Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting ß-catenin pathway.

Benign prostatic hyperplasia (BPH) is a prevalent condition affecting the male urinary system, with its molecular mechanisms of pathogenesis remaining unclear. Y-27632, a non-isoform-selective Rho kinase inhibitor, has shown therapeutic potential in various diseases but its effects on static factors and fibrosis in BPH remain unexplored. This study investigated human prostate tissues, human prostate cell lines, and BPH rat model using immunofluorescence, flow cytometry, quantitative reverse transcription polymerase chain reaction, western blotting, and cell counting kit-8. ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating with clinical parameters. Y-27632 targeted the inhibition of ROCK1 & ROCK2 expression and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transition (EMT), while induced cell apoptosis in a dose-dependent manner. Moreover, knockdown of either ROCK isoform inhibited fibrosis and EMT, induced apoptosis, while ROCK overexpression had the opposite effects. ROCK downregulation inhibited the ß-catenin signaling pathway (such as C-MYC, Snail and Survivin) and decreased ß-catenin protein stability, while inhibiting TGF-ß/Smad2/3 signaling. At the in vivo level, Y-27632 reversed prostatic hyperplasia and fibrosis in BPH model rats to some extent. Our study sheds light on the therapeutic potential of Y-27632 in regulating prostate cell growth, fibrosis and EMT, and demonstrates for the first time the regulatory effect of ROCK isoforms on prostate cells, providing the basis for future research of ROCK isoform-selective inhibitors.

The impact of epidural ropivacaine versus levobupivacaine for labor analgesia on maternal and fetal outcomes: a meta-analysis.

INTRODUCTION: Newer neuraxial local anesthetic agents which have been used as epidural analgesia have shown to provide reliable pain relief during labor. Ropivacaine and levobupivacaine are newer agents now used for labor analgesia. However, even though few studies have made their comparison with bupivacaine, ropivacaine and levobupivacaine have seldom systematically been compared. Therefore, in this analysis, we aimed to systematically show the impact of epidural ropivacaine versus levobupivacaine for labor analgesia on maternal and fetal outcomes. METHODS: http://www. CLINICALTRIALS: gov , Web of Science, MEDLINE, EMBASE, Cochrane database and Google Scholar were searched for studies comparing ropivacaine versus levobupivacaine for labor analgesia. Maternal and fetal outcomes were considered as the endpoints in this analysis. The RevMan software 5.4 was used to analyze data in this study. Risk ratio (RR) with 95% confidence intervals (CI) were used to represent the data post analysis. RESULTS: A total number of 2062 participants were included in this analysis whereby 1054 participants were assigned to ropivacaine and 1008 participants were assigned to levobupivacaine. The main results of this analysis showed that epidural ropivacaine was not associated with significantly higher risk of hypotension (RR: 0.71, 95% CI: 0.43 - 1.17; P = 0.18) and pruritus (RR: 1.12, 95% CI: 0.89 - 1.42; P = 0.34) when compared to levobupivacaine for labor analgesia. However, the risk of nausea and vomiting was significantly higher with ropivacaine (RR: 1.60, 95% CI: 1.05 - 2.44; P = 0.03). Spontaneous vaginal delivery (RR: 0.99, 95% CI: 0.89 - 1.42; P = 0.83), instrumental vaginal delivery (RR: 1.13, 95% CI: 0.89 - 1.45; P = 0.32) and the risk for cesarean section (RR: 0.76, 95% CI: 0.42 - 1.37; P = 0.35) were not significantly different. When fetal outcomes were assessed, Apgar score < 7 at 1 min (RR: 1.01: 95% CI: 0.57 - 1.80; P = 0.97), abnormality of fetal heart rate (RR: 1.45, 95% CI: 0.55 - 3.79; P = 0.45) and neonatal asphyxia (RR: 0.35, 95% CI: 0.10 - 1.18; P = 0.09) were also similarly manifested. CONCLUSIONS: To conclude, our analysis showed both epidural ropivacaine and levobupivacaine to be equally effective for labor analgesia in terms of maternal and fetal outcomes. No major adverse maternal and fetal outcome was observed in this analysis. However, considering the several limitations of this analysis, further larger studies should be able to solve and clarify this issue.

