Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism12. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning7, as a novel and targetable vulnerability in PDAC. In human patient and murine PDAC samples, we discovered that PIKFYVE is overexpressed in PDAC cells compared to adjacent normal cells. Employing a genetically engineered mouse model, we established the essential role of PIKfyve in PDAC progression. Further, through comprehensive metabolic analyses, we found that PIKfyve inhibition obligated PDAC to upregulate de novo lipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggered a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, by upregulating genes such as FASN and ACACA. In PDAC, the KRAS-MAPK signaling pathway is a primary driver of de novo lipid synthesis, specifically enhancing FASN and ACACA levels. Accordingly, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in a syngeneic orthotopic model and tumor regression in a xenograft model of PDAC. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.

Discovery of LLC0424 as a Potent and Selective in Vivo NSD2 PROTAC Degrader.

Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC50 value of 20 nM and a Dmax value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively induce NSD2 degradation in a cereblon- and proteasome-dependent fashion. LLC0424 also caused continuous downregulation of H3K36me2 and growth inhibition of ALL cell lines with NSD2 mutation. Importantly, intravenous or intraperitoneal injection of LLC0424 showed potent NSD2 degradation in vivo.

Discovery and Optimization of Novel hDHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.

As a key rate-limiting enzyme in the de novo synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (hDHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1H-pyrazolo[3,4-b]pyridine scaffold was identified as an hDHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (w2), which was found to be the most promising and drug-like compound with potent inhibitory activity against hDHODH (IC50 = 173.4 nM). Compound w2 demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, w2 exerted better therapeutic effects on ulcerative colitis than hDHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising hDHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.

Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve.

The phosphoinositide kinase PIKfyve has emerged as a new potential therapeutic target in various cancers. However, limited clinical progress has been achieved with PIKfyve inhibitors. Here, we report the discovery of a first-in-class PIKfyve degrader 12d (PIK5-12d) by employing the proteolysis-targeting chimera approach. PIK5-12d potently degraded PIKfyve protein with a DC50 value of 1.48 nM and a Dmax value of 97.7% in prostate cancer VCaP cells. Mechanistic studies revealed that it selectively induced PIKfyve degradation in a VHL- and proteasome-dependent manner. PIKfyve degradation by PIK5-12d caused massive cytoplasmic vacuolization and blocked autophagic flux in multiple prostate cancer cell lines. Importantly, PIK5-12d was more effective in suppressing the growth of prostate cancer cells than the parent inhibitor and exerted prolonged inhibition of downstream signaling. Further, intraperitoneal administration of PIK5-12d exhibited potent PIKfyve degradation and suppressed tumor proliferation in vivo. Overall, PIK5-12d is a valuable chemical tool for exploring PIKfyve-based targeted therapy.

Structure-Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis.

Discovery of novel antitubercular drugs is an effective strategy against drug-resistant tuberculosis (TB). Our previous study has identified LPX-16j as a novel antitubercular compound. Herein, we perform a comprehensive structure-activity relationship (SAR) based on LPX-16j, indicating that the central pyrimidine ring moiety was crucial for the antitubercular activities of its derivatives, and replacing the naphthyl group with hydrophobic substitutes was well tolerated. The representative derivative 5a exhibited potent activity against H37Ra, H37Rv, and clinical drug-resistant TB with minimum inhibitory concentration (MIC) values of 0.5-1.0 µg/mL. Meanwhile, 5a showed an acceptable safety in vivo and displayed a favorable oral bioavailability with a value of 40.7%. The differential scanning fluorescence, isothermal titration calorimetry, and molecular docking assays indicated that PknB could be one of the targets of compound 5a. Overall, this study identified 5a as a novel promising lead compound with the potential to develop candidates for the treatment of drug-resistant TB.

Discovery of potent human dihydroorotate dehydrogenase inhibitors based on a benzophenone scaffold.

