Novel estrogen receptor β/histone deacetylase dual-targeted near-infrared fluorescent probes as theranostic agents for imaging and treatment of prostate cancer

Article

作者: Yu, Huiguang ; Xin, Lilan ; Zhou, Hai-Bing ; He, Pei ; Xu, Bin ; Dong, Chune ; Deng, Xiaofei

Estrogen receptor (ER) β and histone deacetylases (HDACs), when overexpressed, are associated closely with the occurrence and development of prostate cancer and are, therefore, considered important targets and biomarkers used in the clinical treatment of prostate cancer. The present study involved the design and synthesis of the first ERβ and HDAC dual-target near-infrared fluorescent probe with both imaging capacity and antitumor activity for prostate cancer. Both P1 and P2 probes exhibited excellent ERβ selectivity, with P1 being almost exclusively selective for ERβ compared to ERα. In addition, P1 exhibited good optical properties, such as strong near-infrared emission, large Stokes shift, and better anti-interference ability, along with excellent imaging ability for living cells. P1 also exhibited potent inhibitory activity against HDAC6 and DU-145 cells, with IC₅₀ values of 52 nM and 0.96 μM, respectively. Further, P1 was applied successfully for the in vivo imaging of prostate cancer in a mouse model, and significant in vivo antitumor efficacy was achieved. The developed dual-target NIR fluorescent probe is expected to serve as an effective tool in the research on prostate cancer, leading to novel insights for the theranostic study of diseases related to ERβ and HDACs.

2024-01-01·Journal of hazardous materials

A novel mixture sampling strategy combining latin hypercube sampling with optimized one factor at a time method: A case study on mixtures of antibiotics and pesticides

Article

作者: Huang, Peng ; Wang, Ze-Jun ; Gu, Zhong-Wei ; Liu, Shu-Shen ; Tao, Meng-Ting ; Ding, Ting-Ting

Global sensitivity analysis in conjunction with quantitative high-throughput screening presents a novel technique for identifying the key components that induce the toxicities of mixtures. However, the mixtures currently designed with this method suffer from unequal frequency sampling, repeated mixtures, and only odd factor levels being considered. Accordingly, we use latin hypercube sampling to generate the starting points of the trajectories to achieve equal frequency sampling and non-repeated mixtures, as well as apply different one factor at a time methods for factors with odd and even levels to achieve suitability for factors with both odd and even levels. This method is called LHS-OAT. LHS-OAT was successfully applied to design 110 equal-frequency and non-repeated mixtures consisting of six antibiotics and four pesticides. It was found that four factors, roxithromycin (A5), tetracycline (A6), dichlorvos (P1), and demeton-S (P3), induce the toxicities of mixtures, and A5 and P1 in the Shaying River Basin have risk quotients ≥ 1. Additionally, we developed the toxicity deviation ratio to correct the risk quotients of interacting mixtures for effective risk assessments. This study provides a rational and effective method for mixture design that accurately identifies the important factors that induce the toxicities of mixtures.

2024-01-01·Journal of advanced veterinary and animal research

The anti-obesity properties of Anredera cordifolia leaf extract in rats fed a high-fat diet through inhibition of adipogenesis

Article

作者: Rusdiana, Rusdiana ; Widyawati, Tri ; Putra, Deddi Prima ; Widjaja, Sry Suryani ; Sari, Dina Keumala

Objective: Various disease complications are a risk of overweight or obesity, so losing weight can reduce the risk of diseases caused by obesity. Binahong leaf ethanol extract (Anredera cordifolia) is a weight-loss herbal preparation. Aim: This study aims to analyze whether A. cordifolia extract is effective in losing weight by affecting the mechanism of adipogenesis in an animal obesity model. Materials and Methods: Animals were grouped into six groups as follows: the normal diet (K1), the negative control group (K2), the positive control group with Orlistat at a dose of 20 mg/kg BW (K3), an ethanol extract of A. cordifolia leaves at doses of 50 mg/kg BW (P1), 100 mg/kg BW group (P2), and 150 mg/kg BW (P3). All rats were fed a diet that consisted of high fat for eight weeks, except K1. Afterward, the treatments were given based on group distribution. Then, the rats were treated based on their groups for 4 weeks, and the high-fat diet was still given during the treatment for the control groups (K2). Anthropometric examinations such as body weight, length, and the circumference of the abdomen were measured. Metabolic parameters, including blood glucose, cholesterol levels, triglyceride levels, and abdominal fat weight, were measured using molecular parameters that measured PI3K levels and Extracellular signal-regulated kinase (ERK) in abdominal fat tissue samples using the ELISA method. Results: ERK levels of abdominal fat were lowered in the treatment group using the extract of A. cordifolia (50 mg/kg BW (P1) and 100 mg/kg BW (P2)) compared to the control group that was given a high-fat diet without treatment. The control group, which was fed a high-fat diet without treatment, had an average ERK level of 10.17 ± 2.98 ng/ml, P1 (50 mg/kg BW). Furthermore, when ethanol extracts were used as opposed to the control group, which received a high-fat diet without treatment, there was an increase in phosphoinositide three-kinase (PI3K) levels (K2). The control group received 9.35 ± 2.87 ng/ml, the treatment group received 100 mg/kg BW (P2) 9.48 ± 1.54 ng/ml, and the treatment group received 150 mg/kg BW (P3) 7.87 ± 1.79 ng/ml. The weight of fat in the abdomen differed between the groups that received a high-fat diet without treatment (K2) and those that received a high-fat diet with treatment (P1, P2, P3; p < 0.05). Conclusion: Anredera cordifolia extract possesses anti-obesity activities by decreasing ERK and increasing PI3K levels, as well as reducing abdominal fat weight.