Palladium-Catalyzed Site-Selective Hydrogenation of Unactivated Alkenes Directed by 8-Aminoquinoline Amides.

We have developed a method for the site-selective hydrogenation of unactivated alkenes using 8-aminoquinoline amide as the directing group. For unactivated alkenes with two C-C double bonds, Daugulis's 8-aminoquinoline amide facilitated the site-selective hydrogenation of the desired C-C double bond, producing a product in which one C-C double bond was reduced. Site-selective reduction methodologies using intramolecular directing groups are expected to contribute significantly to the synthesis of molecules with multiple reducible functional groups in the future.

Scaffold hopping approach to the novel hexacyclic pyrazol-3-amide derivatives as potential multi-target insect growth regulators candidates.

Ecdysone receptor (EcR) and three insect chitinases (OfChtI, OfChtII, and OfChi-h) are considered as attractive targets for the development of novel insect growth regulators (IGRs) since they are closely related to the insect molting. In this study, to develop potent multi-target IGRs, a series of hexacyclic pyrazol-3-amide derivatives were rationally designed by utilizing the scaffold hopping strategy with the previously reported compound 6j (N-(4-bromobenzyl)-2-phenyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide) as a lead compound. The bioassay results indicated that most of the target compounds exhibited obvious insecticidal activity. Especially, compounds a5 and a21 displayed excellent insecticidal activities against P. xylostella with LC50 values of 82.29 and 69.45 mg/L, respectively, exceeding that of 6j (263.78 mg/L). Compounds a5 and a21 also dramatically disturbed the growth and development of O. furnacalis larvae, and their LC50 values were 124.71 and 127.54 mg/L, respectively, superior to the lead 6j (267.33 mg/L). The action mechanism study revealed that the most active compound a21 could act simultaneously on EcR (21.4 % binding activity at 8 mg/L), OfChtI (94.9 % inhibitory at 10 µM), OfChtII (23.1 % inhibitory at 10 µM), and OfChi-h (94.3 % inhibitory at 10 µM), significantly higher than that of the lead compound 6j. The result of molecular docking indicated that transferring the carboxamide group from pyrazole position 5 to 3 enhanced the interactions of a21 with the key amino acid residues of the OfChtI, OfChtII, and OfChi-h, resulting in stronger affinity to the three targets than 6j. The present work offers a useful guidance for the further development of novel multi-target IGRs.

Treatment of a mutant KRAS lung cancer cell line with polyisoprenylated cysteinyl amide inhibitors activates the MAPK pathway, inhibits cell migration and induces apoptosis.

KRAS mutations are the most common oncogenic mutations in lung adenocarcinoma in Black Americans. Polyisoprenylated Cysteinyl amide Inhibitors (PCAIs) constitute a group of potential cancer therapy agents that we designed to specifically disrupt and suppress hyperactive G-protein signaling, such as that caused by mutated RAS proteins. Here we determine the effects of PCAIs on the viability, G-protein levels, downstream mediators, and apoptosis-related proteins on the KRAS-mutated, Black American-derived lung adenocarcinoma cell line, NCI-H23. Of the 17 PCAIs tested, compounds NSL-YHJ-2-27 and NSL-YHJ-2-46 showed the most potency with EC50 values of 2.7 and 3.3 µM, respectively. Western blotting was used to determine the effect of the PCAIs on the phosphorylation levels of MAPK pathway enzymes. After 48 h exposure to 5 µM of the PCAIs, NSL-YHJ-2-46, the MAPK proteins BRAF, MEK1/2, ERK1/2, and p90RSK were activated through phosphorylation by 90, 190, 150 and 120%, respectively. However, CRAF/RAF1 phosphorylation decreased by 40%, suggesting significant changes in the KRAS/MAPK signaling patterns. Furthermore, 5 µM of NSL-YHJ-2-27 depleted the singly polyisoprenylated monomeric G-proteins RAC 1/2/3 and CDC42 by 77 and 76%, respectively. The depletion of these key cytoskeletal proteins may account for the observed inhibition of cell migration and invasion, and spheroid invasion observed on exposure to NSL-YHJ-2-27 and NSL-YHJ-2-46. Treatment with 5 µM of NSL-YHJ-2-27 suppressed full-length inactive caspase 3 and 7 levels by 72 and 91%, respectively. An analysis of cells treated with the fluorescently labeled active caspase 3/7 irreversible inhibitor, CaspaTagTM Caspase-3/7 in situ reagent revealed a 124% increase in active caspase at 3 µM over controls. These findings clearly show the direct effects of the PCAIs on the RAS signaling pathway. Given the profound increases observed in RPS6KA1/p90RSK phosphorylation, future work will involve a determination whether the proapoptotic isoforms of RPS6KA1/p90RSK are phosphorylated due to the PCAIs treatments. These results support the potential use of the PCAIs as targeted therapies against cancers with KRAS mutations.

