KD025 Is a Casein Kinase 2 Inhibitor That Protects Against Glucolipotoxicity in ß-Cells.

Glucolipotoxicity (GLT), in which elevated levels of glucose and fatty acids have deleterious effects on ß-cell biology, is thought to be one of the major contributors in progression of type 2 diabetes. In search of novel small molecules that protect ß-cells against GLT, we previously discovered KD025, an inhibitor of Rho-associated coiled-coil-containing kinase isoform 2 (ROCK2), as a GLT-protective compound in INS-1E cells and dissociated human islets. To further understand the mechanism of action of KD025, we found that pharmacological and genetic inhibition of ROCK2 was not responsible for the protective effects of KD025 against GLT. Instead, kinase profiling revealed that KD025 potently inhibits catalytic subunits of casein kinase 2 (CK2), a constitutively active serine/threonine kinase. We experimentally verified that the inhibition of one of the catalytic subunits of casein kinase 2, CK2A1, but not CK2A2, improved cell viability when challenged with GLT. We conclude that KD025 inhibits CK2 to protect ß-cells from GLT.

Effect of single-administration of D-sorbitol pretreatment on the bitterness and continued willingness to take asenapine: a randomized, single-blind, placebo-controlled, crossover trial.

BACKGROUND: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of D-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. METHODS: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of D-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). RESULTS: D-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. CONCLUSION: Our findings indicate that single-administration of D-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

Osteogenic Activities of Trifolirhizin as a Bioactive Compound for the Differentiation of Osteogenic Cells.

Plant extracts are widely used as traditional medicines. Sophora flavescens Aiton-derived natural compounds exert various beneficial effects, such as anti-inflammatory, anticancer, antioxidant, and antiregenerative activities, through their bioactive compounds, including flavonoids and alkaloids. In the present study, we investigated the biological effects of an S. flavescens-derived flavonoid, trifolirhizin (trifol), on the stimulation of osteogenic processes during osteoblast differentiation. Trifol (>98% purity) was successfully isolated from the root of S. flavescens and characterized. Trifol did not exhibit cellular toxicity in osteogenic cells, but promoted alkaline phosphatase (ALP) staining and activity, with enhanced expression of the osteoblast differentiation markers, including Alp, ColI, and Bsp. Trifol induced nuclear runt-related transcription factor 2 (RUNX2) expression during the differentiation of osteogenic cells, and concomitantly stimulated the major osteogenic signaling proteins, including GSK3ß, ß-catenin, and Smad1/5/8. Among the mitogen-activated protein kinases (MAPKs), Trifol activated JNK, but not ERK1/2 and p38. Trifol also increased the osteoblast-mediated bone-forming phenotypes, including transmigration, F-actin polymerization, and mineral apposition, during osteoblast differentiation. Overall, trifol exhibits bioactive activities related to osteogenic processes via differentiation, migration, and mineralization. Collectively, these results suggest that trifol may serve as an effective phytomedicine for bone diseases such as osteoporosis.

Transgenerational effect of Afidopyropen on Bemisia tabaci Gennadius (Homoptera: Aleyrodidae).

Bemisia tabaci Gennadius (Homoptera: Aleyrodidae) is the most devastating insect-pest in cotton crop. It is vector of the cotton leaf curl virus (CLCV) and is responsible for huge losses to cotton industry in Pakistan and worldwide. It is mainly controlled by insecticides but the injudicious use of insecticides has resulted in insecticide resistance and population resurgence in addition to various harmful effects on the humans, non-target organisms and the environment. Transgenerational studies are very helpful to choose a best insecticidal option. In the current study, age-stage two-sex life table analysis was used to identify transgenerational effects of sublethal doses of afidopyropen. The adults of B. tabaci were treated with three concentrations of afidopyropen i.e., LC10, LC30 and LC50. The results indicated significant changes in the progeny i.e. the fecundity decreased in treated population; and female and male longevity of their progeny were more in control as compared to treated populations. Similarly, population parameters like intrinsic rate of growth (r), net reproductive rate (R0) and limiting rate of growth (λ) were significantly decreased in the treated adult progeny with values of 0.08-0.11, 4.85-7.46 and 1.09-1.12 per day, respectively. Based on the reduced biotic potential, afidopyropen can be suggested as an effective alternative option for the management of B. tabaci.