项与 Zemaphyte 相关的新闻（医药）

2024-03-20

·GlobeNewswire-Health Care

Patent Allowance Granted for P-1 Molecule by US Patent and Trademark Office

Novel MDMA-Like Drug Could Be Used for Numerous Neurological and Psychiatric IndicationsTORONTO, March 20, 2024 (GLOBE NEWSWIRE) -- PharmAla Biotech Holdings Inc. (“PharmAla” or the “Company”) (CSE: MDMA) (OTC:MDXXF), a biotechnology company focused on the research, development, and manufacturing of LaNeo™ MDMA and novel derivatives of MDMA (MDXX class molecules), is thrilled to announce that allowance has been granted for the Composition of Matter of its PharmAla-1 (P-1) molecule by the US Patent and Trademark Office (USPTO). P-1 is an enantiomerically pure composition of ((R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine. “In proof-of-concept rodent models at the laboratory of Prof. William Fantegrossi, P-1 showed a number of features which we believe to be extremely valuable in a therapeutic context,” said Dr. Harpreet Kaur, Vice President of Research at PharmAla Biotech. “The molecule has an excellent therapeutic window; it shows a strong pro-social signal at dosage levels far below racemic MDMA. We also believe it can induce neuroplasticity, like many drugs in the tryptamine class, by crossing the cell membrane and binding to serotonin receptors within the cell. And of course, like all the molecules we choose to develop, P-1 has an excellent safety profile with low abuse liability.” The composition was identified through PharmAla’s computational chemistry program at the University of Windsor, made possible by a grant from the Ontario Centres of Innovation. P-1 was submitted to the USPTO through the Patent Prosecution Highway program, allowing for accelerated patent examination. As the molecule is ready for pre-clinical and clinical development, the Company has elected to change its designation to APA-001. “We foresee that APA-001 could potentially be used in a number of indications. The company is currently assessing those indications which show the most promise,” said Nick Kadysh, Founding CEO, PharmAla Biotech. “The potential for a drug that could not only assist with psychological trauma, but also neurological damage, could find broad applicability in the treatment of conditions such as Traumatic Brain Injury (TBI) and stroke. In addition there is potential applicability for the fear disorders often discussed in the context of MDMA.” About PharmAla PharmAla Biotech Holdings Inc. (CSE: MDMA)(OTCQB:MDXXF) is a biotechnology company focused on the research, development, and manufacturing of MDXX class molecules, including MDMA. PharmAla was founded with a dual focus: alleviating the global backlog of generic, clinical-grade MDMA to enable clinical trials as well as commercial sales in selected jurisdictions, and to develop novel drugs in the same class. PharmAla is the only company currently provisioning clinical-grade MDMA for patient treatments outside of clinical trials. PharmAla’s research and development unit has completed proof-of-concept research into several IP families, including ALA-002, its lead drug candidate. PharmAla is a “regulatory first” organization, formed under the principle that true success in the psychedelics industry will only be achieved through excellent relationships with regulators. For more information, please contact:Nicholas KadyshChief Executive OfficerPharmAla Biotech Holdings Inc.Email: press@PharmAla.caPhone: 1-855-444-6362Website: www.PharmAla.ca Neither the Canadian Securities Exchange nor its Regulation Services Provider have reviewed or accept responsibility for the adequacy or accuracy of this release. Cautionary Statement This press release contains ‘forward-looking information’ within the meaning of applicable Canadian securities legislation. These statements relate to future events or future performance. The use of any of the words “could”, “intend”, “expect”, “believe”, “will”, “projected”, “estimated” and similar expressions and statements relating to matters that are not historical facts are intended to identify forward-looking information and are based on PharmAla’s current belief or assumptions as to the outcome and timing of such future events. Forward-looking information is based on reasonable assumptions that have been made by PharmAla at the date of the information and is subject to known and unknown risks, uncertainties, and other factors that may cause actual results or events to differ materially from those anticipated in the forward-looking information. The forward-looking information contained in this press release is made as of the date hereof, and PharmAla is not obligated to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as required by applicable securities laws. Factors that could cause actual results to differ materially from those anticipated in these forward-looking statements are described under the caption “Risk Factors” in PharmAla’s management’s discussion and analysis which is available on PharmAla’s profile at www.sedar.com. This news release does not constitute an offer to sell or the solicitation of an offer to buy, and shall not constitute an offer, solicitation or sale in any state, province, territory or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state, province, territory or jurisdiction. A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/351506ca-33a3-4545-a1a7-6d44accfaa0e