DOTAGEL: a hydrogen and amide bonded, gelatin based, tunable, antibacterial, and high strength adhesive synthesized in an unoxidized environment.

The development of bioadhesives that concurrently exhibit high adhesion strength, biocompatibility, and tunable properties and involve simple fabrication processes continues to be a significant challenge. In this study, a novel bioadhesive named DOTAGEL is synthesized by crosslinking gelatin (GA), dopamine (DA), and tannic acid (TA) in an unoxidized environment due to the advantage of controlling the degree of protonation in GA and TA, as well as controlling the degree of intermolecular amide and hydrogen bonding in the acidic medium. DOTAGEL (DA + TA + GA) shows superior adhesion strengths of 104.6 ± 46 kPa on dry skin and 35.6 ± 4.5 kPa on wet skin, up to 13 attachment-detachment cycles, retains adhesion strength under water for up to 10 days and is capable of joining two cut parts of internal organs of mice. Moreover, DOTAGEL shows strong antibacterial properties, self-healing, and biocompatibility since it contains TA, a natural and antibacterial cross-linker with abundant hydroxyl groups and the capability of forming non-covalent bonds in an unoxidized environment, and dopamine hydrochloride, a mussel inspired biomaterial containing both the amine and catechol groups for amide bonding and hydrogen bonding with TA and GA. The cross-linking among 20% (w/v) GA, 0.2% (w/v) DA, and 20% (w/v) TA is done by the centrifugation process at room temperature. Two different acids, hydrochloric acid and acetic acid, were used for tuning the pH of the medium, which led to two different samples named DOTAGEL/AA and DOTAGEL/HCL. The degree of cross-linking and mechanical and biochemical properties, like adhesion strength, degradation rate, antibacterial properties, stickiness, etc., are tuned by adjusting the pH of the medium. DOTAGEL/HCL showed 6.5 times faster degradation in 10 days, a faster release rate in the antibacterial study, 2 times adhesion strength in a dry medium, and more stickiness. The novelty lies not only in increased adhesion strength but also in the single-step fabrication process of the adhesive in the acidic medium. This research proposes the formation of a tunable antibacterial adhesive that is capable of working on wet surfaces within the body and that has the potential to become a successful tissue adhesive with a wide range of possibilities in controlled drug delivery at wound sites and other biomedical applications.

Chemoselective seleno-click amidation in kinetic target-guided synthesis.

Capitalizing on our previous kinetic target-guided synthesis (KTGS) involving the sulfo-click reaction to form N-acylsulfonamide-linked inhibitors in the presence of the protein-protein interaction target Mcl-1, we herein report a seleno-click approach for amide-linked inhibitors of Mcl-1. The seleno-click reaction leverages the enhanced reactivity of selenocarboxylates, enabling the templated amidation with electron-rich azides, thereby expanding the scope of KTGS. The potential of this approach is demonstrated by generating N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide, a known Mcl-1 inhibitor featuring an amide, via KTGS at 37 °C against Mcl-1. Notably, the seleno-click strategy was also effective at 4 °C, offering a variant for thermally sensitive biological targets.

