partially suppressing the secretion of aqueous humor. Thus in this study, we proposed to identify the potential novel compounds targeting the carbonic anhydrase. The diversity set-II molecules library consisting of 1880 compounds from National Cancer Institute were virtually screened (molecular docking) against human carbonic anhydrase protein. For the obtained best compounds, the nature of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), which determine nucleophilic and electrophilic activity, were calculated by using density functional theory (DFT). The in silico screening suggested 5 best compounds that are effective in comparison to the dorzolamide, a widely used carbonic anhydrase inhibitor for glaucoma treatment. Of the five compounds, 4-nitro-7-[(1-oxidopyridin-1-ium-2-yl) thio] benzofurazan (ZINC01757986) exhibited the better binding affinity (??9.2 cal/mol) in comparison to dorzolamide (??7.2 kcal/mol). The DFT studies on novel identified compound, ZINC01757986 exhibited less HOMO–LUMO energy gap, low hardness and more softness (0.2305 eV, 0.1152 eV and 8.6805 eV) when compared to dorzalamide (0.9536 eV, 0.4768 eV and 2.0973 eV). These studies emphasize that ZINC01757986 can be used as potential carbonic anhydrase inhibitor and lead compounds for the development of an effective anti-glaucoma drug. The results emphasize that these compounds could be potential lead molecules for further structure-based discovery of antiglaucoma drugs.

     

Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes

The complex mechanistic array underlying the pathogenesis of myelodysplastic syndrome (MDS) is still unclear. Although dysregulations of different signaling pathways involved in MDS have been described, the identification of specific biomarkers and therapy targets remains an important task in order to establish novel therapeutic approaches. Here, we demonstrated that the Shh signaling pathway is active in MDS and correlated it with disease progression. Additionally, the knockdown of Gli1 significantly inhibited cell proliferation in vitro and in vivo. Gli1 silencing also induced apoptosis and G0/G1 phase arrest. Furthermore, Gli1 silencing enhanced the demethylating effect of 5-aza-2''-deoxycytidine on the p15 gene promoter and subsequently promoted its expression by inhibiting DNA methyltransferase 1(DNMT1). Our findings show that the Shh signaling pathway plays a role in the pathogenesis and disease progression of MDS, and proceeds by modulating DNA methylation. This pathway may prove to be a potential therapeutic target for enhancing the therapeutic effects of 5-azacytidine on malignant transformation of MDS.     

New Donors and Acceptors of Nitrogen Oxide as Potential Therapeutic Agents

The synthesis of new donors and acceptors of nitrogen oxide is described. New lipophilic nitronylnitroxyl radicals (NNR) that act as paramagnetic scavengers of nitrogen oxide are synthesized and characterized. The purity of the preparations is determined, and their structures are confirmed. The lipophilicity of the radicals is tested by ESR spectroscopy. The incorporation into lipid multilayers is shown to protect NNR from reduction in biological samples, while their ability to scavenge nitrogen oxide and form iminonitroxyl radicals is retained. A decreased rate of NNR reduction under these conditions substantially enhances their effectiveness as paramagnetic acceptors of nitrogen oxide in biological systems. The synthesis of a new hydrophilic NO donor, 3-bromo-3,4-dihydro-4,4-dimethyl-3-(2-pyridyl)-diazet-1,2-dioxide (DD_pyr), is described. The constants of DD_pyr decomposition in tris-HCl buffer (pH 7.5) and in DMSO are determined (4.5 × 10^–6 and 0.5 × 10^–6 s^–1, respectively). A substantially higher rate of DD_pyr decomposition in buffer, compared with the decomposition rates determined previously for some diazetines, makes DD_pyr a prospective candidate for the use in aqueous media. It is found in experiments on perfused rat caudal artery that DD_pyr is an effective vasodilator. Intraperitoneal injection of DD_pyr to hereditarily hypertensive rats (ISIAH line) at doses of 100–200 g/kg body mass considerably diminishes their systolic arterial pressure.     

Modified Treatment Approach Using Cardiovascular Disease Risk Calculator for Primary Prevention

Background

The recent guidelines for preventing atherosclerotic cardiovascular events are an important advancement. For primary prevention, statins are recommended if the ten-year risk is ≥ 5% (consideration for therapy) or ≥ 7.5% (definitive treatment unless contraindication after discussion). We rationalized that a significant cohort with ten-year risk below the treatment thresholds would predictably surpass them within the recommended 4–6 year window for reassessing the ten-year risk. As atherosclerosis is a progressive disease, these individuals may therefore benefit with more aggressive therapies even at baseline.

