Contribution of telacebec to novel drug regimens in a murine tuberculosis model.

The clinical efficacy of combination drug regimens containing the first-generation diarylquinoline (DARQ) bedaquiline in the treatment of multidrug-resistant tuberculosis has validated ATP synthesis as a vulnerable pathway in . New DARQs in clinical development may be even more effective than bedaquiline, including against emerging bedaquiline-resistant strains. Telacebec (T) is a novel cytochrome bc:aa oxidase inhibitor that also inhibits ATP synthesis.

Inhibition of hepatocellular carcinoma progression by methotrexate-modified pH-sensitive sorafenib and schisandrin B micelles.

Due to the lack of specific symptoms, hepatocellular carcinoma (HCC) is often detected in advanced stages. However, pharmacological systemic therapy, a common clinical treatment for advanced HCC, is prone to serious toxic side effects. To address these issues, we designed a pH-sensitive sorafenib and schisandrin B micelle modified by methotrexate (MTX-SOR/SchB micelles), a nanosystem that combines the advantages of targeted delivery and pH sensitivity, and is capable of improving drug bioavailability and mitigating drug toxic side effects.

Contribution of direct InhA inhibitors to novel drug regimens in a mouse model of tuberculosis.

Isoniazid is an important first-line medicine to treat tuberculosis (TB). Isoniazid resistance increases the risk of poor treatment outcomes and development of multidrug resistance, and is driven primarily by mutations involving , encoding the prodrug-activating enzyme, rather than its validated target, InhA. The chemical tractability of InhA has fostered efforts to discover direct inhibitors of InhA (DIIs).

Enhanced dynamic covalent chemistry for the controlled release of small molecules and biologics from a nanofibrous peptide hydrogel platform.

Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs).

Hyaluronidase impacts exposures of long-acting injectable paliperidone palmitate in rodent models.

A significant challenge in the development of long-acting injectable drug formulations, especially for anti-infective agents, is delivering an efficacious dose within a tolerable injection volume. Co-administration of the extracellular matrix-degrading enzyme hyaluronidase can increase maximum tolerable injection volumes but is untested for this benefit with long-acting injectable formulations. One concern is that hyaluronidase could potentially alter the tissue response surrounding an injection depot, a response known to be important for drug release kinetics of long-acting injectable formulations.

Trilobolide-6-O-isobutyrate exerts anti-tumor effects on cholangiocarcinoma cells through inhibiting JAK/STAT3 signaling pathway.

Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner.

Neuroimaging research progress of acupuncture treatment for patients with functional dyspepsia.

Neuroimaging technology provides objective and visualized research tool to study the mechanisms of acupuncture effects. Building on a systematic review of previous clinical studies on acupuncture treatment for functional dyspepsia using neuroimaging technology, this paper summarizes and synthesizes past researches from 4 aspects： acupoint-specific effects, factors influencing the effects, different physiological responses, and predictive factors for acupuncture efficacy. It suggests that acupuncture treatment for FD involves central integration with disease-targeted (acupuncture treatment can target and regulate abnormal brain functional activity patterns in patients with FD), meridian-specific (stimulation of specific acupuncture points along the stomach meridian can significantly regulate abnormal brain functional activity patterns in FD patients), and dynamic conditional features(the effects of acupuncture treatment for FD are influenced by multiple factors).

Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis.

The combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We recently found that the addition of GSK2556286 increases the bactericidal and sterilizing activity of BPa-containing regimens in a well-established BALB/c mouse model of tuberculosis.

Contezolid can replace linezolid in a novel combination with bedaquiline and pretomanid in a murine model of tuberculosis.

Contezolid is a new oxazolidinone with and activity against comparable to that of linezolid. Pre-clinical and clinical safety studies suggest it may be less toxic than linezolid, making contezolid a potential candidate to replace linezolid in the treatment of drug-resistant tuberculosis. We evaluated the dose-ranging activity of contezolid, alone and in combination with bedaquiline and pretomanid, and compared it with linezolid at similar doses, in an established BALB/c mouse model of tuberculosis.

Mechano-biomimetic hydrogel 3D cell cultivation as a strategy to improve mammalian cell protein expression.

Eukaryotic expression systems are frequently employed for the production of recombinant proteins as therapeutics as well as research tools. Among which mammalian cell protein expression approach is the most powerful one, which can express complex proteins or genetic engineered biological drugs, such as PD-1. However, the high expense, which partially derives from its low protein yielding efficiency, limited the further application of such approach in large scale production of target proteins.

Using Dynamic Oral Dosing of Rifapentine and Rifabutin to Simulate Exposure Profiles of Long-Acting Formulations in a Mouse Model of Tuberculosis Preventive Therapy.

Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have antituberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens.

DPY30 Promotes Proliferation and Cell Cycle Progression of Colorectal Cancer Cells via Mediating H3K4 Trimethylation.

DPY30, a core subunit of the SET1/MLL histone H3K4 methyltransferase complexes, plays an important role in diverse biological functions through the epigenetic regulation of gene transcription, especially in cancer development. However, its involvement in human colorectal carcinoma (CRC) has not been elucidated yet. Here we demonstrated that DPY30 was overexpressed in CRC tissues, and significantly associated with pathological grading, tumor size, TNM stage, and tumor location.