A clinical trial of ropivacaine in arthocentesis for TMD.

INTRODUCTION: This study aims to compare the efficacy of ropivacaine and lidocaine in the treatment of temporomandibular joint (TMJ) disorders, with the goal of exploring a more effective treatment for TMJ disorders. METHODS: Patients with Wilkes stage III and IV unilateral TMJ disorders were enrolled in the study. 0.5% ropivacaine was used for local anesthesia in group A, 2% lidocaine was used in group B. Sodium hyaluronate was injected after supra-articular lavage in both groups. The patients' general conditions, pain scores, and maximum opening before and after treatment were collected, the time of onset and maintenance of anesthesia, and the levels of inflammatory factors IL-1ß and IL-6 in the joint lavage fluid were detected. RESULTS: Study showed that the onset of anesthesia was faster and longer maintained in group A. The decrease in IL-1ß was more pronounced in group A (16.08 ± 3.10) than in group B (18.03 ± 2.84), p < 0.05. At 2 months after treatment, the joint clicking rate was higher in group A (75%) compared to group B (35%), p < 0.05. At 3 months after treatment, the joint clicking rate was higher in group A (76.69%) compared to group B (40%) and the maximum mouth opening was greater in group A (45.00 ± 2.38) compared to group B (41.73 ± 4.18), p < 0.05. There were no statistically significant differences in VAS score and lateral excursion in group A compared with group B at 2 months and 3 months after treatment. CONCLUSIONS: Compared with lidocaine, the application of ropivacaine combined with sodium hyaluronate supra-articular lavage for the treatment of temporomandibular joint disorder is more clinically effective. CLINICAL TRIALS REGISTRATION NUMBER: ChiCTR2300075241 (30/08/2023).

Amide proton transfer-weighted CEST MRI for radiotherapy target delineation of glioblastoma: a prospective pilot study.

BACKGROUND: Extensive glioblastoma infiltration justifies a 15-mm margin around the gross tumor volume (GTV) to define the radiotherapy clinical target volume (CTV). Amide proton transfer (APT)-weighted imaging could enable visualization of tumor infiltration, allowing more accurate GTV delineation. We quantified the impact of integrating APT-weighted imaging into GTV delineation of glioblastoma and compared two APT-weighted quantification methods-magnetization transfer ratio asymmetry (MTRasym) and Lorentzian difference (LD) analysis-for target delineation. METHODS: Nine glioblastoma patients underwent an extended imaging protocol prior to radiotherapy, yielding APT-weighted MTRasym and LD maps. From both maps, biological tumor volumes were generated (BTVMTRasym and BTVLD) and added to the conventional GTV to generate biological GTVs (GTVbio,MTRasym and GTVbio,LD). Wilcoxon signed-rank tests were performed for comparisons. RESULTS: The GTVbio,MTRasym and GTVbio,LD were significantly larger than the conventional GTV (p ≤ 0.022), with a median volume increase of 9.3% and 2.1%, respectively. The GTVbio,MTRasym and GTVbio,LD were significantly smaller than the CTV (p = 0.004), with a median volume reduction of 72.1% and 70.9%, respectively. There was no significant volume difference between the BTVMTRasym and BTVLD (p = 0.074). In three patients, BTVMTRasym delineation was affected by elevated signals at the brain periphery due to residual motion artifacts; this elevation was absent on the APT-weighted LD maps. CONCLUSION: Larger biological GTVs compared to the conventional GTV highlight the potential of APT-weighted imaging for radiotherapy target delineation of glioblastoma. APT-weighted LD mapping may be advantageous for target delineation as it may be more robust against motion artifacts. RELEVANCE STATEMENT: The introduction of APT-weighted imaging may, ultimately, enhance visualization of tumor infiltration and eliminate the need for the substantial 15-mm safety margin for target delineation of glioblastoma. This could reduce the risk of radiation toxicity while still effectively irradiating the tumor. TRIAL REGISTRATION: NCT05970757 (ClinicalTrials.gov). KEY POINTS: Integration of APT-weighted imaging into target delineation for radiotherapy is feasible. The integration of APT-weighted imaging yields larger GTVs in glioblastoma. APT-weighted LD mapping may be more robust against motion artifacts than APT-weighted MTRasym.

High efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in Black adults in the United States, including those with pre-existing HIV resistance and suboptimal adherence.

BRAAVE (NCT03631732), a Phase 3b, multicenter, open-label US study, demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among Black individuals with suppressed HIV through 48 weeks. Here, 72-week resistance, adherence, and virologic outcomes are presented. Enrollment criteria permitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistance (R), protease inhibitor (PI)-R, and certain nucleos(t)ide reverse transcriptase inhibitor (NRTI)-R (M184V/I allowed; ≥3 thymidine analog mutations [TAMs] excluded); but excluded primary integrase strand transfer inhibitor (INSTI)-R. Pre-existing resistance was determined using historical genotypes and retrospective baseline proviral DNA genotyping. Adherence, virologic outcomes, and viral blips were assessed. Of 489 participants receiving B/F/TAF with ≥1 post-switch HIV-1 RNA measurement: pre-existing NRTI-R (15% of participants), M184V/I (11%), ≥1 TAMs (8%), NNRTI-R (22%), and PI-R (13%) were observed; pre-existing INSTI-R substitutions (2%) were detected post-randomization; mean viral blip frequency was 0.9% across all timepoints (unassociated with virologic failure); 24% of participants had <95% adherence (98% of whom had HIV-1 RNA <50 copies/mL at last visit); none had treatment-emergent study-drug resistance. Overall, 99% of participants, including all with baseline NRTI-R/INSTI-R, had HIV-1 RNA <50 copies/mL at the last visit, demonstrating that B/F/TAF maintained virologic suppression through 72 weeks regardless of pre-existing resistance, viral blips, and suboptimal adherence.

Efficacy of favipiravir in COVID-19: A retrospective two center comparative study.

INTRODUCTION: Favipiravir (FVP) is an antiviral, targeting RNA-dependent RNA polymerase. We aimed to evaluate the efficacy of FVP as a treatment for COVID-19. METHODS: We conducted a retrospective study in two centers (San Martino University Hospital in Genova, Italy, and Marmara University Pendik Training and Research Hospital, Turkey). Adult patients (inpatients) diagnosed with COVID-19 between March and June 2020 were included. All patients in the Italian center received the standard of care (SoC) treatment, while in the Turkish center patients received FVP in addition to SoC. RESULTS: Six hundred-nineteen patients were analyzed (225 from Turkey, all treated with FVP, and 394 from Italy, none treated with FVP). Propensity score-matching was done in 142 patients (71 from the SoC group vs. 71 from the SoC + FVP group). A Higher requirement of NIV/CPAP (n = 38; 53.5%) was registered in the SoC group compared to the SoC + FVP group (n = 9; 12.7%). A higher frequency of intubation was registered in the SoC + FVP group (n = 25; 35.2% vs n = 13, 18.3%). There was a trend towards better survival in SoC + FVP treated patients with HR = 0.64 (95% CI 0.30-1.34). At 28 days the OS was, respectively, 70.3% (95% CI: 53.2-82.1) vs 80.3% (95% CI: 69.0-87.8). CONCLUSIONS: The addition of FVP to SoC did not show a significant difference in survival and invasive and noninvasive (CPAP/NIMV) mechanical ventilation compared to standard of care in moderate and severe COVID-19-infected patients.

Organophotocatalytic Selective Deuteration of Metabolically Labile Heteroatom Adjacent C-H Bonds via H/D Exchange with D2O.

