From mundane to classic: Sinomenine as a multi-therapeutic agent.

Sinomenine is an active substance extracted from the traditional Chinese medicine Sinomenium acutum. Sinomenine has been shown to mediate a wide range of pharmacological actions and is known to possess good anti-inflammatory, immunosuppressive, antitumor, neuroprotective, antiarrhythmic and other pharmacological effects. Understanding the underlying mechanisms and the association between the targets and the pharmaceutical effects on different diseases is crucial to the discovery and design of new treatment strategies. In this review, we aim to give a systematic and comprehensive overview of the research progress of sinomenine over the past 20 years. We first describe the metabolism of sinomenine in vivo and then summarize the pharmacological actions of sinomenine on different diseases. Furthermore, the potential binding properties of sinomenine and the potential of developing new sinomenine-based drugs are also reviewed.

The anti-aging mechanism of ginsenosides with medicine and food homology.

With the acceleration of global aging and the rise in living standards, the achievement of healthy aging is becoming an imperative issue globally. Ginseng, a medicinal plant that has a long history of dietary intake and remarkable medicinal value, has become a research hotspot in the field of food and medicine. Ginsenosides, especially protopanaxadiol-type saponins and protopanaxatriol-type saponins, are among the most important active ingredients in ginseng. Ginsenosides have been found to exhibit powerful and diverse pharmacological activities, such as antiaging, antitumor, antifatigue and immunity enhancement activities. Their effects in antiaging mainly include (1) promotion of metabolism and stem cell proliferation, (2) protection of skin and nerves, (3) modulation of intestinal flora, (4) maintenance of mitochondrial function, and (5) enhancement of telomerase activity. The underlying mechanisms are primarily associated with the intervention of the signaling pathways in apoptosis, inflammation and oxidative stress. In this review, the mechanism of action of ginsenosides in antiaging as well as the potential values of developing ginsenoside-based functional foods and antiaging drugs are discussed.

Prospect of targeting lysine methyltransferase NSD3 for tumor therapy.

Nuclear receptor binding SET domain protein 3 (NSD3) has recently been recognized as a new epigenetic target in the fight against cancer. NSD3, which is amplified, overexpressed or mutated in a variety of tumors, promotes tumor development by regulating the cell cycle, apoptosis, DNA repair and EMT. Therefore, the inhibition, silencing or knockdown of NSD3 are highly promising antitumor strategies. This paper summarizes the structure and biological functions of NSD3 with an emphasis on its carcinogenic or cancer-promoting activity. The development of NSD3-specific inhibitors or degraders is also discussed and reviewed in this paper.

A cell-impermeable luminogenic probe for near-infrared imaging of prostate-specific membrane antigen in prostate cancer microenvironments.

Prostate-specific membrane antigen (PSMA) imaging probes are a promising tool for the diagnosis and image-guided surgery of prostate cancer (PCa). However, PSMA-specific luminescence probes for PCa detection and heterogeneity studies with high imaging contrast are lacking. Here, we report the first near-infrared (NIR) iridium(III) complex for the wash-free and specific imaging of PSMA in PCa cells and spheroids. The conjugation of a PSMA inhibitor, Lys-urea-Glu, to an iridium(III) complex synergizes the PSMA-specific affinity and biocompatibility of the inhibitor with the desirable photophysical properties of the iridium(III) complex, including NIR emission (670 nm), high photostability and a large Stokes shift. The cellular impermeability of the probe along with its strong binding affinity to PSMA enhances its specificity for PSMA, enabling the washing-free luminescent imaging of membrane PSMA with lower cytotoxicity. The probe was successfully applied for selectively visualizing PSMA-expressing cells and for the imaging of PSMA in a multicellular PCa model with good imaging penetration, indicating its potential use in complicated and heterogeneous tumor microenvironments. Furthermore, the probe showed good imaging performance in the PCa-bearing tumor mice via targeting PSMA in vivo. This work provides a novel strategy for the development of highly sensitive and specific NIR probes for PSMA in biological systems in vitro, which is of great significance for the precise diagnosis of PCa and for elucidating PCa heterogeneity.

Active ingredients of traditional Chinese medicine for enhancing the effect of tumor immunotherapy.

Immunotherapy is a type of treatment that uses our own immune system to fight cancer. Studies have shown that traditional Chinese medicine (TCM) has antitumor activity and can enhance host immunity. This article briefly describes the immunomodulatory and escape mechanisms in tumors, as well as highlights and summarizes the antitumor immunomodulatory activities of some representative active ingredients of TCM. Finally, this article puts forward some opinions on the future research and clinical application of TCM, aiming to promote the clinical applications of TCM in tumor immunotherapy and to provide new ideas for the research of tumor immunotherapy using TCM.

Interference reduction isothermal nucleic acid amplification strategy for COVID-19 variant detection.

