Natural-product-based, carrier-free, noncovalent nanoparticles for tumor chemo-photodynamic combination therapy.

Cancer, with its diversity, heterogeneity, and complexity, is a significant contributor to global morbidity, disability, and mortality, highlighting the necessity for transformative treatment approaches. Photodynamic therapy (PDT) has aroused continuous interest as a viable alternative to conventional cancer treatments that encounter drug resistance. Nanotechnology has brought new advances in medicine and has shown great potential in drug delivery and cancer treatment. For precise and efficient therapeutic utilization of such a tumor therapeutic approach with high spatiotemporal selectivity and minimal invasiveness, the carrier-free noncovalent nanoparticles (NPs) based on chemo-photodynamic combination therapy is essential. Utilizing natural products as the foundation for nanodrug development offers unparalleled advantages, including exceptional pharmacological activity, easy functionalization/modification, and well biocompatibility. The natural-product-based, carrier-free, noncovalent NPs revealed excellent synergistic anticancer activity in comparison with free photosensitizers and free bioactive natural products, representing an alternative and favorable combination therapeutic avenue to improve therapeutic efficacy. Herein, a comprehensive summary of current strategies and representative application examples of carrier-free noncovalent NPs in the past decade based on natural products (such as paclitaxel, 10-hydroxycamptothecin, doxorubicin, etoposide, combretastatin A4, epigallocatechin gallate, and curcumin) for tumor chemo-photodynamic combination therapy. We highlight the insightful design and synthesis of the smart carrier-free NPs that aim to enhance PDT efficacy. Meanwhile, we discuss the future challenges and potential opportunities associated with these NPs to provide new enlightenment, spur innovative ideas, and facilitate PDT-mediated clinical transformation.

A General Photoactive H-Bonding EDA Complex Model Drives the Selective Hydrothiolation and Hydroxysulfenylation of Carbonyl Activated Alkenes.

Excitation of photoactive electron donor-acceptor (EDA) complexes to generate radical is a promising approach in radical chemistry. In this study, we introduce a new model of H-bonding EDA complexes for the selective hydrothiolation and hydroxysulfenylation of carbonyl-activated alkenes with diverse thiols under visible light conditions. The reliability of this H-bonding EDA complex model has been confirmed by meticulous experimental and theoretical calculations. Mechanistic investigations have revealed the significant influence of the solvent in determining whether the excitation of photoactive H-bonding EDA complex leads to charge transfer (CT) or energy-charge transfer (En-CT), thereby controlling Markovnikov and anti-Markovnikov selectivity. Notably, the Quantum Theory of Atoms in Molecules (QTAIM) analysis clearly shows that the excited state of the C＝O---H-S EDA complex involves closed-shell partially covalent interactions.

Matrix completion under complex survey sampling.

Multivariate nonresponse is often encountered in complex survey sampling, and simply ignoring it leads to erroneous inference. In this paper, we propose a new matrix completion method for complex survey sampling. Different from existing works either conducting row-wise or column-wise imputation, the data matrix is treated as a whole which allows for exploiting both row and column patterns simultaneously. A column-space-decomposition model is adopted incorporating a low-rank structured matrix for the finite population with easy-to-obtain demographic information as covariates. Besides, we propose a computationally efficient projection strategy to identify the model parameters under complex survey sampling. Then, an augmented inverse probability weighting estimator is used to estimate the parameter of interest, and the corresponding asymptotic upper bound of the estimation error is derived. Simulation studies show that the proposed estimator has a smaller mean squared error than other competitors, and the corresponding variance estimator performs well. The proposed method is applied to assess the health status of the U.S. population.

Broad-spectrum prodrugs with anti-SARS-CoV-2 activities: Strategies, benefits, and challenges.