We report a general approach for efficient deuteration of the metabolically labile α-C-H bonds of widespread amides and amines. Temporarily masking the secondary amine group as a carbamate allows an unprecedented photoredox hydrogen atom transfer-promoted α-carbamyl radical formation for efficient H/D exchange with D2O. The mild protocol delivers structurally diverse α-deuterated secondary amines including "privileged" piperidine and piperazine structures highly regioselectively with excellent levels of deuterium incorporation (≤100%). Furthermore, we successfully implemented the strategy for α-deuteration of amides, lactams, and ureas with high regioselectivity and high levels of D incorporation. Finally, the observed efficient deuteration of secondary alcohol moieties in late-stage modification of complex amine-containing pharmaceuticals allows for the development of a viable method for efficient α-deuteration of the important functionality.

Activity-Based Acylome Profiling with N-(Cyanomethyl)-N-(phenylsulfonyl)amides for Targeted Lysine Acylation and Post-Translational Control of Protein Function in Cells.

Lysine acylations are ubiquitous and structurally diverse post-translational modifications that vastly expand the functional heterogeneity of the human proteome. Hence, the targeted acylation of lysine residues has emerged as a strategic approach to exert biomimetic control over the protein function. However, existing strategies for targeted lysine acylation in cells often rely on genetic intervention, recruitment of endogenous acylation machinery, or nonspecific acylating agents and lack methods to quantify the magnitude of specific acylations on a global level. In this study, we develop activity-based acylome profiling (ABAP), a chemoproteomic strategy that exploits elaborate N-(cyanomethyl)-N-(phenylsulfonyl)amides and lysine-centric probes for site-specific introduction and proteome-wide mapping of posttranslational lysine acylations in human cells. Harnessing this framework, we quantify various artificial acylations and rediscover numerous endogenous lysine acylations. We validate site-specific acetylation of target lysines and establish a structure-activity relationship for N-(cyanomethyl)-N-(phenylsulfonyl)amides in proteins from diverse structural and functional classes. We identify paralog-selective chemical probes that acetylate conserved lysines within interferon-stimulated antiviral RNA-binding proteins, generating de novo proteoforms with obstructed RNA interactions. We further demonstrate that targeted acetylation of a key enzyme in retinoid metabolism engenders a proteoform with a conformational change in the protein structure, leading to a gain-of-function phenotype and reduced drug potency. These findings underscore the versatility of our strategy in biomimetic control over protein function through targeted delivery and global profiling of endogenous and artificial lysine acylations, potentially advancing therapeutic modalities and our understanding of biological processes orchestrated by these post-translational modifications.

Discovery of Thiadiazoleamide Derivatives as Potent, Selective, and Orally Available Antagonists Disrupting Androgen Receptor Homodimer.

Androgen receptor (AR) is an important therapeutic target for prostate cancer (PCa) treatment, but prolonged use of AR antagonists has led to variant drug-resistant mutations. Since all marketed AR antagonists target the ligand binding pocket (LBP) of AR, to mitigate cross-resistance, a new drug pocket named Dimer Interface Pocket was discovered and a novel AR antagonist M17-B15 was identified. M17-B15 showed strong in vitro efficacy against PCa but had poor pharmacokinetic properties in vivo. In this study, through rational design and structure-activity relationship exploration, a series of thiadiazoleamide derivatives represented by N29 (IC50 = 0.018 µM) were identified with dominant AR antagonistic activity and remarkable anti-PCa activity in vitro. Furthermore, N29 effectively inhibited a series of typical drug-resistant AR mutants. The improved oral bioavailability of N29 facilitated its efficacy via oral administration, significantly inhibiting LNCaP xenograft tumor in vivo, presenting a promising therapeutic application for PCa.

Dehydration promotes phosphoramidate-linked amino acidyl and peptido adenosine conjugates.

Cyclic nucleoside phosphates have been shown previously to be adequately activated to oligomerise under dry conditions. Herein, it is demonstrated that 3',5'-cyclic adenosine monophosphate (3',5'-cAMP) and glycine when subjected to dehydration under alkaline conditions form phosphoramidate-linked conjugates. Solid-state reaction mechanisms investigated by DFT suggest why the reaction does not occur efficiently in the aqueous phase.

Transport and retention of COVID-19-related antiviral drugs in saturated porous media under various hydrochemical conditions.