Common reference methods for COVID-19 variant diagnosis include viral sequencing and PCR-based methods. However, sequencing is tedious, expensive, and time-consuming, while PCR-based methods have high risk of insensitive detection in variant-prone regions and are susceptible to potential background signal interference in biological samples. Here, we report a loop-mediated interference reduction isothermal nucleic acid amplification (LM-IR-INA) strategy for highly sensitive single-base mutation detection in viral variants. This strategy exploits the advantages of nicking endonuclease-mediated isothermal amplification, luminescent iridium(III) probes, and time-resolved emission spectroscopy (TRES). Using the LM-IR-INA strategy, we established a luminescence platform for diagnosing COVID-19 D796Y single-base substitution detection with a detection limit of 2.01 × 105 copies/µL in a linear range of 6.01 × 105 to 3.76 × 108 copies/µL and an excellent specificity with a variant/wild-type ratio of significantly less than 0.0625%. The developed TRES-based method was also successfully applied to detect D796Y single-base substitution sequence in complicated biological samples, including throat and blood, and was a superior to steady-state technique. LM-IR-INA was also demonstrated for detecting the single-base substitution D614G as well as the multiple-base mutation H69/V70del without mutual interference, indicating that this approach has the potential to be used as a universal viral variant detection strategy.

Nanocarriers for effective delivery: modulation of innate immunity for the management of infections and the associated complications.

Innate immunity is the first line of defense against invading pathogens. Innate immune cells can recognize invading pathogens through recognizing pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs). The recognition of PAMPs by PRRs triggers immune defense mechanisms and the secretion of pro-inflammatory cytokines such as TNF-α, IL-1ß, and IL-6. However, sustained and overwhelming activation of immune system may disrupt immune homeostasis and contribute to inflammatory disorders. Immunomodulators targeting PRRs may be beneficial to treat infectious diseases and their associated complications. However, therapeutic performances of immunomodulators can be negatively affected by (1) high immune-mediated toxicity, (2) poor solubility and (3) bioactivity loss after long circulation. Recently, nanocarriers have emerged as a very promising tool to overcome these obstacles owning to their unique properties such as sustained circulation, desired bio-distribution, and preferred pharmacokinetic and pharmacodynamic profiles. In this review, we aim to provide an up-to-date overview on the strategies and applications of nanocarrier-assisted innate immune modulation for the management of infections and their associated complications. We first summarize examples of important innate immune modulators. The types of nanomaterials available for drug delivery, as well as their applications for the delivery of immunomodulatory drugs and vaccine adjuvants are also discussed.

Homocysteine-targeting compounds as a new treatment strategy for diabetic wounds via inhibition of the histone methyltransferase SET7/9.

In hypoxia and hyperglycemia, SET7/9 plays an important role in controlling HIF-1α methylation and regulating the transcription of HIF-1α target genes, which are responsible for angiogenesis and wound healing. Here, we report the Ir(III) complex Set7_1a bearing acetonitrile (ACN) ligands as a SET7/9 methyltransferase inhibitor and HIF-1α stabilizer. Interestingly, Set7_1a could engage SET7/9 and strongly inhibit SET7/9 activity, especially after preincubation with homocysteine (Hcy), which is elevated in diabetes. We hypothesize that Set7_1a exchanges ACN subunits for Hcy to disrupt the interaction between SET7/9 and SAM/SAH, which are structurally related to Hcy. Inhibition of SET7/9 methyltransferase activity by Set7_1a led to reduced HIF-1α methylation at the lysine 32 residue, causing increased HIF-1α level and recruitment of HIF-1α target genes that promote angiogenesis, such as VEGF, GLUT1, and EPO, in hypoxia and hyperglycemia. Significantly, Set7_1a improved wound healing in a type 2 diabetic mouse model by activating HIF-1α signaling and downstream proangiogenic factors. To our knowledge, this is the first Hcy-targeting iridium compound shown to be a SET7/9 antagonist that can accelerate diabetic wound healing. More importantly, this study opens a therapeutic avenue for the treatment of diabetic wounds by the inhibition of SET7/9 lysine methyltransferase activity.

Interference Reduction Biosensing Strategy for Highly Sensitive microRNA Detection.

