Evaluation of the significance of complement-related genes mutations in atypical postinfectious glomerulonephritis: a pilot study.

BACKGROUND: Postinfectious glomerulonephritis with C3-dominant glomerular deposition (C3-PIGN) involves C3-dominant glomerular deposition without immunoglobulin. Atypical C3-PIGN involves persistent hypocomplementemia. We investigated the clinical features and explored complement-related gene mutations in atypical PIGN patients. METHODS: We enrolled atypical C3-PIGN patients and collected data regarding the clinical presentation and pathological characteristics and follow-up data. We measured the levels of complement associated antibodies and performed whole-exome sequencing (WES) to detect mutations in complement-related genes. RESULTS: The analysis included six atypical C3-PIGN patients. All patients were antistreptolysin-O (ASO) positive. All patients had varying degrees of hematuria, and four patients had proteinuria. None of the patients were positive for complement-related antibodies. All patients possessed mutations of genes related to the complement pathway, including alternative complement pathway genes-CFI, CFH, CFHR3, CFHR5; the lectin pathway gene-MASP2; and the common complement pathway gene-C8A. The rare variant of CFHR3 has been reported in C3 glomerulonephritis. During 56-73 months of follow-up, the levels of urine markers in three patients recovered within 6 months, and the remaining patients had abnormal urine test results over 12 months. Patients who received glucocorticoid therapy recovered faster. CONCLUSIONS: Our study suggested that complement-related gene mutations may be an important cause of persistent hypocomplementemia in atypical C3-PIGN patients. In addition to variations in alternate pathway-related genes, we also found variations in lectin pathway-related genes, especially MASP2 genes. Although the overall prognosis was good, atypical C3-PIGN patients exhibited a longer period for recovery. Our results suggested that atypical C3-PIGN patients should receive more medical attention and need testing for mutations in complement-related genes.

Reversal mechanism of multidrug-resistant cancer cells by lectin as chemo-adjuvant and targeted therapy- a systematic review.

BACKGROUND: Cancer is characterized as the leading cause of death, and the susceptibility of cancer cells to develop resistance due to long-term exposure to complementary chemotherapeutic treatment is referred to as multidrug resistance cancer cells (MDRC), which is a significant obstacle in the treatment of malignancies. Since complementary medicine lost its effectiveness, the development of potential alternative and novel therapeutic approaches has been elevated to a top priority in recent years. In this context, a bioactive protein lectin from plant and animal sources exhibits an invaluable source of anticancer agents with vast therapeutic potential. PURPOSE: This manuscript's primary purpose is to enlighten the evidence-based (from 1986 to 2022) possible molecular mechanism of alternative treatment approaches using lectins over the complementary medicines used for cancer treatment. METHODS: The PRISMA rules have been followed properly and qualitative and quantitative data are synthesized systematically. Articles were identified based on Clinical and preclinical reports published on lectin that investigated the in-depth cellular mechanisms, of reverse drug integrative oncology, as a nano-carried targeted delivery. Articles were systematically screened from 1986 to 2022 and selected based on electronic database searches, Medline (PubMed), Google Scholar, Web of Science, Encyclopaedias, Scopus, and ClinicalTrials.gov database. RESULTS: The search turned up 4,212 publications from 38 different nations, of which 170 reference articles were used in our analysis, in 16 combination therapy and their mode of action, and 27 clinical trial studies including dosage and mechanism of action were included. Reports from the 30 lectins belonging to 28 different families have been included. The reversal mechanism of lectin and alternative therapy against MDRC is critically screened and according to a few clinical and preclinical reports, lectin can suppress the overexpressing genes like P-53, EGFR, and P-gp, MRP, and ABC transporter proteins associated with intracellular transportation of drugs. Since, the drug efflux mechanism leads to MDRC, in this phenomenon, lectin plays a key role in reversing the efflux mechanism. Few preclinical reports have mentioned that lectin shows synergism in combination with complementary medicine and as a nano drug carrier helps to deliver to the targeted site. CONCLUSION: We have discussed the alternative therapy using lectin and an in-depth insight into the reversal drug resistance mechanisms to combat MDRC cancer, enhance the efficacy, reduce toxicity and adverse events, and ensure targeted delivery, and their application in the field of cancer diagnosis and prognosis has been discussed. However, further investigation is necessary in drug development and clinical trials which could be helpful to elaborate the reversal mechanism and unlock newer treatment modalities in MDRC cancer.

Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and potentially severe complication of hematopoietic cell transplantation. TA-TMA-directed therapy with eculizumab, a complement C5 inhibitor, has resulted in a survival benefit in some studies. However, children with TA-TMA refractory to C5 inhibition with eculizumab (rTA-TMA) have mortality rates exceeding 80%, and there are no other known therapies. Narsoplimab, an inhibitor of the MASP-2 effector enzyme of the lectin pathway, has been studied in adults with TA-TMA as first-line therapy with a response rate of 61%. Although there are limited data on narsoplimab use as a second-line agent in children, we hypothesized, that complement pathways proximal to C5 are activated in rTA-TMA, and that narsoplimab may ameliorate rTA-TMA in children. In this single-center study, children were enrolled on single-patient, Institutional Review Board-approved compassionate use protocols for narsoplimab treatment. Clinical complement lab tests were obtained at the discretion of the treating physician, although all patients were also offered participation in a companion biomarker study. Research blood samples were obtained at the time of TA-TMA diagnosis, prior to eculizumab treatment, at the time of refractory TA-TMA diagnosis prior to the first narsoplimab dose, and 2 weeks after the first narsoplimab dose. Single ELISA kits were used to measure markers of complement activation according to the manufacture's instructions. Five children with rTA-TMA received narsoplimab; 3 were in multiorgan failure and 2 had worsening multiorgan dysfunction at the time of treatment. Additional comorbidities at the time of treatment included sinusoidal obstructive syndrome (SOS; n = 3), viral infection (n = 3), and steroid-refractory stage 4 lower gut grade IV acute graft-versus-host disease (aGVHD, n = 3). Two infants with concurrent SOS and no aGVHD had resolution of organ dysfunction; 1 also developed transfusion-independence (complete response), and the other's hematologic response was not assessable in the setting of leukemia and chemotherapy (partial response). One additional patient achieved transfusion independence but had no improvement in organ manifestations (partial response), and 2 patients treated late in the course of disease had no response. Narsoplimab was well tolerated without any attributed adverse effects. Three patients consented to provide additional research blood samples. One patient with resolution of organ failure demonstrated evidence of proximal pathway activation prior to narsoplimab treatment with subsequent declines in Ba, Bb, C3a, and C5a and increases in C3 in both clinical and research lab tests. Otherwise, there was no clear pattern of other complement markers, including MASP-2 levels, after therapy. In this cohort of ill children with rTA-TMA and multiple comorbidities, 3 patients benefited from narsoplimab. Notably, the 2 patients with resolution of organ involvement did not have steroid-refractory aGVHD, which is thought to be a critical driver of TA-TMA. Additional studies are needed to determine which patients are most likely to benefit from narsoplimab and which markers may be most helpful for monitoring lectin pathway activation and inhibition.

Therapeutic potential of lectins in the treatment of breast cancer: A review.

Breast cancer is one of the most common malignancies and the leading cause of cancer-related deaths in women. There are 3 major subtypes of breast cancer that are distinguished by expression of estrogen or progesterone receptors and ERBB2 gene amplification. The 3 subtypes have different risk profiles and treatment strategies. Abnormal glycosylation is thought to play an important role in the development of the tumorigenic and metastatic phenotype of breast cancer and resistance to therapy. They may also be a potentially attractive target for breast cancer treatment. Proteins such as lectins, a family of carbohydrate-binding proteins found in a variety of organisms from viruses to humans, can specifically interact with abnormally glycosylated carbohydrate residues in cancer cells and induce cytotoxic effects. In recent years, there has been a growing number of research addressing studies demonstrating their antitumorigenic and antimalignant effects. This review summarizes recent findings on lectins from plants, animals, fungi, and bacteria that are potentially therapeutic agents against breast cancer and outlines the basis of their mechanism of action.