Antiviral drugs have garnered considerable attention, particularly in the global battle against the COVID-19 pandemic, amid heightened concerns regarding environmentally acquired antiviral resistance. A comprehensive understanding of their transport in subsurface environments is imperative for accurately predicting their environmental fate and risks. This study investigated the mobility and retention characteristics of six COVID-19 antiviral drugs in saturated quartz sand columns. Results showed that the mobility of the drugs was primarily contingent on their hydrophobicity, with ribavirin and favipiravir exhibiting the highest transportability, while arbidol displaying the greatest retention. The transport characteristics of ribavirin and favipiravir remained largely unaffected by pH, whereas the retention of the other four antivirals remained consistently minimal under alkaline conditions. Elevating ionic strength marginally facilitated the transport of these antivirals, while the presence of Ca2+ notably enhanced their retention in quartz sand compared to Na+. Ribavirin and remdesivir warrant particular attention due to their relatively high transportability and propensity for environmentally acquired antiviral resistance. These findings contribute to an enhanced understanding of the leachate potential and transport of COVID-19-related antivirals in sandy porous media, furnishing fundamental data for predicting their environmental fate and associated risks.

Discovery of novel substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors.

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2), a critical regulator of proliferation pathways and immune checkpoint signaling in various cancers, is an attractive target for cancer therapy. Here, we report the discovery of a novel series of substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors. Among them, compound C6 showed excellent inhibitory activity against SHP2 and antiproliferative effect on MV-4-11 cell line with IC50 values of 0.13 and 3.5 nM, respectively. Importantly, orally administered C6 displayed robust in vivo antitumor efficacy in the MV-4-11 xenograft mouse model (TGI = 69.5 %, 30 mg/kg). Subsequent H&E and Ki67 staining showed that C6 significantly suppressed the proliferation of tumor cells. Notably, flow cytometry, ELISA and immunofluorescence experiments showed that C6 remarkably decreased the population of CD206+/Ly6C+ M2-like tumor-associated macrophages (TAMs), the expression level of interleukin-10 (IL-10), and the number of F4/80+/CD206+ M2-like TAMs, suggesting that C6 could effectively alleviate the activation and infiltration of M2-like TAMs. Taken together, these results illustrate that C6 is a promising SHP2 inhibitor worthy of further development.

Efficacy and Safety of the Combination of Palmitoylethanolamide, Superoxide Dismutase, Alpha Lipoic Acid, Vitamins B12, B1, B6, E, Mg, Zn and Nicotinamide for 6 Months in People with Diabetic Neuropathy.

AIM: To investigate the efficacy of Palmitoylethanolamide (PEA, 300 mg), Superoxide Dismutase (SOD, 70 UI), Alpha Lipoic Acid (ALA, 300 mg), vitamins B6 (1.5 mg), B1 (1.1 mg), B12 (2.5 mcg), E (7.5 mg), nicotinamide (9 mg), and minerals (Mg 30 mg, Zn 2.5 mg) in one tablet in people with Diabetic Neuropathy (DN). PATIENTS-METHODS: In the present pilot study, 73 people (age 63.0 ± 9.9 years, 37 women) with type 2 Diabetes Mellitus (DMT2) (duration 17.5 ± 7.3 years) and DN were randomly assigned to receive either the combination of ten elements (2 tablets/24 h) in the active group (n = 36) or the placebo (n = 37) for 6 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured vibration perception threshold (VPT) with biothesiometer, and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Sudomotor function was assessed with SUDOSCAN, which measures electrochemical skin conductance in hands and feet (ESCH and ESCF). Pain score (PS) was assessed with Pain DETECT questionnaire. Quality of life was assessed by questionnaire. RESULTS: In the active group, there was a large improvement of pain (PS from 20.9 to 13.9, p < 0.001). There was also a significant improvement of vitamin B12 (B12) levels, MNSIQ, SNCV, VPT, and ESCF (222.1 vs. 576.3 pg/ mL, p < 0.001; 6.1 vs. 5.9, p = 0.017; 28.8 vs. 30.4, p = 0.001; 32.1 vs. 26.7, p = 0.001; and 72.2 vs. 74.8, p < 0.001 respectively). In the placebo group, neither pain (21.6 vs. 21.7, p = 0.870) or any other aforementioned parameters changed significantly, and MNSIE worsened (2.9 vs. 3.4, p < 0.001). As a result, changes from baseline to follow-up in pain, B12 levels, VPT, and MNSIQ differed significantly between the two groups (p < 0.001, 0.025, 0.009, and <0.001, respectively). CARTs, SNAP, ESCH did not significantly change in either of the two groups. CONCLUSIONS: The combination of the ten elements in one tablet for 6 months at a daily dose of two tablets in people with DN significantly improves pain, vibration perception threshold, and B12 levels.