MicroRNAs are potential biomarkers for human cancers and other diseases due to their roles as post-transcriptional regulators for gene expression. However, the detection of miRNAs by conventional methods such as RT-qPCR, in situ hybridization, northern blot-based platforms, and next-generation sequencing is complicated by short length, low abundance, high sequence homology, and susceptibility to degradation of miRNAs. In this study, we developed a nicking endonuclease-mediated interference reduction rolling circle amplification (NEM-IR-RCA) strategy for the ultrasensitive and highly specific detection of miRNA-21. This method exploits the advantages of the optical properties of long-lived iridium(III) probes, in conjunction with time-resolved emission spectroscopy (TRES) and exponential rolling circle amplification (E-RCA). Under the NEM-IR-RCA-based signal enhancement processes, the limit of detection of miRNA-21 was down to 0.0095 fM with a linear range from 0.05 to 100 fM, which is comparable with the conventional RT-qPCR. Unlike RT-qPCR, the strategy was performed at a lower and constant temperature without heating/cooling cycles and reverse transcription. The strategy could clearly discriminate between matched and mismatched targets, demonstrating high specificity. Moreover, the potential application of this method was demonstrated in cancer cells and mouse serum samples, showing good agreement with RT-qPCR results. Apart from miRNA-21 detection, this platform could be also adapted for detecting other miRNAs, such as let-7a and miRNA-22, indicating its excellent potential for biomedical research and clinical diagnostics.

Nicking enzyme-free strand displacement amplification-assisted CRISPR-Cas-based colorimetric detection of prostate-specific antigen in serum samples.

Immunosorbent assay is the gold standard diagnostic technique for the detection of protein biomarkers. However, this technique tends to have low sensitivity and requires laborious manipulation. Although advanced CRISPR-Cas-based biosensors offer advantages of simplicity, low cost and high accuracy, the synergy of using CRISPR-Cas-assisted dual signal amplification system for rapid diagnosis of protein biomarkers remains scarce. In this work, we report a synergetic signal amplification system comprising CRISPR-Cas12a and nicking enzyme-free strand displacement amplification (SDA) technique for accurate detection of prostate-specific antigen (PSA). The presence of PSA will initiate the nicking enzyme-free SDA process, generating amplicons that can be recognized by the CRISPR-Cas12a system. The activated CRISPR-Cas system will then mediate trans-ssDNA cleavage of neighboring linker DNA, which unlocks the gold nanoparticles (AuNPs) signal probes and gives a distance-dependent colorimetric readout. This assay could detect PSA in aqueous buffer sensitively and selectively with a limit of detection (LOD) down to 0.030 ng mL-1. Importantly, this assay was successfully applied for discriminating four blood samples from prostate cancer patients among thirteen blood samples from normal individuals/cancer patients accurately. This work will open an avenue for the development of SDA-CRISPR-AuNPs hybrid sensing systems, offering great potential for the development of non-invasive point-of-care diagnostic tools for prostate cancer.

Dehydroeburicoic Acid, a Dual Inhibitor against Oxidative Stress in Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a complicated disease which can lead to hepatocellular carcinoma; however, there is a lack of satisfactory therapeutics. Dehydroeburicoic acid (DEA) (1), a triterpenoid isolated from Antrodia cinnamomea, has been reported to act against ALD, but its mechanisms of action are still not clear. In this study, we report for the first time the use of DEA (1) as a dual inhibitor of the Keap1-Nrf2 protein-protein interaction (PPI) and GSK3ß in an in vitro ALD cell model. DEA (1) engages Keap1 to disrupt the Keap1-Nrf2 PPI and inhibits GSK3ß to restore Nrf2 activity in a Keap1-independent fashion. DEA (1) promotes Nrf2 nuclear translocation to activate downstream antioxidant genes. Importantly, DEA (1) restores the mitochondrial dysfunction induced by ethanol and generates antioxidant activity in the ALD cell model with minimal toxicity. We anticipate that DEA (1) could be a potential scaffold for the further development of clinical agents for treating ALD.

COVID-19: Update on Its Ocular Involvements, and Complications From Its Treatments and Vaccinations.

ABSTRACT: The coronavirus disease 2019 (COVID-19) came under the attention of the international medical community when China first notified the World Health Organization of a pneumonia outbreak of then-unknown etiology in Wuhan in December 2019. Since then, COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has appalled the world by spreading at a pandemic speed. Although ophthalmologists do not directly engage in the clinical care of COVID-19 patients, the ophthalmology community has become aware of the close ties between its practice and the pandemic. Not only are ophthalmologists at heightened risk of SARS-CoV-2 exposure due to their physical proximity with patients in routine ophthalmic examinations, but SARS-CoV-2 possesses ocular tropism resulting in ocular complications beyond the respiratory tract after viral exposure. Furthermore, patients could potentially suffer from adverse ocular effects in the therapeutic process. This review summarized the latest literature to cover the ophthalmic manifestations, effects of treatments, and vaccinations on the eye to aid the frontline clinicians in providing effective ophthalmic care to COVID-19 patients as the pandemic continues to evolve.

A bioactive ligand-conjugated iridium(III) metal-based complex as a Keap1-Nrf2 protein-protein interaction inhibitor against acetaminophen-induced acute liver injury.