Identifying FmlH lectin-binding small molecules for the prevention of Escherichia coli-induced urinary tract infections using hybrid fragment-based design and molecular docking.

Nearly 50% of women are affected by urinary tract infections (UTIs) during their lifetimes. The most common agent to cause UTIs is Uropathogenic Escherichia coli (UPEC). UPEC expresses fibers known as chaperone-usher pathway pili with adhesins that specifically bind to receptors as they colonize various host tissues. UPEC uses an F9/Yde/Fml pilus, tipped with FmlH, which interacts with terminal galactoside/galactosaminoside units in glycoproteins in the epithelial cells of the bladder and kidney. The extensive use of traditional antibiotics has led to the rise of various antibiotic-resistant strains of UPEC. An alternative therapeutic approach is to use an anti-adhesion strategy mediated by competitive tight-binding FmlH inhibitors. In the current study, we have applied various computational modeling techniques, including fragment-based e-pharmacophore virtual screening, molecular docking, molecular dynamics simulations and binding free energy calculations for the design of small molecules that exhibit binding to FmlH. Our modeling protocol successfully predicted ligand moieties, such as a thiazole group, which were previously found as components of UPEC adhesin pili inhibitors, thereby validating our designed screening protocol. The screening protocol developed here could be utilized for design of ligands for other homologous protein targets. We also identified several novel galactosaminoside-containing molecules that, according to the computational modeling, are predicted to interact strongly with FmlH and hence we predict will be good FmlH inhibitors. Additionally, we have prepared and supplied a database of ∼190K small molecules obtained from virtual screening, which can serve as an excellent resource for the discovery of novel FmlH inhibitors.

Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results.

Background Blockade of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high-affinity monoclonal blocking antibody to LOX-1. Methods and Results This phase 1, first-in-human, placebo-controlled study (NCT03654313) randomized 88 patients with type 2 diabetes to receive single ascending doses (10, 30, 90, 250, or 500 mg) or multiple ascending doses (90, 150, or 250 mg once monthly for 3 months) of MEDI6570 or placebo. Primary end point was safety; secondary and exploratory end points included pharmacokinetics, immunogenicity, free soluble LOX-1 levels, and change in coronary plaque volume. Mean age was 57.6/58.1 years in the single ascending doses/multiple ascending doses groups, 31.3%/62.5% were female, and mean type 2 diabetes duration was 9.7/8.7 years. Incidence of adverse events was similar among cohorts. MEDI6570 exhibited nonlinear pharmacokinetics, with terminal half-life increasing from 4.6 days (30 mg) to 11.2 days (500 mg), consistent with target-mediated drug disposition. Dose-dependent reductions in mean soluble LOX-1 levels from baseline were observed (>66% at 4 weeks and 71.61-82.96% at 10 weeks in the single ascending doses and multiple ascending doses groups, respectively). After 3 doses, MEDI6570 was associated with nonsignificant regression of noncalcified plaque volume versus placebo (-13.45 mm3 versus -8.25 mm3). Conclusions MEDI6570 was well tolerated and demonstrated dose-dependent soluble LOX-1 suppression and a pharmacokinetic profile consistent with once-monthly dosing. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT03654313.

Purification, Partial Characterization, and Evaluation of the Antiulcer Activity of Calotropis procera Leaf Lectin.

BACKGROUND: Lectins are proteins with therapeutic and diagnostic potential that can be applied in battling various ailments. AIM AND OBJECTIVE: This study was designed to purify and characterize the hemagglutinating activity derived from the leaves of Calotropis procera and its possible role in protecting the stomach against ethanol-induced lesions. METHODS: The Calotropis procera leaf lectin (ProLec), was isolated by homogenization of the defatted leaf powder in Phosphate-Buffered Saline (PBS) and purified by affinity chromatography on Sephadex G-100. The lectin was eluted from the affinity column by 3% acetic acid and was physicochemically characterized. In a dose-dependent manner, ProLec was administered to rats with ethanol-induced ulcers, and biochemical, histopathological, and toxicological examinations were performed. RESULTS: ProLec is a heterodimer of 75 and 68 kDa. It agglutinated all human RBCs, whereas it showed weak interaction with animal erythrocytes. The protein was optimally active at 25 °C and was labile above this temperature. ProLec exhibited two pH optima and was a metalloprotein requiring Ca, Mn, and Ni. It contains 1.6% tryptophan residues of which about 1% is exposed and critical for lectin activity. The lectin exhibited a potent gastroprotective effect against ethanolinduced gastric lesions with no apparent toxicity to both kidneys and liver. Examination of the pH of the gastric juice of lectin-treated animals indicated a possible role of lectin in maintaining stomach acidity within the normal ranges compared to the gastric juice pH of animals that received ethanol only. CONCLUSION: These results may suggest that ProLec could conceivably be a good future drug for the treatment of gastric ulcers, however, extensive immunological and toxicological research remains to be done.