Toward "E-Ring-Free" Lamellarin Analogues: Synthesis and Preliminary Biological Evaluation.

Since the discovery of anticancer properties of a naturally occurring hexacyclic marine alkaloid Lamellarin D, the attempts have been made to prepare its synthetic analogues and elucidate the effects of each structural component on their activity profile. While F-ring-free, A-ring-free and B-ring-open lamellarins are known, E-ring-free analogues have never been investigated. In this work, we developed a facile and straightforward synthetic method toward E-ring-free lamellarin analogues based on the [3+2]-cycloaddition. For the first time, we prepared several pentacyclic lamellarin analogues without E-ring in their structure and assessed their cytotoxicity in a panel of cancer cell lines in comparison with several hexacyclic lamellarins. E-ring-free lamellarins were devoid of cytotoxicity due to their poor solubility in cellular environment.

Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains.

The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state models (MSMs) built from over 2 ms of aggregate molecular dynamics simulations with explicit solvent. We find that blebbistatin's binding pocket readily opens in simulations of blebbistatin-sensitive myosin isoforms. Comparing these conformational ensembles reveals that the probability of pocket opening correctly identifies which isoforms are most sensitive to blebbistatin inhibition and that docking against MSMs quantitatively predicts blebbistatin binding affinities (R2=0.82). In a blind prediction for an isoform (Myh7b) whose blebbistatin sensitivity was unknown, we find good agreement between predicted and measured IC50s (0.67 µM vs. 0.36 µM). Therefore, we expect this framework to be useful for the development of novel specific drugs across numerous protein targets.

Efficacy and Safety of Bictegravir-Based Regimen in Pregnant Women Living with HIV: A Case Report.

Bictegravir (BIC) is included in international guidelines as the first line of therapy for patients living with Human Immunodeficiency Virus (HIV), either as initial therapy or as a replacement for patients with prior antiretroviral therapy (ART). Due to limited efficacy and safety data, BIC is currently not recommended during pregnancy. Data on the safety and efficacy of BIC during pregnancy were unavailable at the time of drug approval. In our case, BIC/TAF/FTC was effective in suppressing viral load (VL) in pregnancy, and there were no reported safety issues for the mother or the baby.

Real World Data on Forgiveness to Uncomplete Adherence to Bictegravir/ Emtricitabine/Tenofovir Alafenamide.

Background: forgiveness is the ability of a given regimen to maintain complete viral suppression despite a documented imperfect adherence. We explored forgiveness of bictegravir/emtricitabine/tenofovir alafenamide. Methods: drug refills were used to calculate the percent day covered (PDC) as a proxy of adherence. Forgiveness was calculated as the achieved rate of a selected HIV-RNA threshold by a given level of imperfect adherence. Results: 281 adult PLWH were followed for 343 patient/years. Adherence was very high with a median of 98% (IQR 95-100%). A PDC as low as 70% was sufficient to obtain 100% and maintain virologic suppression. According to probit analysis adherence was not related to the possibility to maintain an HIV-RNA TND or < 50 copies/ml. Conclusions: Long-term success of ART needs effective regimens that are the least intrusive of the patient's lifestyle, an elevated forgiveness may be considered as an additional feature that can further improve long-term outcomes.

High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients.

Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-ß-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.

The selective NLRP3 inflammasome inhibitor MCC950 improves isoproterenol-induced cardiac dysfunction by inhibiting cardiomyocyte senescence.