2024-03-20

·BioSpace

Patent Allowance Granted for P-1 Molecule by US Patent and Trademark OfficeNovel MDMA-Like Drug Could Be Used for Numerous Neurological and Psychiatric Indications

TORONTO, March 20, 2024 (GLOBE NEWSWIRE) -- PharmAla Biotech Holdings Inc. (“PharmAla” or the “Company”) (CSE: MDMA) (OTC:MDXXF), a biotechnology company focused on the research, development, and manufacturing of LaNeo™ MDMA and novel derivatives of MDMA (MDXX class molecules), is thrilled to announce that allowance has been granted for the Composition of Matter of its PharmAla-1 (P-1) molecule by the US Patent and Trademark Office (USPTO). P-1 is an enantiomerically pure composition of ((R)-2-[(2H-1,3-benzodioxol-5-yl)methyl]pyrrolidine. “In proof-of-concept rodent models at the laboratory of Prof. William Fantegrossi, P-1 showed a number of features which we believe to be extremely valuable in a therapeutic context,” said Dr. Harpreet Kaur, Vice President of Research at PharmAla Biotech. “The molecule has an excellent therapeutic window; it shows a strong pro-social signal at dosage levels far below racemic MDMA. We also believe it can induce neuroplasticity, like many drugs in the tryptamine class, by crossing the cell membrane and binding to serotonin receptors within the cell. And of course, like all the molecules we choose to develop, P-1 has an excellent safety pro low abuse liability.” The composition was identified through PharmAla’s computational chemistry program at the University of Windsor, made possible by a grant from the Ontario Centres of Innovation. P-1 was submitted to the USPTO through the Patent Prosecution Highway program, allowing for accelerated patent examination. As the molecule is ready for pre-clinical and clinical development, the Company has elected to change its designation to APA-001. “We foresee that APA-001 could potentially be used in a number of indications. The company is currently assessing those indications which show the most promise,” said Nick Kadysh, Founding CEO, PharmAla Biotech. “The potential for a drug that could not only assist with psychological trauma, but also neurological damage, could find broad applicability in the treatment of conditions such as Traumatic Brain Injury (TBI) and stroke. In addition there is potential applicability for the fear disorders often discussed in the context of MDMA.” About PharmAla PharmAla Biotech Holdings Inc. (CSE: MDMA)(OTCQB:MDXXF) is a biotechnology company focused on the research, development, and manufacturing of MDXX class molecules, including MDMA. PharmAla was founded with a dual focus: alleviating the global backlog of generic, clinical-grade MDMA to enable clinical trials as well as commercial sales in selected jurisdictions, and to develop novel drugs in the same class. PharmAla is the only company currently provisioning clinical-grade MDMA for patient treatments outside of clinical trials. PharmAla’s research and development unit has completed proof-of-concept research into several IP families, including ALA-002, its lead drug candidate. PharmAla is a “regulatory first” organization, formed under the principle that true success in the psychedelics industry will only be achieved through excellent relationships with regulators. For more information, please contact: Nicholas Kadysh Chief Executive Officer PharmAla Biotech Holdings Inc. Email: press@PharmAla.ca Phone: 1-855-444-6362 Website: Neither the Canadian Securities Exchange nor its Regulation Services Provider have reviewed or accept responsibility for the adequacy or accuracy of this release. Cautionary Statement This press release contains ‘forward-looking information’ within the meaning of applicable Canadian securities legislation. These statements relate to future events or future performance. The use of any of the words “could”, “intend”, “expect”, “believe”, “will”, “projected”, “estimated” and similar expressions and statements relating to matters that are not historical facts are intended to identify forward-looking information and are based on PharmAla’s current belief or assumptions as to the outcome and timing of such future events. Forward-looking information is based on reasonable assumptions that have been made by PharmAla at the date of the information and is subject to known and unknown risks, uncertainties, and other factors that may cause actual results or events to differ materially from those anticipated in the forward-looking information. The forward-looking information contained in this press release is made as of the date hereof, and PharmAla is not obligated to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as required by applicable securities laws. Factors that could cause actual results to differ materially from those anticipated in these forward-looking statements are described under the caption “Risk Factors” in PharmAla’s management’s discussion and analysis which is available on PharmAla’s pro This news release does not constitute an offer to sell or the solicitation of an offer to buy, and shall not constitute an offer, solicitation or sale in any state, province, territory or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state, province, territory or jurisdiction. A photo accompanying this announcement is available at P-1 molecular structure P-1 molecular structure