Sutimlimab for treatment of cold agglutinin disease: why, how and for whom?

Therapies for cold agglutinin disease have been directed at the pathogenic B-cell clone. Sutimlimab, a monoclonal antibody that targets C1s, is the first complement inhibitor to be extensively studied in cold agglutinin disease. Sutimlimab selectively blocks the classical activation pathway and leaves the alternative and lectin pathways intact. Trials have documented high response rates with rapid improvement in hemolysis, hemoglobin levels and fatigue scores and low toxicity. Sutimlimab was recently approved in the USA. This drug appears to be particularly useful in severely anemic patients who require a rapid response, in acute exacerbations that do not resolve spontaneously and in patients in whom chemoimmunotherapy is contraindicated or has failed. The choice of therapy in cold agglutinin disease should be individualized.

In cold agglutinin disease (CAD), red blood cells are destroyed by cold agglutinin, a type of antibody against the patient's own red blood cells. Previous treatments for CAD have aimed at killing the cold agglutinin-producing abnormal cells in the bone marrow. Sutimlimab, a new drug for treatment of CAD, is an artificially produced antibody that binds to a protein called C1s. This binding results in inhibition of complement, a system of active proteins that is part of the immune system and promotes red blood cell destruction in CAD. Clinical trials have shown that most patients with CAD respond well to treatment with sutimlimab, with rapid improvement in anemia and fatigue. The risk of serious side effects is very low provided the patient is vaccinated against certain types of bacteria. Sutimlimab, which is administered by intravenous infusion, was recently approved in the USA. This drug appears to be particularly useful in CAD patients with severe anemia, in those who cannot tolerate other treatment options and in those in whom other therapies have failed. The choice of treatment in CAD should be individualized.

Plant lectin: A promising future anti-tumor drug.

Since the early discovery of plant lectins at the end of the 19th century, and the finding that they could agglutinate erythrocytes and precipitate glycans from their solutions, many applications and biological roles have been described for these proteins. Later, the observed erythrocytes clumping features were attributed to the lectin-cell surface glycoconjugates recognition. Neoplastic transformation leads to various cellular alterations which impact the growth of the cell and its persistence, among which is the mutation in the outer surface glycosylation signatures. Quite a few lectins have been found to act as excellent biomarkers for cancer diagnosis while some were presented with antiproliferative activity that initiated by lectin binding to the respective glycocalyx receptors. These properties are blocked by the hapten sugar that is competing for the lectin affinity binding site. In vitro investigations of lectin-cancer cell's glycocalyx interactions lead to a series of immunological reactions that result in autophagy or apoptosis of the transformed cells. Mistletoe lectin, an agglutinin purified from the European Viscum album is the first plant lectin employed in the treatment of cancer to enter into the clinical trial phases. The entrapment of lectin in nanoparticles besides other techniques to promote bioavailability and stability have also been recently studied. This review summarizes our up-to-date understanding of the future applications of plant lectins in cancer prognosis and diagnosis. With the provision of many examples of lectins that exhibit anti-neoplastic properties.

Preclinical Enzyme Replacement Therapy with a Recombinant ß-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis.