In this era, broad-spectrum prodrugs with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activities are gaining considerable attention owing to their potential clinical benefits and role in combating the fast-spreading coronavirus disease 2019 (COVID-19) pandemic. The last 2 years have seen a surge of reports on various broad-spectrum prodrugs against SARS-CoV-2, and in in vitro studies, animal models, and clinical practice. Currently, only remdesivir (with many controversies and limitations) has been approved by the U.S. FDA for the treatment of SARS-CoV-2 infection, and additional potent anti-SARS-CoV-2 drugs are urgently required to enrich the defense arsenals. The world has ubiquitously grappled with the COVID-19 pandemic, and the availability of broad-spectrum prodrugs provides great hope for us to subdue this global threat. This article reviews promising treatment strategies, antiviral mechanisms, potential benefits, and daunting clinical challenges of anti-SARS-CoV-2 agents to provide some important guidance for future clinical treatment.

Spatial distribution and ecological risk assessment of heavy metals in surface sediments from the northern Bohai Strait, China.

The epicontinental seas to the east of China have become highly anthropogenically impacted due to rapid economic development in recent decades, resulting in various environmental problems, including heavy metal pollution. The Bohai Strait, as a key junction connecting the material-energy exchange between the Bohai and Yellow Seas, is extremely critical in regional pollution prevention and control. To ascertain the spatial distribution and contamination levels of heavy metals in the surface sediments of the northern Bohai Strait, a systematic investigation was conducted. Geochemical analysis revealed that the concentrations (in ppm) of heavy metal elements in surface sediments vary in the range of 4.19-77.6 for As, 0.04-0.21 for Cd, 5.1-65.7 for Pb, 0.30-39.40 for Cu, 7.77-46.50 for Ni, 1.50-86.60 for Cr, 11.70-91.80 for Zn, and 0.005-0.038 for Hg. Ecological statistics indicate that the northern Bohai Strait suffers from prominent heavy metal pollution primarily induced by As, Cd, and Pb, accompanied by relatively weak pollution of Cu and Ni. Sediments collected from the submarine depressions and the southeast region exhibit higher heavy metal concentrations, and as a consequence, more serious ecological risk. Correlation analysis indicated that the accumulations of Hg, Cr, and Zn were associated with the deposition of organic matter. Preliminary provenance discrimination suggested that the pollutants were mainly derived from the eastern parts of the North Yellow Sea, rather than the Bohai region.

Individuals at ultra-high risk of psychosis and first-degree relatives of patients with schizophreniaexperience impaired family functionality and social support deficit in comparison to healthy controls.

AIM: The present study was designed to assess the role of family function and social support in the context of different phases of schizophrenia. METHODS: First-episode patients with experiences of schizophrenia (FEP), ultra-high risk for psychosis (UHR), first-degree relatives (FDR) of patients with experiences of schizophrenia, and healthy controls (HC) (40 per group) were subjected to in-person clinical interviews. The results of these interviews were then used to gauge social support and family function using the Perceived Social Support Scale (PSSS) and the Family Adaptability and Cohesion Scales (FACESII-CV). Data were analyzed through ANCOVA, correlation analysis and logistic regression analyses. RESULTS: We found that family function and social support showed a approximately gradual downward trend through the HC, FDR, UHR, and FEP groups but no significant differences were found in the family function of the FDR, UHR and FDR group. Logistic regression analyses indicated that UHR group patients exhibited decreased family support and family cohesion relative to members of the HC group, but had greater perceived social support than did members of the FEP group. Results for members of the FDR group were in line with those of members of the UHR group. CONCLUSIONS: These findings suggested that both UHR and FDR individuals experience impaired family functionality and social support which expanded the understanding of the psychological characteristics of the prodromal period of schizophrenia. Further explorations are warranted to develop optimal psychosocial interventions.

Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,ß-Unsaturated Aldehydes.

Chirality is one of the most important attributes for its presence in a vast majority of bioactive natural products and pharmaceuticals. Asymmetric organocatalysis methods have emerged as a powerful methodology for the construction of highly enantioenriched structural skeletons of the target molecules. Due to their extensive application of organocatalysis in the total synthesis of bioactive molecules and some of them have been used in the industrial synthesis of drugs have attracted increasing interests from chemists. Among the chiral organocatalysts, chiral secondary amines (MacMillan's catalyst and Jorgensen's catalyst) have been especially considered attractive strategies because of their impressive efficiency. Herein, we outline advances in the asymmetric total synthesis of natural products and relevant drugs by using the strategy of chiral secondary amine catalyzed reactions of α,ß-unsaturated aldehydes in the last eighteen years.