BACKGROUND: Activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome contributes to heart failure (HF) pathogenesis. However, the effect of NLRP3 inhibition on ß-adrenergic receptor agonist-induced HF remains unknown. Here, we evaluated the role of MCC950, a selective NLRP3 inhibitor, in isoproterenol (ISO)-induced cardiac dysfunction. METHODS: Mice were administered ISO (30 mg/kg/day) for 14 days with or without MCC950 (10 mg/kg) injection every other day. Cardiac function and the extent of hypertrophy and fibrosis were measured by echocardiography, HE and Masson trichrome staining, respectively. Immunohistochemistry, quantitative real-time PCR and Western blotting were performed to investigate the impact of MCC950 on ISO-induced cardiac dysfunction. The levels of oxidative stress and cell senescence were detected in H9C2 cells to explore the mechanism of MCC950 on ISO-induced myocardial injury in vitro. RESULTS: We found that the NLRP3 inflammasome was significantly activated in response to ISO treatment in mice. Selective inhibition of the NLRP3 inflammasome by MCC950 ameliorated cardiac fibrosis, hypertrophy and inflammation in ISO-treated mice, ultimately improving heart function. Furthermore, MCC950 significantly inhibited ISO-induced oxidative stress in the myocardium, accompanied by increased superoxide dismutase 2 (SOD2) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein. In addition, MCC950 attenuated cardiomyocyte death and senescence in ISO-treated H9C2 cells, which was attributed to the decreased oxidative stress. CONCLUSION: NLRP3 inhibition by MCC950 ameliorated ISO-induced cardiac dysfunction by inhibiting cardiomyocyte senescence and oxidative stress. Therefore, inhibition of the NLRP3 inflammasome may be a potential therapeutic strategy for preventing cardiac dysfunction, especially age-related HF.

MCC950 inhibits the inflammatory response and excessive proliferation of canine corneal stromal cells induced by Staphylococcus pseudintermedius.

BACKGROUND: The stromal layer is the thickest layer of the cornea, and corneal stromal cells play an important role in the inflammatory response and wound repair. This study investigated the effect of MCC950, an inhibitor of NLRP3 inflammasome, on the inflammatory response and proliferation of canine corneal stromal cells (CCSCs) induced by Staphylococcus pseudintermedius (S. pseudintermedius). METHODS: CCSCs were pretreated with MCC950 and infected with S. pseudintermedius. The phosphorylation of p65, IκBα, PI3K, and AKT and the expression of NLRP3, caspase-1 p20, cleaved IL-1ß, ASC, ß-catenin, c-Myc, and CyclinD1 were detected by western blotting. The expression of inflammatory factors (IL-1ß, IL-6, IL-8, IL-18, and TNF-α) and growth factors (EGF, FGF, TGF-ß1, VEGF, and CTGF) were measured by RT-PCR. The levels of MDA content and LDH activity were detected by an assay kit. The cell cycle was detected by flow cytometry. RESULTS: MCC950 down-regulated the phosphorylation of p65, IκBα, PI3K, and AKT and decreased the expression of NLRP3, caspase-1 p20, cleaved IL-1ß, ASC, ß-catenin, c-Myc, and CyclinD1 compared to those in the S. pseudintermedius infection group (p < 0.05). MCC950 significantly inhibited the expression of inflammatory factors (IL-1ß, IL-6, IL-8, IL-18, and TNF-α) and growth factors (EGF, FGF, TGF-ß1, VEGF, and CTGF) induced by S. pseudintermedius (p < 0.01). Compared to the S. pseudintermedius infection group, the MDA content and LDH activity of CCSCs were significantly decreased after treatment with MCC950 (p < 0.01). CONCLUSION: MCC950 attenuates S. pseudintermedius-induced inflammatory responses in CCSCs. At the same time, MCC950 can inhibit excessive proliferation of cells, which is beneficial for alleviating corneal fibrosis healing.

SIRT1720 promotes survival of corneal epithelial cells via the P53 pathway.

PURPOSE: To investigate the protective role of SRT1720 (SIRT1 activator) against the oxidative stress caused by H2O2 in the corneal cell line. METHODS: Human corneal (2.040 pRSV-T) cell lines were cultured and treated with SRT1720 (as SIRT1 activator) and nicotinamide (NAM, a SIRT1 inhibitor), and incubated with H2O2. The expression level of SIRT1, p53, and acetyl-p53 was measured by western blot. Propidium iodine/annexin V-FITC staining, and flow cytometry was used to evaluate apoptosis. The trypan blue assay was used to assess the morphological modifications that occurred after the treatment, and Pifithrin-α (PFT-α) was used to inhibit the p53 pathway. RESULTS: The investigation revealed that under oxidative stress, SRT1720 caused a reduction in acetyl-p53 expression and increased SIRT1 expression. It was also found that under oxidative stress, SRT1720 suppressed apoptosis. In comparison, NAM promoted cell apoptosis under oxidative stress. NAM's destructive effect was eliminated by PFT-α, a suppressor of the p53 pathway. PFT-α reduced the morphological changes in 2.040 pRSV-T cell lines compared to NAM treatment and inhibited apoptosis. CONCLUSIONS: The protective effects of the SIRT1 activator (SRT1720) indicate that H2O2 induces oxidative stress-associated cell damage. The results also encouraged us to consider using SRT1720 to improve corneal safety and reduce the adverse effects of oxidative damage.