Blocking the de novo biosynthesis of pyrimidine by inhibiting human dihydroorotate dehydrogenase (hDHODH) is an effective way to suppress the proliferation of cancer cells and activated lymphocytes. Herein, eighteen teriflunomide derivatives and four ASLAN003 derivatives were designed and synthesized as novel hDHODH inhibitors based on a benzophenone scaffold. The optimal compound 7d showed a potent hDHODH inhibitory activity with an IC50 value of 10.9 nM, and displayed promising antiproliferative activities against multiple human cancer cells with IC50 values of 0.1-0.8 µM. Supplementation of exogenous uridine rescued the cell viability of 7d-treated Raji and HCT116 cells. Meanwhile, 7d significantly induced cell cycle S-phase arrest in Raji and HCT116 cells. Furthermore, 7d exhibited favorable safety profiles in mice and displayed effective antitumor activities with tumor growth inhibition (TGI) rates of 58.3% and 42.1% at an oral dosage of 30 mg/kg in Raji and HCT116 cells xenograft models, respectively. Taken together, these findings provide a promising hDHODH inhibitor 7d with potential activities against some tumors.

[Short term clinical observation of cervical anterior Hybrid surgery].

OBJECTIVE: To investigate the short-term clinical effect of the cervical anterior Hybrid surgery in the treatment of two-segment and three-segment cervical spondylosis. METHODS: From January 2018 to January 2019, 108 patients who were performed anterior Hybrid surgery with cervical degenerative diseases were collected. The patients were divided into a two-segment group with 52 patients and a three-segment group with 56 patients according to surgical segments. In two-segment group, there were 24 males and 28 females, aged from 35 to 67 years old with an average of(45.94±14.67) years old. In three-segment group, there were 23 males and 33 females, aged from 32 to 65 years old with an average of (47.54±15.34) years old. The outcome indicators of the two groups were compared. Clinical indicators:neck disability index(NDI) was used to evaluate daily life ability, Japanese Orthopedic Association(JOA) score was used to evaluate neurological function improvement, visual analogue scale(VAS) was used to evaluate pain intensity, and general clinical results were graded according to Odom's score. Cervical range of motion (ROM), fusion and complications were measured by X-ray, CT and MRI. RESULTS: All operations were successfully completed and all patients were followed up for more than 12 months. The operation time of two-segment group and three-segment group were 95 to 180 min with an average of(152.30±44.74) min and 110 to 210 min with an average of (165.18±45.86) mins, the blood loss were 20 to 100 ml with an average of (32.88±8.75) ml and 20 to 150 ml with an average of(34.64±10.63) ml respectively which has no statistical differences between the two groups (P>0.05). Compared with those before surgery, NDI, JOA, VAS and Odom's scores between two groups were significantly improved at 12 months after operation(P<0.05). However, there was no significant difference in the NDI, JOA and Odom's scores between two groups (P>0.05), and VAS in three-segment group was higher than that in two-segment group. There was no significant difference in C3-C7 cervical mobility between two groups. Surgical incisions healed smoothly in all patients without complication such as spinal cord injury and cerebrospinal fluid leakage. The bone fusion of the two groups were 43 cases (82.69%) and 45 cases(80.35%) respectively. In two-segment group, there were 2 cases of adjacent segmental hyperosteogeny, and there were 3 cases of adjacent segmental hyperosteogeny and 1 case of adjacent posterior longitudinal ligament ossification in the three-segment group. In addition, in three-segment group, there was 1 case of looseness of implants with no obvious clinical symptoms. CONCLUSION: The anterior Hybrid surgery in treating multi-level cervical spondylosis could not only improve clinical symptoms of patients but also preserve mobility. Meanwhile, the efficacy and safety of Hybrid surgery in different multi-level cervical disc diseases are confirmed, proving its value in clinical practice.

Discovery and Mechanistic Study of Mycobacterium tuberculosis PafA Inhibitors.

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis (Mtb) and is ranked as the second killer infectious disease after COVID-19. Proteasome accessory factor A (PafA) is considered an attractive target because of its low sequence conservation in humans and its role in virulence. In this study, we designed a mutant of Mtb PafA that enabled large-scale purification of active PafA. Using a devised high-throughput screening assay, two PafA inhibitors were discovered. ST1926 inhibited Mtb PafA by binding in the Pup binding groove, but it was less active against Corynebacterium glutamicum PafA because the ST1926-binding residues are not conserved. Bithionol bound to the conserved ATP-binding pocket, thereby, inhibits PafA in an ATP-competitive manner. Both ST1926 and bithionol inhibited the growth of an attenuated Mtb strain (H37Ra) at micromolar concentrations. Our work thus provides new tools for tuberculosis research and a foundation for future PafA-targeted drug development for treating tuberculosis.