Increased nitrogen input enhances Kandelia obovata seedling growth in the presence of invasive Spartina alterniflora in subtropical regions of China.

Mangroves in China are severely affected by the rapid invasion of the non-native species Spartina alterniflora Although many studies have addressed the possible impacts of S. alterniflora on the performance of mangrove seedlings, how excessive nitrogen (N) input due to eutrophication affects the interactions between mangrove species and S. alterniflora remains unknown. Here, we report the results from a mesocosm experiment using seedlings of the native mangrove species Kandelia obovata and the exotic S. alterniflora grown in monoculture and mixed culture under no nitrogen addition and nitrogen (N) addition treatments for 18 months. Without N addition, the presence of S. alterniflora inhibited the growth of K. obovata seedlings. Excessive N addition significantly increased the growth rate of K. obovata in both cultures. However, the positive and significantly increasing relative interaction intensity index under excessive N input suggested that the invasion of S. alterniflora could favour the growth of K. obovata under eutrophication conditions. Our results imply that excessive N input in southeastern China can increase the competitive ability of mangrove seedlings against invasive S. alterniflora.

In vivo evaluation of a simvastatin-loaded nanostructured lipid carrier for bone tissue regeneration.

Alveolar bone loss has long been a challenge in clinical dental implant therapy. Simvastatin (SV) has been demonstrated to exert excellent anabolic effects on bone. However, the successful use of SV to increase bone formation in vivo largely depends on the local concentration of SV at the site of action, and there have been continuing efforts to develop an appropriate delivery system. Specifically, nanostructured lipid carrier (NLC) systems have become a popular type of encapsulation carrier system. Therefore, SV-loaded NLCs (SNs) (179.4 nm in diameter) were fabricated in this study, and the osteogenic effect of the SNs was evaluated in a critical-sized rabbit calvarial defect. Our results revealed that the SNs significantly enhanced bone formation in vivo, as evaluated by hematoxylin and eosin (HE) staining, immunohistochemistry, and a fluorescence analysis. Thus, this novel nanostructured carrier system could be a potential encapsulation carrier system for SV in bone regeneration applications.

TiO2 /Cu2 O Core/Ultrathin Shell Nanorods as Efficient and Stable Photocatalysts for Water Reduction.

P-type Cu2 O has been long considered as an attractive photocatalyst for photocatalytic water reduction, but few successful examples has been reported. Here, we report the synthesis of TiO2 (core)/Cu2 O (ultrathin film shell) nanorods by a redox reaction between Cu(2+) and in-situ generated Ti(3+) when Cu(2+) -exchanged H-titanate nanotubes are calcined in air. Owing to the strong TiO2 -Cu2 O interfacial interaction, TiO2 (core)/Cu2 O (ultrathin film shell) nanorods are highly active and stable in photocatalytic water reduction. The TiO2 core and Cu2 O ultrathin film shell respectively act as the photosensitizer and cocatalyst, and both the photoexcited electrons in the conduction band and the holes in the valence band of TiO2 respectively transfer to the conduction band and valence band of the Cu2 O ultrathin film shell. Our results unambiguously show that Cu2 O itself can act as the highly active and stable cocatalyst for photocatalytic water reduction.

Synthesis and anti-hypertensive effects of the twin drug of nicotinic acid and quercetin tetramethyl ether.

A novel twin drug consisting of nicotinic acid (VB3) and quercetin tetramethyl ether (QTME) has been synthesized as an antihypertensive in a total yield of 79.2% through methylation, hydrolysis, acylation and esterification starting from rutin. The structures of synthesized compounds were elucidated by 1H-NMR, 13C-NMR and elemental analysis. The anti-hypertensive effects of an oral daily dose (15 mg/kg) of the synthesized compounds in spontaneously hypertensive (SHR) rats and normotensive Wistar Kyoto (WKY) rats were analysed. The data demonstrate that the twin drug VB3-QTME both reduces the elevated blood pressure and prolongs the action time in SHR rats without effect on WKY rats. However, definitive evidence of a precise mechanism of action by which VB3-QTME might decrease blood pressure remains elusive. Based on the results, the therapeutic potential of this twin drug is discussed.