Combined bictegravir, emtricitabine and tenofovir alafenamide for treating people with HIV: a plain language summary of the BICSTaR study up to 1 year.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article about an ongoing study called the BICSTaR study.The BICSTaR study includes people with HIV (human immunodeficiency virus) who are taking a medicine called bictegravir/emtricitabine/tenofovir alafenamide (shortened to B/F/TAF). B/F/TAF is a single tablet that contains 3 different drugs for the treatment of HIV. The drugs work together to reduce the levels of HIV so that the virus can no longer be detected by a blood test.People taking part in the study are adults with HIV living in Europe, Canada, Israel, Japan, South Korea, Singapore and Taiwan. People take 1 tablet of B/F/TAF once a day. They are either taking B/F/TAF as their first treatment for HIV, or they have switched to B/F/TAF from another HIV treatment.Researchers looked at how well B/F/TAF worked and how safe it was in people who took B/F/TAF for a year. WHAT ARE THE KEY TAKEAWAYS?: Researchers found that B/F/TAF worked well in almost all people in the study by reducing levels of HIV in the blood. The virus could not be found in the blood of more than 9 out of 10 (94%) people who were taking B/F/TAF as their first HIV medicine and more than 9 out of 10 people (97%) who had taken another HIV medicine before starting B/F/TAF. This is known as having an 'undetectable viral load' and is a major goal for HIV treatment success. Researchers did not find any evidence of HIV developing resistance to B/F/TAF, which might stop B/F/TAF from working properly.Around 1 out of 10 people (13%) had side effects (any unwanted sign or symptom that people have when taking a medicine that researchers think might be caused by the medicine) that might have been caused by B/F/TAF. Most of these side effects were not classified as serious. Less than 1 out of 100 (0.1%) people had serious side effects that might have been caused by B/F/TAF. Only 6 out of 100 people stopped taking B/F/TAF due to side effects caused by B/F/TAF. As a result, more than 9 out of 10 people (95%) took B/F/TAF for at least 1 year. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: B/F/TAF worked well in people with HIV in this study. Most people (around 9 out of 10) did not have any side effects.

Design and discovery of carboxamide-based pyrazole conjugates with multifaceted potential against Triple-Negative Breast cancer MDA-MB-231 cells.

We report the design, synthesis, and validation of carboxamide-based pyrazole and isoxazole conjugates with a multifaceted activity against Breast Cancer Cell Line MDA-MB-231. The study established that amongst the series, N-(3,5-bis(trifluoromethyl)benzyl)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazole-5-carboxamide (5g) exhibits the highest potency in inhibiting Breast Cancer Cell Line MDA-MB-231 with an IC50 value of 15.08 ± 0.04 µM. The MDA-MB-231 cells, upon treatment with compound 5g, exhibited characteristic apoptotic specific activities such as nuclear fragmentation, phosphatidylserine translocation to the outer plasma membrane, release of lactate dehydrogenase (LDH), and upregulation of caspase 3 and caspase 9 activities. Also, the modulation of pro and antiapoptotic proteins in 5g treated MDA-MB-231 cells was revealed by membrane array analysis. More importantly, the combination of paclitaxel and compound 5g has exhibited improved activity by several folds via their synergistic effects.