The effect of resistance training on patients with knee osteoarthritis: a systematic review and meta-analysis.

The objective of this study is to investigate the beneficial effects of resistance training (RT) on individuals suffering from knee osteoarthritis (KOA). In order to gather relevant studies from the beginning of various databases until January 2023, a comprehensive search was conducted on PubMed, Embase, Scopus, Web of Science, and The Cochrane Library. Additionally, manual searches were performed on the reference lists. The association between RT and KOA was analysed using a random-effects model. The results indicated that patients with KOA who underwent RT experienced a significant reduction in the WOMAC (Western Ontario and McMaster Universities Osteoarthritis) Pain index (WMD = -2.441; 95% CI = -3.610 to -1.273; p < 0.01), the WOMAC Stiffness index (WMD = -1.018; 95% CI = -1.744 to -0.293; p < 0.01), the WOMAC Function index (WMD = -7.208; 95% CI = -10.412 to -4.004; p < 0.01), and the VAS (Visual Analogue Scale) index (WMD = -5.721; 95% CI = -9.320 to -2.121; p < 0.01). These improvements were observed when compared to the control group. However, no significant difference was found in the 6-MWT (6-Minute Walk Test) index between the two groups (WMD = 2.659; 95% CI= -16.741 to 22.058; p = 0.788). Consequently, RT has the potential to positively enhance pain, stiffness, and function in patients with KOA, while the 6-MWT index may not exhibit significant improvement.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

[Box: see text].

Missing WD40 Repeats in ATG16L1 Delays Canonical Autophagy and Inhibits Noncanonical Autophagy.

Canonical autophagy is an evolutionarily conserved process that forms double-membrane structures and mediates the degradation of long-lived proteins (LLPs). Noncanonical autophagy (NCA) is an important alternative pathway involving the formation of microtubule-associated protein 1 light chain 3 (LC3)-positive structures that are independent of partial core autophagy proteins. NCA has been defined by the conjugation of ATG8s to single membranes (CASM). During canonical autophagy and NCA/CASM, LC3 undergoes a lipidation modification, and ATG16L1 is a crucial protein in this process. Previous studies have reported that the WDR domain of ATG16L1 is not necessary for canonical autophagy. However, our study found that WDR domain deficiency significantly impaired LLP degradation in basal conditions and slowed down LC3-II accumulation in canonical autophagy. We further demonstrated that the observed effect was due to a reduced interaction between ATG16L1 and FIP200/WIPI2, without affecting lysosome function or fusion. Furthermore, we also found that the WDR domain of ATG16L1 is crucial for chemical-induced NCA/CASM. The results showed that removing the WDR domain or introducing the K490A mutation in ATG16L1 significantly inhibited the NCA/CASM, which interrupted the V-ATPase-ATG16L1 axis. In conclusion, this study highlights the significance of the WDR domain of ATG16L1 for both canonical autophagy and NCA functions, improving our understanding of its role in autophagy.

Noncanonical autophagy is a new strategy to inhibit HSV-1 through STING1 activation.