CuOx-TiO2 junction: what is the active component for photocatalytic H2 production?

CuOx based junctions e.g. CuOx-TiO2 have been demonstrated to be very effective in photocatalytic H2 production, but the active component at the junction is less understood. We herein report that an as-prepared CuOx-TiO2 photocatalyst undergoes an in situ restructuring process during photocatalytic H2 production under solar light irradiation to form the active Cu2O-TiO2 interfacial structure on the surface. These results unambiguously demonstrate that Cu2O is the active copper species in CuOx-TiO2 photocatalysts.

The Therapeutic Potential of Natural Dietary Flavonoids against SARS-CoV-2 Infection.

The exploration of non-toxic and cost-effective dietary components, such as epigallocatechin 3-gallate and myricetin, for health improvement and disease treatment has recently attracted substantial research attention. The recent COVID-19 pandemic has provided a unique opportunity for the investigation and identification of dietary components capable of treating viral infections, as well as gathering the evidence needed to address the major challenges presented by public health emergencies. Dietary components hold great potential as a starting point for further drug development for the treatment and prevention of SARS-CoV-2 infection owing to their good safety, broad-spectrum antiviral activities, and multi-organ protective capacity. Here, we review current knowledge of the characteristics-chemical composition, bioactive properties, and putative mechanisms of action-of natural bioactive dietary flavonoids with the potential for targeting SARS-CoV-2 and its variants. Notably, we present promising strategies (combination therapy, lead optimization, and drug delivery) to overcome the inherent deficiencies of natural dietary flavonoids, such as limited bioavailability and poor stability.

Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China.

The ongoing COVID-19 pandemic has resulted in millions of deaths globally, highlighting the need to develop potent prophylactic and therapeutic strategies against SARS-CoV-2. Small molecule inhibitors (remdesivir, Paxlovid, and molnupiravir) are essential complements to vaccines and play important roles in clinical treatment of SARS-CoV-2. Many advances have been made in development of anti-SARS-CoV-2 inhibitors in China, but progress in discovery and characterization of pharmacological activity, antiviral mechanisms, and clinical efficacy are limited. We review development of small molecule anti-SARS-CoV-2 drugs (azvudine [approved by the NMPA of China on July 25, 2022], VV116 [approved by the NMPA of China on January 29, 2023], FB2001, WPV01, pentarlandir, and cepharanthine) in China and summarize their pharmacological activity, potential mechanisms of action, clinical trials and use, and important milestones in their discovery. The role of structural biology in drug development is also reviewed. Future studies should focus on development of diverse second-generation inhibitors with excellent oral bioavailability, superior plasma half-life, increased antiviral activity against SARS-CoV-2 and its variants, high target specificity, minimal side effects, reduced drug-drug interactions, and improved lung histopathology.

Unraveling the mechanism of action of cepharanthine for the treatment of novel coronavirus pneumonia (COVID-19) from the perspectives of systematic pharmacology.

Natural products play an irreplaceable role in the treatment of SARS-CoV-2 infection. Nevertheless, the underlying molecular mechanisms involved remain elusive. To better understand their potential therapeutic effects, more validation studies are needed to explore underlying mechanisms systematically. This study aims to explore the potential targets of action and signaling pathways of cepharanthine for the treatment of COVID-19. This study revealed that a total of 173 potential targets of action for Cepharanthine and 86 intersectional targets for Cepharanthine against COVID-19 were screened and collected. Gene Ontology enrichment analysis suggested that inflammatory, immune cell and enzyme activities were the critical terms for cepharanthine against COVID-19. Pathway enrichment analysis showed that five pathways associated with COVID-19 were the main signaling pathways for the treatment of COVID-19 via cepharanthine. Molecular docking and molecular dynamics simulations suggested that 6 core targets were regarded as potential targets for cepharanthine against COVID-19. In brief, the study demonstrates that cepharanthine may play an important role in the treatment of SARS-CoV-2 infection through its harmonious activity against SARS-CoV-2 pathways and multiple related targets. This article provides valuable insights required to respond effectively to concerns of western medical community.