Using dynamic oral dosing of rifapentine and rifabutin to simulate exposure profiles of long-acting formulations in a mouse model of tuberculosis preventive therapy.

Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have anti-tuberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens.

Adhesive cryogel particles for bridging confined and irregular tissue defects.

Background: Reconstruction of damaged tissues requires both surface hemostasis and tissue bridging. Tissues with damage resulting from physical trauma or surgical treatments may have arbitrary surface topographies, making tissue bridging challenging.

Methods: This study proposes a tissue adhesive in the form of adhesive cryogel particles (ACPs) made from chitosan, acrylic acid, 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS).

Next-Generation Diarylquinolines Improve Sterilizing Activity of Regimens with Pretomanid and the Novel Oxazolidinone TBI-223 in a Mouse Tuberculosis Model.

A regimen comprised of bedaquiline (BDQ, or B), pretomanid, and linezolid (BPaL) is the first oral 6-month regimen approved by the U.S. Food and Drug Administration and recommended by the World Health Organization for the treatment of extensively drug-resistant tuberculosis.

Retinoic Acid Receptor Gamma (RAR) Promotes Cartilage Destruction through Positive Feedback Activation of NF-B Pathway in Human Osteoarthritis.

Osteoarthritis (OA) is a severe inflammation-related disease which leads to cartilage destruction. The retinoic acid receptor gamma (RAR) has been indicated to be involved in many inflammation processes. However, the role and mechanism of RAR in cartilage destruction caused by inflammation in OA are still unknown.

Effects of (L.) L'Hér. ex Vent. fruits water extract on hippocampal neurogenesis in the treatment of APP/PS1 transgenic mice.

Adult neurogenesis plays an important role in repairing damaged neurons and improving cognitive impairment in Alzheimer's disease (AD). (L.) L'Hér.

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described.

GSK2556286 Is a Novel Antitubercular Drug Candidate Effective with the Potential To Shorten Tuberculosis Treatment.

As a result of a high-throughput compound screening campaign using Mycobacterium tuberculosis-infected macrophages, a new drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (50% inhibitory concentration [IC] = 0.07 μM), is active against extracellular bacteria in cholesterol-containing culture medium, and exhibits no cross-resistance with known antitubercular drugs.

Comparative Efficacy of the Novel Diarylquinoline TBAJ-876 and Bedaquiline against a Resistant Mutant in a Mouse Model of Tuberculosis.

Bedaquiline (BDQ, B) is the first-in-class diarylquinoline to be approved for treatment of tuberculosis (TB). Recent guidelines recommend its use in treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB). The newly approved regimen combining BDQ with pretomanid and linezolid is the first 6-month oral regimen proven to be effective against MDR/XDR-TB.

Trilobolide-6-O-isobutyrate suppresses hepatocellular carcinoma tumorigenesis through inhibition of IL-6/STAT3 signaling pathway.

Currently available therapies for hepatocellular carcinoma (HCC), with a high morbidity and high mortality, are only marginally effective and with sharp adverse side effects, which makes it compulsory to explore novel and more effective anticancer molecules. Chinese medicinal herbs exhibited prominent anticancer effects and were applied to supplement clinical cancer treatment. Here, we reported a compound, trilobolide-6-O-isobutyrate (TBB), isolated from the flowers of Wedelia trilobata with a markedly cytotoxic effect on HCC cells.

Diosgenin exerts anti-tumor effects through inactivation of cAMP/PKA/CREB signaling pathway in colorectal cancer.

Colorectal cancer (CRC) is the most fatal gastrointestinal tumor and it is urge to explore powerful drugs for the treatment. Diosgenin (DSG) as a new steroidal had been reported exerts anti-tumor activity in multiple cancers, including CRC. However, the potential mechanism of DSG suppresses CRC remains further to be revealed.

Deletion at an 1q24 locus reveals a critical role of long noncoding RNA DNM3OS in skeletal development.

Background: Skeletal development and maintenance are complex processes known to be coordinated by multiple genetic and epigenetic signaling pathways. However, the role of long non-coding RNAs (lncRNAs), a class of crucial epigenetic regulatory molecules, has been under explored in skeletal biology.

Results: Here we report a young patient with short stature, hypothalamic dysfunction and mild macrocephaly, who carries a maternally inherited 690 kb deletion at Chr.

Differential Activities of Individual Drugs and Bedaquiline-Rifabutin Combinations against Actively Multiplying and Nutrient-Starved Mycobacterium abscessus.

Current treatment options for lung disease caused by complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the bactericidal activity of single drugs against actively multiplying and net nonreplicating populations in nutrient-rich and nutrient-starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing , respectively.

Mutations in () as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis.

The nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior studies suggest a relatively low barrier to nitroimidazole resistance in , but clinical evidence is limited to date. We selected pretomanid-resistant mutants in two mouse models of TB using a range of pretomanid doses.