2024-01-08

·BioSpace

PharmAla-1 Molecule Receives US Patent Prosecution Highway Acceptance

VANCOUVER, British Columbia, Jan. 08, 2024 (GLOBE NEWSWIRE) -- PharmAla Biotech Holdings Inc. (“PharmAla” or the “Company”) (CSE: MDMA) (OTC:PMBHF), a biotechnology company focused on the research, development, and manufacturing of novel derivatives of MDMA (MDXX class molecules), is proud to announce that it has received approval to move its PharmAla-1 (P1) molecule through the US Patent and Trademark Office (USPTO) Patent Prosecution Highway pathway based on the positive Patent Cooperation Treaty (PCT) initial office action previously announced by PharmAla. “The dawn of MDMA as a therapeutic molecule is just beginning, and while we are actively working to treat patients with that molecule, we are also looking towards a future with novel molecular assets,” said Nick Kadysh, CEO, PharmAla Biotech. “P-1 is one of a number of next-generation assets which we are developing, and which promise to bring together both increased safety, and highly beneficial effects like increased neuroplasticity.” The Patent Prosecution Highway (PPH) speeds up the examination process for corresponding applications filed in participating intellectual property offices. Under PPH, participating patent offices have agreed that when an applicant receives a ruling from a first patent office indicating that at least one claim is allowable, the applicant may request fast track examination of corresponding claims. PharmAla-1 was first discovered through computational in-silico modelling exercises via PharmAla Biotech’s partnership with the University of Windsor, for which PharmAla has also received a grant from the Ontario Centres for Innovation. Proof-of-concept testing for P-1 showed significant efficacy and pro-social effect at dosage levels far lower than MDMA, PharmAla’s primary comparator molecule, as well as excellent safety pharmacology. P-1 is not considered a controlled substance anywhere in the world. PharmAla will attend the J.P. Morgan 42nd Annual Healthcare Conference taking place in San Francisco on January 8-11th, where it intends to share the recent developments for P-1 and its other research programs with potential pharmaceutical industry partners. For more information, please visit , where you can sign up to receive regular new updates. About PharmAla PharmAla Biotech Holdings Inc. (CSE: MDMA) is a biotechnology company focused on the research, development, and manufacturing of MDXX class molecules, including MDMA. PharmAla was founded with a dual focus: alleviating the global backlog of generic, clinical-grade MDMA to enable clinical trials as well as commercial sales in selected jurisdictions, and to develop novel drugs in the same class. PharmAla is the first publicly-traded company to manufacture clinical-grade MDMA. PharmAla’s research and development unit has completed proof-of-concept research into several IP families, including ALA-002, its lead drug candidate. PharmAla is a “regulatory first” organization, formed under the principle that true success in the psychedelics industry will only be achieved through excellent relationships with regulators. For more information, please contact: Nicholas Kadysh Chief Executive Officer PharmAla Biotech Holdings Inc. Email: press@PharmAla.ca Phone: 1-855-444-6362 Website: Neither the Canadian Securities Exchange nor its Regulation Services Provider have reviewed or accept responsibility for the adequacy or accuracy of this release. Cautionary Statement This press release contains ‘forward-looking information’ within the meaning of applicable Canadian securities legislation. These statements relate to future events or future performance. The use of any of the words “could”, “intend”, “expect”, “believe”, “will”, “projected”, “estimated” and similar expressions and statements relating to matters that are not historical facts are intended to identify forward-looking information and are based on PharmAla’s current belief or assumptions as to the outcome and timing of such future events. Forward-looking information is based on reasonable assumptions that have been made by PharmAla at the date of the information and is subject to known and unknown risks, uncertainties, and other factors that may cause actual results or events to differ materially from those anticipated in the forward-looking information. The forward-looking information contained in this press release is made as of the date hereof, and PharmAla is not obligated to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as required by applicable securities laws. Factors that could cause actual results to differ materially from those anticipated in these forward-looking statements are described under the caption “Risk Factors” in PharmAla’s management’s discussion and analysis which is available on PharmAla’s pro This news release does not constitute an offer to sell or the solicitation of an offer to buy, and shall not constitute an offer, solicitation or sale in any state, province, territory or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state, province, territory or jurisdiction.

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