STING1 (stimulator of interferon response cGAMP interactor 1) plays an essential role in immune responses for virus inhibition via inducing the production of type I interferon, inflammatory factors and macroautophagy/autophagy. In this study, we found that STING1 activation could induce not only canonical autophagy but also non-canonical autophagy (NCA) which is independent of the ULK1 or BECN1 complexes to form MAP1LC3/LC3-positive structures. Whether STING1-induced NCA has similar characters and physiological functions to canonical autophagy is totally unknown. Different from canonical autophagy, NCA could increase single-membrane structures and failed to degrade long-lived proteins, and could be strongly suppressed by interrupting vacuolar-type H+-translocating ATPase (V-ATPase) activity. Importantly, STING1-induced NCA could effectively inhibit DNA virus HSV-1 in cell model. Moreover, STING1 [1-340], a STING1 mutant lacking immunity and inflammatory response due to deletion of the tail end of STING1, could degrade virus through NCA alone, suggesting that the antiviral effect of activated STING1 could be separately mediated by inherent immunity, canonical autophagy, and NCA. In addition, the translocation and dimerization of STING1 do not rely on its immunity function and autophagy pathway. Similar to canonical autophagy, LC3-positive structures of NCA induced by STING1 could finally fuse with lysosomes, and the degradation of HSV-1 could be reverted by inhibition of lysosome function, suggesting that the elimination of DNA virus via NCA still requires the lysosome pathway. Collectively, we proved that besides its classical immunity function and canonical autophagy pathway, STING1-induced NCA is also an efficient antiviral pathway for the host cell.Abbreviations: ATG: autophagy related; Baf: bafilomycin A1; CASM: conjugation of LC3 to a single membrane; CGAS: cyclic GMP-AMP synthase; cGAMP: cyclic GMP-AMP; CQ: chloroquine; CTD: C-terminal domain; CTT: C-terminal tail; ER: endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment; HSV-1: herpes simplex virus 1; IRF3: interferon regulatory factor 3; IFNs: interferons; LAMP1: lysosomal associated membrane protein 1; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; RB1CC1/FIP200: RB1 inducible coiled-coil 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TGOLN2/TGN46: trans-golgi network protein 2; ULK1: unc-51 like autophagy activating kinase 1; V-ATPase: vacuolar-type H+-translocating ATPase; VSV: vesicular stomatitis virus.

Enantioselective Cu-Catalyzed Nucleophilic Substitutions of Polyfluoroarenes: Synthesis of Chiral Polyfluoroaryl Diarylmethanes.

Optically pure diarylmethanes are frequently presented in pharmaceuticals and bioactive molecules. However, minor efforts have been devoted to chiral polyfluoroarene-containing diarylmethanes, and their synthesis is still challenging. Herein, we describe an enantioselective Cu/sulfoxide phosphine (SOP) catalyzed nucleophilic substitution reaction by using polyfluoroarenes as the polyfluoroaryl reagent. Under mild conditions, this protocol enables the efficient synthesis of chiral polyfluoroaryl diarylmethanes with fluorinated quaternary stereogenic center in good yields (up to 93%), high regioselectivties, and excellent enantioselectivities (up to 99% ee). Moreover, gram-scale experiments, product derivations, and late-stage diversifications were performed to demonstrate the utility of this method.

Synthesis of Sulfilimines via Selective S-C Bond Formation in Water.

Sulfilimines are valuable compounds both in organic synthesis and in pharmaceuticals. Here we developed a mild and simplified method for preparation of sulfilimines via selective S-C bond formation rather than traditional S-N bond formation. The method is both attractive and useful for the following reasons: it uses a readily available alkylation reagent such alkyl bromide or alkyl iodide, it uses water as solvent, it is easy to perform, and it is convenient for late-stage diversification of drugs.

Enantioselective Double Carbonylation Enabled by High-Valent Palladium Catalysis.

Palladium-catalyzed carbonylation reactions are efficient methods for synthesizing valuable molecules. However, realizing a carbonylation with excellent yield and chemo-, regio-, and enantioselectivities by classical low-valent palladium catalysis is highly challenging. Herein, we describe an enantioselective carbonylation reaction using a high-valent palladium catalysis strategy and employing a chiral sulfoxide phosphine (SOP) ligand. This double aminocarbonylation reaction begins with the formation of a carbamoylpalladium(II) species, which undergoes enantioselective oxidative addition with a cyclic diaryliodonium salt to generate a palladium(IV) intermediate, followed by a second CO insertion and reductive elimination. The mechanism has been illustrated with experimental and computational studies.

Discovery of an autophagy inducer J3 to lower mutant huntingtin and alleviate Huntington's disease-related phenotype.