GM1-gangliosidosis is a catastrophic, neurodegenerative lysosomal storage disease caused by a deficiency of lysosomal ß-galactosidase (ß-Gal). The primary substrate of the enzyme is GM1-ganglioside (GM1), a sialylated glycosphingolipid abundant in nervous tissue. Patients with GM1-gangliosidosis present with massive and progressive accumulation of GM1 in the central nervous system (CNS), which leads to mental and motor decline, progressive neurodegeneration, and early death. No therapy is currently available for this lysosomal storage disease. Here, we describe a proof-of-concept preclinical study toward the development of enzyme replacement therapy (ERT) for GM1-gangliosidosis using a recombinant murine ß-Gal fused to the plant lectin subunit B of ricin (mß-Gal:RTB). We show that long-term, bi-weekly systemic injection of mß-Gal:RTB in the ß-Gal-/- mouse model resulted in widespread internalization of the enzyme by cells of visceral organs, with consequent restoration of enzyme activity. Most importantly, ß-Gal activity was detected in several brain regions. This was accompanied by a reduction of accumulated GM1, reversal of neuroinflammation, and decrease in the apoptotic marker caspase 3. These results indicate that the RTB lectin delivery module enhances both the CNS-biodistribution pattern and the therapeutic efficacy of the ß-Gal ERT, with the potential to translate to a clinical setting for the treatment of GM1-gangliosidosis.

Oncolytic Vaccinia Virus Harboring Aphrocallistes vastus Lectin Inhibits the Growth of Hepatocellular Carcinoma Cells.

Oncolytic vaccinia virus has been developed as a novel cancer therapeutic drug in recent years. Our previous studies demonstrated that the antitumor effect of oncolytic vaccina virus harboring Aphrocallistes vastus lectin (oncoVV-AVL) was significantly enhanced in several cancer cells. In the present study, we investigated the underlying mechanisms of AVL that affect virus replication and promote the antitumor efficacy of oncolytic virus in hepatocellular carcinoma (HCC). Our results showed that oncoVV-AVL markedly exhibited antitumor effects in both hepatocellular carcinoma cell lines and a xenograft mouse model. Further investigation illustrated that oncoVV-AVL could activate tumor immunity by upregulating the expression of type I interferons and enhance virus replication by inhibiting ISRE mediated viral defense response. In addition, we inferred that AVL promoted the ability of virus replication by regulating the PI3K/Akt, MAPK/ERK, and Hippo/MST pathways through cross-talk Raf-1, as well as metabolism-related pathways. These findings provide a novel perspective for the exploitation of marine lectins in oncolytic therapy.

Glycan expression profile of signet ring cell gastric cancer cells and potential applicability of rBC2LCN-targeted lectin drug conjugate therapy.

BACKGROUND: Signet ring cell carcinoma (SRC) is a distinct subtype of gastric cancer (GC); however, the specific characteristics of cancer cell surface glycans and glycosylation remain unclear. In this study, we investigated SRC-specific glycans using lectin microarray and evaluated the potential applicability of a glycan-targeting therapy. METHODS: SRC cell lines (NUGC-4 and KATO-III) and non-SRC (NSRC) cell lines (NCI-N87, SNU-1, and MKN-45) were subjected to lectin microarray analysis to identify the SRC-specific glycans. Additionally, we performed immunohistochemical lectin staining and evaluated the anti-tumor effects of lectin drug conjugates (LDCs) using high-affinity lectins for SRC. RESULTS: Among the 96 lectins tested, 11 high-affinity and 8 low-affinity lectins were identified for SRC. Glycan-binding motifs varied in the high-affinity lectins, but 5 (62.5%) low-affinity lectins bound the same glycan structure, α2-6-linked sialic acids. The ratio of signal intensity in SRC to NSRC (SRC/NSRC) was highest in the rBC2LCN lectin (1.930-fold), followed by the BPL lectin (1.786-fold). rBC2LCN lectin showed high affinity for both SRC cell lines and one of the three NSRC cell lines (NCI-N87). The therapeutic effects of the LDC, rBC2LCN-PE38 (rBC2LCN, and Pseudomonas exotoxin A), showed cytocidal effects in vitro and tumor regression in in vivo mouse xenograft models. CONCLUSION: We reported specific glycan profiles in SRC cells, showing reduced α2-6-linked sialic acids. Additionally, we found a targeted therapy using rBC2LCN lectin might be applicable as an alternative treatment option for patients with SRC.