A novel series of teriflunomide derivatives as orally active inhibitors of human dihydroorotate dehydrogenase for the treatment of colorectal carcinoma.

Human dihydroorotate dehydrogenase (hDHODH) is a key enzyme in the de novo synthesis pathway of pyrimidine nucleotide in cells. The moderate efficiency of teriflunomide, an approved hDHODH inhibitor for the treatment of multiple sclerosis, limited its therapeutic application of malignancy. Herein, thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated. As a result, the optimal compound A37 exhibited a potent hDHODH inhibitory activity with an IC50 value of 10.2 nM, which was about 40-fold stronger than that of teriflunomide (IC50 = 407.8 nM), and showed favorable antiproliferative activities against HCT116 cells with an IC50 value of 0.3 µM. Meanwhile, A37 displayed an acceptable safety profile at an oral dosage of 400 mg/kg in the acute toxicity assay, and exhibited a promising antitumor effect with tumor growth inhibition rate of 54.4% at an oral dosage of 30 mg/kg in HCT116 xenograft model. These results indicate that A37 is an efficacious hDHODH inhibitor with potential in the treatment of colorectal carcinoma.

Identification of selective mtbDHFR inhibitors by virtual screening and experimental approaches.

mtbDHFR-targeting inhibition has become a promising approach for tuberculosis treatment. In the current research, a multi-step virtual screening effort toward ZINC and MCE databases was devoted to discover novel mtbDHFR inhibitors. Based on binding affinity of small molecules through molecular docking study in AutoDock Vina, the number of compounds was reduced to 952,688. Further, these compounds were employed by a step-by-step multiple docking programs of Schrödinger suite and filtered by pharmacokinetics and PAINS parameters. Finally, nine ZINC compounds and 400 MCE compounds were obtained. These compounds of binding ability were tested with mtbDHFR by FluoPol-ABPP approach established in this work. Finally, AF-353 compound was found to have strong binding effect to mtbDHFR. AF-353 was further tested for mtb and hDHFR enzymatic activities, and it was proved to possess 50-fold selectivity toward mtbDHFR over hDHFR. In silico MD simulation results supported this selectivity.

Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment.

Human dihydroorotate dehydrogenase (hDHODH), as the fourth and rate-limiting enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as hDHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited hDHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t. Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of hDHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.

Corrigendum to "Repurposing Napabucasin as an Antimicrobial Agent against Oral Streptococcal Biofilms".

[This corrects the article DOI: 10.1155/2020/8379526.].

[Efficacy of Hybrid anterior cervical spine surgery on range of motion and curvature in the treatment of cervical degenerative diseases].

OBJECTIVE: To observe the change of cervical curvature and range of motion (ROM) on imaging at 6 months after Hybrid surgery. METHODS: A total of 29 patients with cervical degenerative disease who underwent Hybrid surgery from January 2017 to July 2018 were retrospectively analyzed. Also, they all met the inclusion criteria and had complete preoperative and 6 months postoperative imaging data. There were 11 males and 18 females, aged from 34 to 76 (55.86±10.69) years, and the operation time was from 2 to 4(3.03±0.51) hours. The Cobb angle method was used to measure the changes of cervical curvature and ROM of C2-C7, replacement segments, fusion segments, and upper adjacent segments on cervical lateral X-rays before and 6 months after surgery. RESULTS: There was no statistically significant difference in C2-C7 curvature and ROM between 6 months after operation and before operation (P>0.05). The degree of curvature and ROM of the replacement segment increased compared with that before operation (P<0.05). The curvatureof the fusion segment was increased than that before operation (P<0.05). There was no statistically significant difference in ROM of the fusion segment compared with that before operation (P>0.05). There was no statistically significant difference in the curvature and ROM of the upper adjacent segments compared with those before operation (P>0.05). There was no significant difference in the curvature between the replacement and fusion segments before and 6 months after operation (P>0.05);the ROM of the replacement segment was higher than that of the fusion segment at 6 months after operation (P<0.05). CONCLUSION: Hybrid surgery reconstructs the lordotic curvature of the entire cervical spine and the responsible segment, retains the ROM of the cervical replacement segment, and restores the biomechanical function of cervical spine.