Huntington's disease (HD) is a neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein encoded from extra tracts of CAG repeats in exon 1 of the HTT gene. mHTT proteins are neurotoxic to render the death of neurons and a series of disease-associated phenotypes. The mHTT is degraded through autophagy pathway and ubiquitin-proteasome system (UPS). This study identified a small molecule, J3, as an autophagy inducer by high-content screening. The results revealed that J3 could inhibit mTOR, thus promoting autophagic flux and long-lived protein degradation. Further, J3 selectively lowered the soluble and insoluble mHTT but not wild type HTT levels in cell models. The HdhQ140 mice showed reduced HD-associated activity and loss of motor functions. However, administration of J3 showed increased activity and a slight improvement in the motor function in the open-field test, balance beam test, and rotarod tests. Furthermore, in vivo studies revealed that J3 decreased T-HTT and misfolded protein levels in the striatum and increased the levels of the medium spiny neuron marker DARPP-32. In addition, J3 showed good permeability across the brain-blood barrier efficiently, suggesting that J3 was a promising candidate for the treatment of HD.

Cyclopiazonic Acid and Okaramine Analogues, Including Chlorinated Compounds, from Chrysosporium undulatum YT-1.

Eight new cyclopiazonic acid (1-8) and five new okaramine (9-13) alkaloids together with 13 known compounds were isolated from the fungus Chrysosporium undulatum YT-1. Compounds 2, 4, 5, 7, 10, 11, and 13 were chlorinated indole alkaloids. The structures of compounds 1-13 were elucidated by HRESIMS and NMR spectroscopic data. Their relative and absolute configurations were established by J-based configuration analysis, NOESY, NOEDIFF experiments, ECD spectroscopic data, and biogenetic considerations. Compound 4 inhibited the growth of Bacillus subtilis with an MIC value of 6.3 µg/mL. Compounds 9-11 exhibited strong insecticidal capacity against the third instar larvae of silkworm and cotton bollworm (LD50: ≤7.56 µg/g). At 40 µM, compound 1 showed obvious neuroprotection to the PC12 cells with 6-OHDA treatment.

Suppression of ATG4B by copper inhibits autophagy and involves in Mallory body formation.

Autophagy is an evolutionarily conserved self-protecting mechanism implicated in cellular homeostasis. ATG4B plays a vital role in autophagy process via undertaking priming and delipidation of LC3. Chemical inhibitors and regulative modifications such as oxidation of ATG4B have been demonstrated to modulate autophagy function. Whether and how ATG4B could be regulated by metal ions is largely unknown. Copper is an essential trace metal served as static co-factors in redox reactions in physiology process. Excessive accumulation of copper in ATP7B mutant cells leads to pathology progression such as insoluble Mallory body (MB) in Wilson disease (WD). The clearance of MB via autophagy pathway was thought as a promising strategy for WD. Here, we discovered that copper ion instead of other ions could inhibit the activity of ATG4B followed by autophagy suppression. In addition, copper could induce ATG4B oligomers depending on cysteine oxidation which could be abolished in reduced condition. Copper also promotes the formation of insoluble ATG4B aggregates, as well as p62-and ubiquitin-positive aggregates, which is consistent with the components of MB caused by copper overload in WD cell model. Importantly, overexpression of ATG4B could partially reduce the formation of MB and rescue impaired autophagy. Taken together, our results uncovered for the first time a new damage mechanism mediated by copper and implied new insights of the crosstalk between the toxicity of copper and autophagy in the pathogenesis of WD.

Enantioselective Cu-Catalyzed Nucleophilic Addition of Fluorinated Reagents: C-C Bond Formation for the Synthesis of Chiral Vicinal Difluorides.

Herein we described the first enantioselective Cu/sulfoxide phosphine (SOP) complex catalyzed nucleophilic addition of fluorinated enolates to gem-difluoroalkenes. The enantioenriched vicinal difluorides, containing a chiral tertiary fluoride and a fluoroalkene, were successfully afforded via C-C bond formation in good yields (up to 94% yield), high Z/E-selectivity (5:1 → 50:1 for Z-isomer), and excellent enantioselectivities (up to 98.5:1.5 er). Utility of this approach was demonstrated by modification of complex biologically active compounds.