A clinical review of HIV integrase strand transfer inhibitors (INSTIs) for the prevention and treatment of HIV-1 infection.

Integrase strand transfer inhibitors (INSTIs) have improved the treatment of human immunodeficiency virus (HIV). There are currently four approved for use in treatment-naïve individuals living with HIV; these include first generation raltegravir, elvitegravir, and second generation dolutegravir and bictegravir. The most recent INSTI, cabotegravir, is approved for (1) treatment of HIV infection in adults to replace current antiretroviral therapy in individuals who maintain virologic suppression on a stable antiretroviral regimen without history of treatment failure and no known resistance to its components and (2) pre-exposure prophylaxis in individuals at risk of acquiring HIV-1 infection. Cabotegravir can be administered intramuscularly as a monthly or bi-monthly injection depending on the indication. This long-acting combination has been associated with treatment satisfaction in clinical studies and may be helpful for individuals who have difficulty taking daily oral medications. Worldwide, second generation INSTIs are preferred for treatment-naïve individuals. Advantages of these INSTIs include their high genetic barrier to resistance, limited drug-drug interactions, excellent rates of virologic suppression, and favorable tolerability. Few INSTI resistance-associated mutations have been reported in clinical trials involving dolutegravir, bictegravir and cabotegravir. Other advantages of specific INSTIs include their use in various populations such as infants and children, acute HIV infection, and individuals of childbearing potential. The most common adverse events observed in clinical studies involving INSTIs included diarrhea, nausea, insomnia, fatigue, and headache, with very low rates of treatment discontinuation versus comparator groups. The long-term clinical implications of weight gain associated with second generation INSTIs dolutegravir and bictegravir warrants further study. This review summarizes key clinical considerations of INSTIs in terms of clinical pharmacology, drug-drug interactions, resistance, and provides perspective on clinical decision-making. Additionally, we summarize major clinical trials evaluating the efficacy and safety of INSTIs in treatment-naïve patients living with HIV as well as individuals at risk of acquiring HIV infection.

Second-Generation Human Immunodeficiency Virus Integrase Inhibitors Induce Differentiation Dysregulation and Exert Toxic Effects in Human Embryonic Stem Cell and Mouse Models.

BACKGROUND: Each year, approximately 1.1 million children are exposed in utero to human immunodeficiency virus antiretrovirals, yet their safety is often not well characterized during pregnancy. The Tsepamo study reported a neural tube defect signal in infants exposed to the integrase strand transfer inhibitor (InSTI) dolutegravir from conception, suggesting that exposure during early fetal development may be detrimental. METHODS: The effects of InSTIs on 2 human embryonic stem cell (hESC) lines were characterized with respect to markers of pluripotency, early differentiation, and cellular health. In addition, fetal resorptions after exposure to InSTIs from conception were analyzed in pregnant mice. RESULTS: At subtherapeutic concentrations, second-generation InSTIs bictegravir, cabotegravir, and dolutegravir decreased hESC counts and pluripotency and induced dysregulation of genes involved in early differentiation. At therapeutic concentrations, bictegravir induced substantial hESC death and fetal resorptions. It is notable that first-generation InSTI raltegravir did not induce any hESC toxicity or differentiation, at any concentration tested. CONCLUSIONS: Exposure to some InSTIs, even at subtherapeutic concentrations, can induce adverse effects in hESCs and pregnant mice. Given the increasingly prevalent use of second-generation InSTIs, including in women of reproductive age, it is imperative to further elucidate the effect of InSTIs on embryonic development, as well as their long-term safety after in utero exposure.

Impact of preexisting nucleos(t)ide reverse transcriptase inhibitor resistance on the effectiveness of bictegravir/emtricitabine/tenofovir alafenamide in treatment experience patients.