Structure-Guided Design of the First Noncovalent Small-Molecule Inhibitor of CRM1.

Nuclear export factor chromosome region maintenance 1 (CRM1) is an attractive anticancer and antiviral drug target that spurred several research efforts to develop its inhibitor. Noncovalent CRM1 inhibitors are desirable, but none is reported to date. Here, we present the crystal structure of yeast CRM1 in complex with S109, a substructure of CBS9106 (under clinical test). Superimposition with the LFS-829 (another covalent CRM1 inhibitor) complex inspired the design of a noncovalent CRM1 inhibitor. Among nine synthesized compounds, noncovalent CRM1 inhibitor 1 (NCI-1) showed a high affinity to human and yeast CRM1 in the absence or presence of GST-bound Ras-related nuclear protein (RanGTP). Unlike covalent inhibitors, the crystal structure showed that NCI-1 is bound in the "open" nuclear export signal (NES) groove of CRM1, simultaneously occupying two hydrophobic pockets. NCI-1 additionally inhibited the nuclear export and proliferation of cells harboring the human CRM1-C528S mutant. Our work opens up the avenue of noncovalent CRM1 inhibitor development toward a more potent, less toxic, and broad-spectrum anticancer/antiviral therapy.

A Novel Small Molecule, LCG-N25, Inhibits Oral Streptococcal Biofilm.

Dental caries is a chronic oral infectious disease caused by cariogenic biofilm adhered on the tooth surface. Our previous study demonstrated that a repurposed natural compound napabucasin (NAP) showed good antimicrobial activity against oral streptococcal biofilms. The current study designed a novel small molecule, namely LCG-N25, using NAP as a lead compound, and aimed to investigate its potential as an antimicrobial agent in the control of dental caries. LCG-N25 was designed and synthesized with reference to the structure of NAP. The minimal inhibitory concentrations and the minimal bactericidal concentrations of LCG-N25 against Streptococcus mutans, Streptococcus sanguinis, and Streptococcus gordonii were evaluated by microdilution method. The antimicrobial activity of LCG-N25 was further evaluated by crystal violet staining, colony forming units counting, biofilm metabolism assay, dead/live fluorescent staining, and scanning electron microscopy. The effect of LCG-N25 on the extracellular polysaccharides of biofilms was determined by both anthrone-sulfuric acid method and fluorescent staining. The microbial composition of streptococcal biofilms after LCG-N25 treatment was further visualized and quantified by fluorescence in situ hybridization. Besides, the cytotoxicity of LCG-N25 was evaluated by Cell Counting Kit-8 assay, and repeated exposure of S. mutans to LCG-N25 treatment was performed to assess if this novel compound could induce drug resistance of this cariogenic bacterium. We found that LCG-N25 exhibited a good antibacterial activity, low-cytotoxicity, and did not induce drug resistance of cariogenic S. mutans. These findings suggest that LCG-N25 may represent a promising antimicrobial agent that can be used as an adjuvant to the management of dental caries.

[Clinical observation on the treatment of cervical degenerative diseases with Hybrid surgery].