Hepatotoxicity caused by an overdose of acetaminophen (APAP) is the leading reason for acute drug-related liver failure. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein that helps to regulate redox homeostasis and coordinate stress responses via binding to the Kelch-like ECH-associated protein 1 (Keap1). Targeting the Keap1-Nrf2 interaction has recently emerged as a potential strategy to alleviate liver injury caused by APAP. Here, we designed and synthesized a number of iridium (III) and rhodium (III) complexes bearing ligands with reported activity against oxidative stress, which is associated with Nrf2 transcriptional activation. The iridium (III) complex 1 bearing a bioactive ligand 2,9-dimethyl-1,10-phenanthroline and 4-chloro-2-phenylquinoline, a derivative of the bioactive ligand 2-phenylquinoline, was identified as a direct small-molecule inhibitor of the Keap1-Nrf2 protein-protein interaction. 1 could stabilize Keap1 protein, upregulate HO-1 and NQO1, and promote Nrf2 nuclear translocation in normal liver cells. Moreover, 1 reversed APAP-induced liver damage by disrupting Keap1-Nrf2 interaction and without inducing organ damage and immunotoxicity in mice. Our study demonstrates the identification of a selective and efficacious antagonist of Keap1-Nrf2 interaction possessed good cellular permeability in cellulo and ideal pharmacokinetic parameters in vivo, and, more importantly, validates the feasibility of conjugating metal complexes with bioactive ligands to generate metal-based drug leads as non-toxic Keap1-Nrf2 interaction inhibitors for treating APAP-induced acute liver injury.

A small molecule HIF-1α stabilizer that accelerates diabetic wound healing.

Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL-HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

COVID-19: Ocular Manifestations and the APAO Prevention Guidelines for Ophthalmic Practices.

The World Health Organization declared the Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 a "Pandemic" on March 11, 2020. As of June 1, 2020, Severe Acute Respiratory Syndrome Coronavirus 2 has infected >6.2 million people and caused >372,000 deaths, including many health care personnel. It is highly infectious and ophthalmologists are at a higher risk of the infection due to a number of reasons including the proximity between doctors and patients during ocular examinations, microaerosols generated by the noncontact tonometer, tears as a potential source of infection, and some COVID-19 cases present with conjunctivitis. This article describes the ocular manifestations of COVID-19 and the APAO guidelines in mitigating the risks of contracting and/or spreading COVID-19 in ophthalmic practices.

COVID-19: Special Precautions in Ophthalmic Practice and FAQs on Personal Protection and Mask Selection.

The Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory coronavirus-2, was first reported in December 2019. The World Health Organization declared COVID-19 a pandemic on March 11, 2020 and as of April 17, 2020, 210 countries are affected with >2,000,000 infected and 140,000 deaths. The estimated case fatality rate is around 6.7%. We need to step up our infection control measures immediately or else it may be too late to contain or control the spread of COVID-19. In case of local outbreaks, the risk of infection to healthcare workers and patients is high. Ophthalmic practice carries some unique risks and therefore high vigilance and special precautions are needed. We share our protocols and experiences in the prevention of infection in the current COVID-19 outbreak and the previous severe acute respiratory syndrome epidemic in Hong Kong. We also endeavor to answer the key frequently asked questions in areas of the coronaviruses, COVID-19, disease transmission, personal protection, mask selection, and special measures in ophthalmic practices. COVID-19 is highly infectious and could be life-threatening. Using our protocol and measures, we have achieved zero infection in our ophthalmic practices in Hong Kong and China. Preventing spread of COVID-19 is possible and achievable.

A Long-Lived Phosphorescence Amplification System Integrated with Graphene Oxide and a Stable Split G-Quadruplex Protector as an Isothermal "Off-On" Biosensor for the HBV Gene.

Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). Chronic HBV infection is a major global health issue, causing an estimated 750,000 of deaths annually. Despite intense interest of biomedical and clinical researchers, the lack of an accurate, selective, and simple diagnostic approach for the early stage of the disease remains a major challenge. In this work, we developed a strand displacement amplification (SDA)-assisted G-quadruplex (GQ)-graphene oxide (GO) system for the accurate quantification of the HBV gene. Iridium (III) complex 2a, a red-emitting luminophore with a large Stokes shift and long-lived phosphorescence, was identified as the most effective probe for the split GQ-GO system among the eight selected complexes in the systematic optimization campaign. The length of nucleic acid bases in between the critical positions of the split GQ hybridization was also optimized using circular dichroism (CD) and phosphorescence experiments. Important rules on the proximity and flexibility of the stable split GQ-GO system were developed for the first time. This approach was selective for the wild HBV gene over the interfering anions, cations, proteins, and the mutated HBV genes differing by only one nucleotide base. Compared to the simple GQ-GO system, the SDA-assisted GQ-GO system produced a 211% higher phosphorescence restoration signal. The ability of the SDA-assisted GQ-GO system to detect the HBV gene in human serum and sheep red blood cells demonstrates the feasibility of using this system in practical applications.