Stand Up to Stand Out: Natural Dietary Polyphenols Curcumin, Resveratrol, and Gossypol as Potential Therapeutic Candidates against Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

The COVID-19 pandemic has stimulated collaborative drug discovery efforts in academia and the industry with the aim of developing therapies and vaccines that target SARS-CoV-2. Several novel therapies have been approved and deployed in the last three years. However, their clinical application has revealed limitations due to the rapid emergence of viral variants. Therefore, the development of next-generation SARS-CoV-2 therapeutic agents with a high potency and safety profile remains a high priority for global health. Increasing awareness of the "back to nature" approach for improving human health has prompted renewed interest in natural products, especially dietary polyphenols, as an additional therapeutic strategy to treat SARS-CoV-2 patients, owing to its good safety profile, exceptional nutritional value, health-promoting benefits (including potential antiviral properties), affordability, and availability. Herein, we describe the biological properties and pleiotropic molecular mechanisms of dietary polyphenols curcumin, resveratrol, and gossypol as inhibitors against SARS-CoV-2 and its variants as observed in in vitro and in vivo studies. Based on the advantages and disadvantages of dietary polyphenols and to obtain maximal benefits, several strategies such as nanotechnology (e.g., curcumin-incorporated nanofibrous membranes with antibacterial-antiviral ability), lead optimization (e.g., a methylated analog of curcumin), combination therapies (e.g., a specific combination of plant extracts and micronutrients), and broad-spectrum activities (e.g., gossypol broadly inhibits coronaviruses) have also been emphasized as positive factors in the facilitation of anti-SARS-CoV-2 drug development to support effective long-term pandemic management and control.

Design of Learning Environment for Undergraduate Comprehensive Literacy Education under Blended Learning Environment.

Blended learning has become the dominant teaching approach in colleges and universities as they evolve. A good learning environment design can represent college and university teaching quality, improve undergraduates' literacy, and boost talent training. This paper introduces the data mining method of undergraduate comprehensive literacy education, discovers the association rules of the evaluation data, and introduces the undergraduate comprehensive literacy evaluation model and BP neural network model driven by theory and technology in a mixed learning environment, which promotes students' comprehensive literacy evaluation and builds a good learning environment. The results demonstrate that undergraduate classification prediction accuracy is similar by data mining, and most reach 99.58 percent. So, whether it is the training sample or the test sample, the prediction result of undergraduate comprehensive literacy is acceptable, which illustrates the validity of the data mining algorithm model and has strong application importance for developing a better learning environment.

Bioactive natural products in COVID-19 therapy.

The devastating COVID-19 pandemic has caused more than six million deaths worldwide during the last 2 years. Effective therapeutic agents are greatly needed, yet promising magic bullets still do not exist. Numerous natural products (cordycepin, gallinamide A, plitidepsin, telocinobufagin, and tylophorine) have been widely studied and play a potential function in treating COVID-19. In this paper, we reviewed published studies (from May 2021 to April 2022) relating closely to bioactive natural products (isolated from medicinal plants, animals products, and marine organisms) in COVID-19 therapy in vitro to provide some essential guidance for anti-SARS-CoV-2 drug research and development.

Oral GS-441524 derivatives: Next-generation inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase.

GS-441524, an RNA-dependent RNA polymerase (RdRp) inhibitor, is a 1'-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS-441524 poses a challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, the intravenously administered version (version 1.0) of GS-441524, is the first FDA-approved agent for SARS-CoV-2 treatment. However, clinical trials have presented conflicting evidence on the value of remdesivir in COVID-19. Therefore, oral GS-441524 derivatives (VV116, ATV006, and GS-621763; version 2.0, targeting highly conserved viral RdRp) could be considered as game-changers in treating COVID-19 because oral administration has the potential to maximize clinical benefits, including decreased duration of COVID-19 and reduced post-acute sequelae of SARS-CoV-2 infection, as well as limited side effects such as hepatic accumulation. This review summarizes the current research related to the oral derivatives of GS-441524, and provides important insights into the potential factors underlying the controversial observations regarding the clinical efficacy of remdesivir; overall, it offers an effective launching pad for developing an oral version of GS-441524.