Methods and Findings

We used publicly available NHANES dataset for ten-year risk calculation. There were 1805 participants. To evaluate the ten-year risk change at five years, we considered two scenarios: no change in the baseline parameters except increased age by five (No Change) and alternatively 10% improvement in systolic BP, total and HDL-c, no smoking with five-year increase in age (Reduced Risk Profile). Amongst non-diabetics with <5% risk at baseline, 35% reached or exceeded 5% risk in five years (5% reached or exceed the 7.5% risk) with No Change and 9% reached or exceeded 5% risk in five years (none reached 7.5% risk) with Reduced Risk Profile; furthermore, 94% of the non-diabetic cohort with baseline risk between 3.5%–5% would exceed the 5% and/or 7.5% boundary limit with No Change. Amongst non-diabetics with 5–7.5% baseline risks, 87% reached or exceeded 7.5% with No Change while 30% reached or exceeded 7.5% risk with Reduced Risk Profile.

Conclusions

A significant population cohort at levels below the treatment thresholds will predictably exceed these limits with time with or without improvement in modifiable risk factors and may benefit with more aggressive therapy at baseline. We provide an improved risk calculator that allows for integrating expected risk modification into discussion with an individual. This needs to be prospectively tested in clinical trials.     

An Innovative Approach for Using the GRAI Methodology for Reengineering the New Product Introduction Process

This paper represents the culmination of a four-year ethnographic research project in a leading U.K. manufacturing company. A number of organizational deficiencies in the new product introduction (NPI) process are identified. Proposals subsequently are implemented that enhance the effectiveness of this process. The paper identifies the critical need for organizations to communicate effectively among different functional areas with respect to new products. A review of modeling techniques identifies the GRAI grid as an effective model for analyzing and improving cooperative business processes. The GRAI grid is set within the framework of a novel implementation methodology and subsequently is applied to the NPI process within the collaborating company. The paper concludes by reporting the substantial benefits gained.     

Nanotechnology as a New Therapeutic Approach to Prevent the HIV-Infection of Treg Cells

Background

HIV-1 has proved to infect regulatory T cells (Treg) modifying their phenotype and impairing their suppressive capacity. As Treg cells are a crucial component in the preservation of the immune homeostasis, we researched that the antiviral capacity of carboxilan dendrimers prevents the HIV-1 infection of Treg and their effects. The phenotype and suppressive capacity of Treg treated or non-treated with carbosilane dendrimers were studied by flow cytometry. Treated and non-treated Treg from healthy donors were infected with HIV-1_NL4.3. The infection of Treg cells by HIV-1, and protective effect of two dendrimers were determined by measuring antigen p24^gag in the supernatant of the culture and intracellular.

Results

The Treg cells were treated with cationic and anionic carbosilane dendrimers. The results showed that both dendrimers did not modify the phenotype and functionality of Treg cells compared with non- treated Treg cells. Anionic dendrimers showed high biocompatibility with normal activity of the Treg cells and in antiviral assays. These dendrimers were highly active against HIV-1 preventing the infection of Treg, and were able to protect the Treg from the Foxp3 downregulation induced by the HIV-1 infection.

Conclusions

This is the first work showing that the in vitro use of anionic dendrimers prevent the HIV-1 replication and the infection of expanded Treg cells in culture, which raises the possibility to use Treg cells therapeutically in HIV-1-infected subjects.     

Therapeutic Potential of Berberine in the Treatment of Glioma: Insights into Its Regulatory Mechanisms

Glioma is known as one of the most common primary intracranial tumors accounting for four-fifths of malignant brain tumors. There are several biological pathways that play a synergistic, pathophysiological role in glioma, including apoptosis, autophagy, oxidative stress, and cell cycle arrest. According to previous rese arches, the drugs used in the treatment of glioma have been associated with significant limitations. Therefore, improved and/or new therapeutic platforms are required. In this regard, multiple flavonoids and alkaloids have been extensively studied in the treatment of glioma. Berberine is a protoberberine alkaloid with wide range of pharmacological activities, applicable to various pathological conditions. Few studies have reported beneficial roles of berberine in glioma. Berberine exerts its pharmacological functions in glioma by controlling different molecular and cellular pathways. We reviewed the existing knowledge supporting the use of berberine in the treatment of glioma and its effects on molecular and cellular mechanisms.