An Insight on the Pathways Involved in Crizotinib and Sunitinib Induced Hepatotoxicity in HepG2 Cells and Animal Model.

Both crizotinib and sunitinib, novel orally-active multikinase inhibitors, exhibit antitumor activity and extend the survival of patients with a malignant tumor. However, some patients may suffer liver injury that can further limit the clinical use of these drugs, however the mechanisms underlying hepatotoxicity are still to be elucidated. Thus, our study was designed to use HepG2 cells in vitro and the ICR mice model in vivo to investigate the mechanisms of hepatotoxicity induced by crizotinib and sunitinib. Male ICR mice were treated orally with crizotinib (70 mg/kg/day) or sunitinib (7.5 mg/kg/day) for four weeks. The results demonstrated that crizotinib and sunitinib caused cytotoxicity in HepG2 cells and chronic liver injury in mice, which were associated with oxidative stress, apoptosis and/or necrosis. Crizotinib- and sunitinib-induced oxidative stress was accompanied by increasing reactive oxygen species and malondialdehyde levels and decreasing the activity of superoxide dismutase and glutathione peroxidase. Notably, the activation of the Kelch-like ECH-associated protein-1/Nuclear factor erythroid-2 related factor 2 signaling pathway was involved in the process of oxidative stress, and partially protected against oxidative stress. Crizotinib and sunitinib induced apoptosis via the mitochondrial pathway, which was characterized by decreasing Bcl2/Bax ratio to dissipate the mitochondrial membrane potential, and increasing apoptotic markers levels. Moreover, the pan-caspase inhibitor Z-VAD-FMK improved the cell viability and alleviated liver damage, which further indicated the presence of apoptosis. Taken together, this study demonstrated that crizotinib- and sunitinib-caused oxidative stress and apoptosis finally impaired hepatic function, which was strongly supported by the histopathological lesions and markedly increased levels of serum alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase.

Clinical study on polycystic ovary syndrome treated with Diane-35 and Pioglitazone.

OBJECTIVE: To observe the effects of Diane-35 and pioglitazone on endocrine, blood lipid, and blood glucose metabolism in patients with polycystic ovary syndrome (PCOS). METHODS: 70 PCOS patients were selected as subjects between January 2019 and January 2020 and were randomized into two groups. The control group was provided with Diane-35 for 1 tablet/day. The patients in the observation group took additional pioglitazone twice a day. The therapeutic effect of the two schemes was analyzed by observing hormone, blood lipid, and blood glucose levels. The body mass index (BMI), waist-hip ratio (WHR), and Ferriman-Gallwey score (F-G) of the two groups of patients at different time points were compared. RESULTS: Compared with the control group, after pioglitazone treatment, a significant decrease was observed in the levels of various hormone factors. In the observation group (all P<0.01) and the observation group yielded lower levels of fasting blood glucose (FBG), fasting insulin (FIN), Homeostatic Model Assessment for Insulin Resistance (Homa IR), and Homeostatic Model Assessment for ß-cell function (Homa B), as compared to the control group (all P<0.01). Additionally, compared with the control group, the high-density lipoprotein (HDL) levels in the observation group saw a spike (P<0.01). The low-density lipoprotein (LDL) levels witnessed a downturn (P<0.01). Immediately after treatment and 1 month after treatment, the BMI, WHR, and F-G scores of the two groups declined gradually, with lower WHR and F-G scores of the observation group than those of the control group (P<0.01). CONCLUSION: Diane-35 and pioglitazone can effectively improve the symptoms of sex hormone secretion, blood glucose, and blood lipid disorder in PCOS patients, which has high clinical application value.

Enantioselective Copper-Catalyzed Electrophilic Sulfenylation of Cyclic Imino Esters.

Herein we report an enantioselective sulfenylation of cyclic imino esters with the efficient and versatile sulfenylation reagent S-alkyl 4-methylbenzenesulfonothioates. By utilizing the Cu/tBu-Phosferrox catalytic system, we can assemble diverse S-alkyl groups into the cyclic imino esters under mild conditions in good yields and with excellent enantioselectivities. Remarkably, this method demonstrates a high tolerance of diverse functional groups and proves to be applicable in the late-stage functionalization of pharmaceuticals.