OBJECTIVE: To investigate the clinical effect of anterior cervical Hybrid surgery in the treatment of cervical degenerative diseases (CDD) and observe the incidence of heterotopic ossification of disc replacement segment at 1 year after surgery. METHODS: From January 2015 to April 2018, 35 patients who received anterior cervical hybrid surgery met the inclusion and exclusion criteria and the complete clinical follow up data were analyzed retrospectively. Complete imaging follow-up data were obtained from 24 patients. There were 15 males and 20 females, aged from 39 to 70(55.57±7.73) years old. The amount of bleeding was for 20 to 100 (40.29±18.39) ml, and the hospitalstay was for 4 to 28(11.03±4.63) days, and the follow-up time was(12.97±1.36) months. Clinical outcomes were assessed by the Tanaka Yasushi cervical spondylitis symptom scale 20 score (YT20), and Japanese Orthopaedic Association (JOA) score. The occurrence of heterotopic ossification after Hybrid surgery was evaluated by X-ray according to McAfee standard one year after operation. Patients with or without heterotopic ossificationwere divided into two groups and their clinical effects were compared. RESULTS: At the final follow up, the mean YT20 score and JOA score were significantly higher than those before operation (P <0.05), and the average improvement rate of JOA was (70.66 ±0.44)%. One year after operation, the heterotopic ossification occurred in 10 of 24 segments, with incidence of 41.70%(10/24), including 29.20% in gradeⅠand 12.50% in gradeⅡ. The results of clinical efficacy comparison between patients with and without heterotopic ossification were as follows:there was no significant difference in JOA score before and after operation (P>0.05);there was no significant difference in YT20 score before operation (P>0.05), and YT20 score in patients with heterotopic ossification was significantly lower than that in patients without heterotopic ossification(P<0.05). CONCLUSION: The short-term clinical effect of Hybrid surgery is satisfactory for cervical degenerative diseases, and the cause of heterotopic ossification still needs tobe further explored.

Effect of Platelet-Rich Plasma Injection on Mild or Moderate Carpal Tunnel Syndrome: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To evaluate efficacy of platelet-rich plasma (PRP) injection in carpal tunnel syndrome (CTS), we conducted this meta-analysis, as well as proposed a protocol for its application in curative processes. METHODS: All randomized controlled trials (RCTs) of PRP for the management of mild or moderate CTS were included in this study. Database search was conducted from study inception to July 2020, including PubMed, Embase, Web of Science, and Cochrane Library. We used visual analogue scores (VAS) and the Boston Carpal Tunnel Questionnaire (BCTQ) as evaluation tools for primary outcomes. Second outcomes comprised cross-sectional area (ΔCSA) and electrophysiological indexes including distal motor latency (DML), sensory peak latency (SPL), motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), compound muscle action potential (CMAP), and sensory nerve action potential (SNAP). The pooled data were analyzed using RevMan 5.3. Subgroup and sensitivity analyses were conducted with the evidence of heterogeneity. Egger' test was used to investigate publication bias. RESULTS: 9 RCTs were finally screened out with 434 patients included. Control groups comprised corticosteroid injection in 5 trials, saline injection in 1 trial, and splint in 3 trials. At the 1st month after follow-up, only ΔCSA between the PRP group and the control group showed significant difference (P < 0.05). In the 3rd month, there were statistically significant differences in VAS, BCTQ, SPL, SNCV, and ΔCSA between two groups (P < 0.05), while no statistically significant differences were found in the remaining outcomes. In the 6th month, there were statistically significant differences at BCTQ (P < 0.05) in primary outcomes and ΔCSA (P < 0.05) in secondary outcomes between two groups. As to adverse events in PRP injection, only one study reported increased pain sensation within 48 h after injections. CONCLUSION: This systematic review and meta-analysis demonstrates that the PRP could be effective for mild to moderate CTS and superior to traditional conservative treatments in improving pain and function and reducing the swelling of the median nerve for a mid-long-term effect. To some extent, the electrophysiological indexes also improved after PRP injection compared with others conservative treatments.

Repurposing Napabucasin as an Antimicrobial Agent against Oral Streptococcal Biofilms.