Oncolytic Vaccinia Virus Harboring Aphrocallistes vastus Lectin Inhibits the Growth of Cervical Cancer Cells Hela S3.

Aphrocallistes vastus lectin (AVL) is a C-type marine lectin produced by sponges. Our previous study demonstrated that genes encoding AVL enhanced the cytotoxic effect of oncolytic vaccinia virus (oncoVV) in a variety of cancer cells. In this study, the inhibitory effect of oncoVV-AVL on Hela S3 cervical cancer cells, a cell line with spheroidizing ability, was explored. The results showed that oncoVV-AVL could inhibit Hela S3 cells growth both in vivo and in vitro. Further investigation revealed that AVL increased the virus replication, promote the expression of OASL protein and stimulated the activation of Raf in Hela S3 cells. This study may provide insight into a novel way for the utilization of lection AVL.

Lectins applied to diagnosis and treatment of prostate cancer and benign hyperplasia: A review.

Environmental factors, as well as genetic factors, contribute to the increase in prostate cancer cases (PCa), the second leading cause of cancer death in men. This fact calls for the development of more reliable, quick and low-cost early detection tests to distinguish between malignant and benign cases. Abnormal cell glycosylation pattern is a promising PCa marker for this purpose. Proteins, such as lectins can decode the information contained in the glycosylation patterns. Several studies have reported on applications of plant lectins as diagnostic tools for PCa considering the ability to differentiate it from benign cases. In addition, they can be used to detect, separate and differentiate the glycosylation patterns of cells or proteins present in serum, urine and semen. Herein, we present an overview of these studies, showing the lectins that map glycans differentially expressed in PCa, as well as benign hyperplasia (BPH). We further review their applications in biosensors, histochemical tests, immunoassays, chromatography, arrays and, finally, their therapeutic potential. This is the first study to review vegetable lectins applied specifically to PCa.

Man-Specific Lectins from Plants, Fungi, Algae and Cyanobacteria, as Potential Blockers for SARS-CoV, MERS-CoV and SARS-CoV-2 (COVID-19) Coronaviruses: Biomedical Perspectives.

Betacoronaviruses, responsible for the "Severe Acute Respiratory Syndrome" (SARS) and the "Middle East Respiratory Syndrome" (MERS), use the spikes protruding from the virion envelope to attach and subsequently infect the host cells. The coronavirus spike (S) proteins contain receptor binding domains (RBD), allowing the specific recognition of either the dipeptidyl peptidase CD23 (MERS-CoV) or the angiotensin-converting enzyme ACE2 (SARS-Cov, SARS-CoV-2) host cell receptors. The heavily glycosylated S protein includes both complex and high-mannose type N-glycans that are well exposed at the surface of the spikes. A detailed analysis of the carbohydrate-binding specificity of mannose-binding lectins from plants, algae, fungi, and bacteria, revealed that, depending on their origin, they preferentially recognize either complex type N-glycans, or high-mannose type N-glycans. Since both complex and high-mannose glycans substantially decorate the S proteins, mannose-specific lectins are potentially useful glycan probes for targeting the SARS-CoV, MERS-CoV, and SARS-CoV-2 virions. Mannose-binding legume lectins, like pea lectin, and monocot mannose-binding lectins, like snowdrop lectin or the algal lectin griffithsin, which specifically recognize complex N-glycans and high-mannose glycans, respectively, are particularly adapted for targeting coronaviruses. The biomedical prospects of targeting coronaviruses with mannose-specific lectins are wide-ranging including detection, immobilization, prevention, and control of coronavirus infection.

Algae-Derived Bioactive Molecules for the Potential Treatment of SARS-CoV-2.