Binding Features and Functions of ATG3.

Autophagy is an evolutionarily conserved catabolic process that is essential for maintaining cellular, tissue, and organismal homeostasis. Autophagy-related (ATG) genes are indispensable for autophagosome formation. ATG3 is one of the key genes involved in autophagy, and its homologs are common in eukaryotes. During autophagy, ATG3 acts as an E2 ubiquitin-like conjugating enzyme in the ATG8 conjugation system, contributing to phagophore elongation. ATG3 has also been found to participate in many physiological and pathological processes in an autophagy-dependent manner, such as tumor occurrence and progression, ischemia-reperfusion injury, clearance of pathogens, and maintenance of organelle homeostasis. Intriguingly, a few studies have recently discovered the autophagy-independent functions of ATG3, including cell differentiation and mitosis. Here, we summarize the current knowledge of ATG3 in autophagosome formation, highlight its binding partners and binding sites, review its autophagy-dependent functions, and provide a brief introduction into its autophagy-independent functions.

Synthesis of Tribenzo[b,d,f]azepines via Palladium-Catalyzed Annulation Reaction of 2-Iodobiphenyls with 2-Halogenoanilines.

A palladium-catalyzed annulation reaction of 2-iodobiphenyls with 2-halogenoanilines has been developed. A variety of 2-iodobiphenyls and 2-halogenoanilines can undergo this transformation. Diversified tribenzo[b,d,f]azepine derivatives can be synthesized in moderate to excellent yields according to this method.

Palladium-Catalyzed Linear Hydrothiocarbonylation of Unactivated Terminal Alkenes: Synthesis of Aliphatic Thioesters.

A Pd-catalyzed hydrothiocarbonylation of unactivated terminal alkenes is presented. According to this protocol, aliphatic thioesters were synthesized with exclusive linear selectivity under mild reaction conditions. Good to excellent yields (up to 91% yield), broad substrate scope, broad functional group tolerance, and utility of the method demonstrated the advantages of this protocol.

Diterpenoids caryopterisoids D - Q and iridoid glucoside derivatives caryopterisides F - H from Caryopteris glutinosa.

Fourteen undescribed diterpenoids caryopterisoids D - Q, three undescribed iridoid glucoside derivatives caryopterisides F - H, and 8 known diterpenoids were isolated from the 95% aqueous ethanolic extract of Caryopteris glutinosa. Their structures were elucidated on the basis of spectroscopic data analysis and chemical derivation studies. The structure and absolute configuration of caryopterisoid D were confirmed by X-ray crystallographic analysis. Caryopterisoids K and R, royleanone, 6α-hydroxydemethylcryptojaponol, and teuvincenone E were shown to reduce the biosynthesis of estrogen E2 with IC50 values from 0.25 to 3.06 µM in cell-based estrogen biosynthesis assays system.

Synthesis and Evaluation of a Series of New Bulleyaconitine A Derivatives as Analgesics.

As a nonaddictive analgesic widely used in clinics, the LD50 of bulleyaconitine A is just only 0.92 mg/kg, which exhibits obvious toxicity. Therefore, 31 new non-natural C19-diterpenoid alkaloids (2a-w, 2'a-e, 3, 4a, and 4b) were designed and synthesized from bulleyaconitine A to develop nonaddictive analgesics with low toxicity. The chemical structures were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS) spectra. The analgesic activities were evaluated by a hot plate test in mice. At the dosage of 10 mg/kg, six compounds (2d, 2j, 2k, 2m, 2t, 2w) exhibited good analgesic activities (increased pain threshold >100%) with a long duration. Among them, 2w showed the best analgesic activity and the longest duration. Its pain threshold reached 166.35% in 15 min, peaked at 30 min (182.35%), and remained 82.59% even at 60 min.