OBJECTIVES: Disruption of microbial biofilms is an effective way to control dental caries. Drug resistance and side effects of the existing antimicrobials necessitate the development of novel antibacterial agents. The current study was aimed at investigating the antibacterial activities of the repurposed natural compound napabucasin against oral streptococci. METHODS: The minimum inhibitory concentration, minimum bactericidal concentration, minimum biofilm inhibition concentration, and minimum biofilm reduction concentration of Streptococcus mutans, Streptococcus gordonii, and Streptococcus sanguinis were examined by a microdilution method. Cytotoxicity of napabucasin against human oral keratinocytes, human gingival epithelia, and macrophage RAW264.7 was evaluated by CCK8 assays. The dead/live bacterium and exopolysaccharide in the napabucasin-treated multispecies biofilms were evaluated by confocal laser scanning microscopy. Microbial composition within the napabucasin-treated biofilms was further visualized by fluorescent in situ hybridization and qPCR. And the cariogenicity of napabucasin-treated biofilms was evaluated by transverse microradiography. RESULTS: Napabucasin exhibited good antimicrobial activity against oral streptococcal planktonic cultures and biofilms but with lessened cytotoxicity as compared to chlorhexidine. Napabucasin reduced the cariogenic S. mutans and increased the proportion of the commensal S. gordonii in the multispecies biofilms. More importantly, napabucasin significantly reduced the demineralization capability of biofilms on tooth enamels. CONCLUSION: Napabucasin shows lessened cytotoxicity and comparable antimicrobial effects to chlorhexidine. Repurposing napabucasin may represent a promising adjuvant for the management of dental caries.

Repurposed drug candidates for antituberculosis therapy.

Antibiotics have been a key part of clinical treatments for more than 70 years. Long-term use of antimicrobial treatments has led to the development of severe bacterial resistance, which has become increasingly serious due to antibiotic abuse, resulting in the treatment of bacterial infections becoming challenging. The repurposing of approved drugs presents a promising strategy to address current bottlenecks in the development of novel antibacterial agents. Drug repurposing is a cost-effective emerging strategy, which aims to treat resistant infectious diseases by identifying known drugs with predicted efficacy for diseases other than the target disease. This strategy has potential in the treatment of tuberculosis (TB), particularly drug-resistant TB. In recent years, a panel of drugs approved for clinical use or clinical trials, such as linezolid, vancomycin and celecoxib, have been found to have anti-TB activities. However, the utility of drug repurposing is limited by the number of candidate compounds and their low activities. The low activities of repurposed drugs have slowed the development of a drug-repurposing strategy for anti-TB drugs. The present review discusses progress in the discovery of new anti-TB agents through drug repurposing since 2014. We also discuss the challenges faced and analyze the innovative ways that are being used to overcome these difficulties. This review may provide a useful guide for researchers in the field of drug repurposing.

Scaffold hopping of agomelatine leads to enhanced antidepressant effects by modulation of gut microbiota and host immune responses.

The mechanisms underlying the pathophysiology of depression remain elusive, and the development of novel, effective antidepressant drugs remains necessary. A dihydroquinoline analog of agomelatine (AGO), N-(2-(7-methoxy-3,4-dihydroisoquinolin-1-yl)ethyl)acetamide hydrochloride (NMDEA), was synthesized by employing a scaffold-hopping strategy in our previous study. In this study, NMDEA was demonstrated to attenuate depression-related behaviors in mice models of chronic unpredictable mild stress (CUMS), using a sucrose preference test, a forced swimming test, and a tail suspension test. However, the antidepressant mechanism of NMDEA appears to differ from that for AGO. Based on the analysis of fecal microbiota from mice, stress can alter the richness of the gut bacterial community, increasing the expression of immune-modulating microbiota, such as Clostridia, and decreasing the expression of probiotic bacteria, such as Lactobacillus. Treatment with NMDEA was able to recover the richness and to regulate the dysbiosis among bacterial species. Several studies have demonstrated that the gut microbiota population can induce inflammatory processes. To explore the effects of NMDEA on the suppression of pro-inflammatory factors, we used Western blotting to analyze the levels of interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), p65, and inducible nitric oxide synthase (iNOS). NMDEA suppressed the activation of IL-1ß and IL-6, in the hippocampus, and IL-1ß, IL-6, p65, and iNOS, in lipopolysaccharide (LPS)-induced BV-2 cells. These results suggested that NMDEA may affect the microbiota-inflammasome-brain axis, regulating relevant neuro-inflammatory markers and gut microbiota. Our data also suggested that using small molecules to modify the gut microbiota population or alter inflammasome signaling may represent a new therapeutic opportunity for the mitigation of depression.