INTRODUCTION: Few clinical trials and cohort studies have evaluated the efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with HIV (PWH) with preexisting M184V/I or other nucleos(t)ide reverse transcriptase inhibitor (NRTI) resistance-associated mutations (RAMs). Real-world data are also scarce. METHODS: Retrospective review of treatment-experienced patients who started B/F/TAF in a cohort of PWH. HIV-RNA less than 50 copies/ml was analyzed at 48 weeks in an intention-to-treat (ITT) analysis (missing=failure) and per protocol analysis (patients with missing data or changes for reasons other than virological failure were excluded). Results were compared in patients with and without previous NRTI-RAMs. RESULTS: Five hundred and six PWH were included (16.2% women). Median age and time with HIV infection were 52.3 and 18.9 years, respectively. At baseline, viral load was less than 50 copies/ml in 440 patients (86.6%). Overall, 69 (13.6%) participants had documented preexisting NRTI-RAMs: 57 (11.2%) M184V/I and 30 (5.9%) tenofovir RAMs. In the ITT analysis, 83% (420/506) had HIV-RNA less than 50 copies/ml [82.2% (359/437) and 88.4% (61/69) in persons without and with NRTI-RAMs, respectively ( P  = 0.2)]. In the per protocol analysis 94.2% (420/445) had HIV-RNA less than 50 copies/ml [94.4% (359/380) vs. 93.8% (61/65); P  = 0.2]. A total of 61 participants were excluded from the per protocol analysis (23 missing data, 19 discontinued B/F/TAF because of toxicity, 13 for other reasons, and 6 died). CONCLUSION: Switching to B/F/TAF is well tolerated and effective in the real-world setting, even in patients with preexisting NRTI RAMs, such as M184V and RAMs conferring resistance to tenofovir. These results confirm the robustness of this combination.

Flonicamid metabolite 4-trifluoromethylnicotinamide is a chordotonal organ modulator insecticide†.

BACKGROUND: The selective aphicide flonicamid is known to cause symptoms in aphids that are like those of chordotonal organ TRPV channel modulator insecticides such as pymetrozine, pyrifluquinazon and afidopyropen. Flonicamid is classified by the Insecticide Resistance Action Committee as a chordotonal organ modulator with an undefined target site. However, although it has been shown not to act on TRPV channels, flonicamid's action on chordotonal organs has not been documented in the literature. RESULTS: Flonicamid causes locusts to extend their hindlegs, indicating an action on the femoral chordotonal organ. In fruit flies, it abolishes negative gravitaxis behavior by disrupting transduction and mechanical amplification in antennal chordotonal neurons. Although flonicamid itself only weakly affects locust chordotonal organs, its major animal metabolite 4-trifluoromethylnicotinamide (TFNA-AM) potently stimulates both locust and fly chordotonal organs. Like pymetrozine, TFNA-AM rapidly increases Ca2+ in antennal chordotonal neurons in wild-type flies, but not iav1 mutants, yet the effect is nonadditive with the TRPV channel agonist. CONCLUSIONS: Flonicamid is a pro-insecticide form of TFNA-AM, a potent chordotonal organ modulator. The functional effects of TFNA-AM on chordotonal organs of locusts and flies are indistinguishable from those of the TRPV agonists pymetrozine, pyrifluquinazon and afidopyropen. Because our previous results indicate that TFNA-AM does not act directly on TRPV channels, we conclude that it acts upstream in a pathway that leads to TRPV channel activation. © 2022 Society of Chemical Industry.

Lurbinectedin Inhibits the EWS-WT1 Transcription Factor in Desmoplastic Small Round Cell Tumor.

Desmoplastic small round cell tumor (DSRCT) is a rare pediatric sarcoma with poor overall survival. This tumor is absolutely dependent on the continued expression and activity of its defining molecular lesion, the EWS-WT1 transcription factor. Unfortunately, the therapeutic targeting of transcription factors is challenging, and there is a critical need to identify compounds that inhibit EWS-WT1. Here we show that the compound lurbinectedin inhibits EWS-WT1 by redistributing the protein within the nucleus to the nucleolus. This nucleolar redistribution interferes with the activity of EWS-WT1 to reverse the expression of over 70% of the transcriptome. In addition, the compound blocks the expression of the EWS-WT1 fusion protein to inhibit cell proliferation at the lowest GI50 ever reported for this compound in any cell type. The effects occur at concentrations that are easily achievable in the clinic and translate to the in vivo setting to cause tumor regressions in multiple mice in a xenograft and PDX model of DSRCT. Importantly, this mechanism of nucleolar redistribution is also seen with wild-type EWSR1 and the related fusion protein EWS-FLI1. This provides evidence for a "class effect" for the more than 18 tumors driven by EWSR1 fusion proteins. More importantly, the data establish lurbinectedin as a promising clinical candidate for DSRCT.

Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes.

For people living with HIV, treatment with integrase-strand-transfer-inhibitors (INSTIs) can promote adipose tissue (AT) gain. We previously demonstrated that INSTIs can induce hypertrophy and fibrosis in AT of macaques and humans. By promoting energy expenditure, the emergence of beige adipocytes in white AT (beiging) could play an important role by limiting excess lipid storage and associated adipocyte dysfunction. We hypothesized that INSTIs could alter AT via beiging inhibition. Fibrosis and gene expression were measured in subcutaneous (SCAT) and visceral AT (VAT) from SIV-infected, dolutegravir-treated (SIVART) macaques. Beiging capacity was assessed in human adipose stromal cells (ASCs) undergoing differentiation and being exposed to dolutegravir, bictegravir, or raltegravir. Expression of beige markers, such as positive-regulatory-domain-containing-16 (PRDM16), were lower in AT of SIVART as compared to control macaques, whereas fibrosis-related genes were higher. Dolutegravir and bictegravir inhibited beige differentiation in ASCs, as shown by lower expression of beige markers and lower cell respiration. INSTIs also induced a hypertrophic insulin-resistant state associated with a pro-fibrotic phenotype. Our results indicate that adipocyte hypertrophy induced by INSTIs is involved via hypoxia (revealed by a greater hypoxia-inducible-factor-1-alpha gene expression) in fat fibrosis, beiging inhibition, and thus (via positive feedback), probably, further hypertrophy and associated insulin resistance.

Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome.

NOD-like receptor protein 3 (NLRP3), an important intracellular pattern recognition receptor, is a component of the NLRP3 inflammasome along with apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and pro-caspase-1. Previous studies have shown that dysregulation of NLRP3 inflammasome may be associated with several human diseases, and therefore blocking NLRP3 inflammasome activation may represent a therapeutic strategy for various diseases. MCC950 is a specific small-molecule inhibitor that selectively blocks activation of the NLRP3 inflammasome. In recent years, research on MCC950 has expanded; its targets are gradually being elucidated, and its metabolism and toxicity have been a focus of study. Preclinical research of MCC950 has yielded promising findings, and MCC950 has shown good efficacy in the treatment of autoimmune diseases, cardiovascular diseases, metabolic diseases and other diseases. Furthermore, clinical trials of MCC950 and other inhibitors of NLRP3 inflammasome have also been conducted. In this review, we discuss the drug targets, metabolism, toxicity and preclinical and clinical research advances of MCC950. We further discuss the clinical therapeutic potential of MCC950 to provide insights for the further study and application of MCC950.

Trifolirhizin regulates the balance of Th17/Treg cells and inflammation in the ulcerative colitis mice through inhibiting the TXNIP-mediated activation of NLRP3 inflammasome.

Ulcerative colitis (UC) is a chronic and recurrent autoimmune disease, characterized by recurrence and remission of mucosal inflammation. Although the understanding of the pathogenesis of UC has been improved, effective therapeutic drugs are required for treating patients with UC. In current work, the mouse model of colitis was established. Trifolirhizin was demonstrated to improve symptom in dextran sulfate sodium (DSS)-induced colitis mice. The body weight of mice was elevated, whereas the disease activity index (DAI) was reduced. Moreover, trifolirhizin was involved in inhibition of inflammation and regulation of the balance of T helper 17 (Th 17) cells and regulatory T (Treg) cells in DSS-induced colitis mice. Further, the activation NLRP3 inflammasome was suppressed by trifolirhizin in DSS-induced colitis mice. Trifolirhizin was also identified to regulate AMP-activated protein kinase (AMPK)-thioredoxin-interacting protein (TXNIP) pathway. The trifolirhizin-mediated anti-inflammatory effect was inhibited by suppressing AMPK in DSS-induced UC mice. In summary, the research suggested that administration of trifolirhizin significantly improved the symptoms and the pathological damage in DSS-induced UC mice. Trifolirhizin regulated the balance of Th17/Treg cells and inflammation in the UC mice through inhibiting the TXNIP-mediated activation of NLRP3 inflammasome.