The recently emerged COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has adversely affected the whole world. As a significant public health threat, it has spread worldwide. Scientists and global health experts are collaborating to find and execute speedy diagnostics, robust and highly effective vaccines, and therapeutic techniques to tackle COVID-19. The ocean is an immense source of biologically active molecules and/or compounds with antiviral-associated biopharmaceutical and immunostimulatory attributes. Some specific algae-derived molecules can be used to produce antibodies and vaccines to treat the COVID-19 disease. Algae have successfully synthesized several metabolites as natural defense compounds that enable them to survive under extreme environments. Several algae-derived bioactive molecules and/or compounds can be used against many diseases, including microbial and viral infections. Moreover, some algae species can also improve immunity and suppress human viral activity. Therefore, they may be recommended for use as a preventive remedy against COVID-19. Considering the above critiques and unique attributes, herein, we aimed to systematically assess algae-derived, biologically active molecules that could be used against this disease by looking at their natural sources, mechanisms of action, and prior pharmacological uses. This review also serves as a starting point for this research area to accelerate the establishment of anti-SARS-CoV-2 bioproducts.

In vitro Study on Synergistic Interactions Between Free and Encapsulated Q-Griffithsin and Antiretrovirals Against HIV-1 Infection.

INTRODUCTION: Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV), raltegravir (RAL), and dapivirine (DAP) have been developed to prevent and treat HIV-1 via different mechanisms of action. In parallel, a promising biological candidate, griffithsin (GRFT), has demonstrated outstanding preclinical safety and potency against HIV-1. While ARV co-administration has been shown to enhance virus inhibition, synergistic interactions between ARVs and the oxidation-resistant variant of GRFT (Q-GRFT) have not yet been explored. Here, we co-administered Q-GRFT with TFV, RAL, and DAP, in free and encapsulated forms, to identify unique protein-drug synergies. METHODS: Nanoparticles (NPs) were synthesized using a single or double-emulsion technique and release from each formulation was assessed in simulated vaginal fluid. Next, each ARV, in free and encapsulated forms, was co-administered with Q-GRFT or Q-GRFT NPs to evaluate the impact of co-administration in HIV-1 pseudovirus assays, and the combination indices were calculated to identify synergistic interactions. Using the most synergistic formulations, we investigated the effect of agent incorporation in NP-fiber composites on release properties. Finally, NP safety was assessed in vitro using MTT assay. RESULTS: All active agents were encapsulated in NPs with desirable encapsulation efficiency (15-100%), providing ~20% release over 2 weeks. The co-administration of free Q-GRFT with each free ARV resulted in strong synergistic interactions, relative to each agent alone. Similarly, Q-GRFT NP and ARV NP co-administration resulted in synergy across all formulations, with the most potent interactions between encapsulated Q-GRFT and DAP. Furthermore, the incorporation of Q-GRFT and DAP in NP-fiber composites resulted in burst release of DAP and Q-GRFT with a second phase of Q-GRFT release. Finally, all NP formulations exhibited safety in vitro. CONCLUSIONS: This work suggests that Q-GRFT and ARV co-administration in free or encapsulated forms may improve efficacy in achieving prophylaxis.

Immunostimulatory and anti-allergic potential of novel heterotrimeric lectin from seeds of Zizyphus mauritiana Lam.

Zizyphus mauritiana Lam. seeds (ZMS) have been used medicinally as sedative or hypnotic drugs in most of Asian countries. ZMS has significant benefits to the human health. Therefore, we have evaluated immunomodulatory effect of lectin extracted from these ZMSL in both in vitro and in vivo study. Anaphylaxis is a severe life-threatening allergic reaction and Arthus reaction is deposition of immune complex and complement system activation, so we hypothesized that if ZMSL can protect these severe allergic diseases. We have studied the effect of ZMSL on macrophages and Wistar albino rats and confirmed its protective effect against anaphylaxis and Arthus reaction. Results of this study suggest ZMSL have immunostimulatory and antiallergic activity.

Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model.

BACKGROUND & AIMS: Infection with hepatitis C virus (HCV) remains a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry receptors. However, there is no approved therapeutic targeting this potentially druggable biomarker. METHODS: The anti-HCV activity of a fusion protein consisting of Avaren lectin and the fragment crystallizable (Fc) region of a human immunoglobulin G1 antibody, Avaren-Fc (AvFc) was evaluated through the use of in vitro neutralization assays as well as an in vivo challenge in a chimeric human liver (PXB) mouse model. Drug toxicity was assessed by histopathology, serum alanine aminotransferase, and mouse body weights. RESULTS: AvFc was capable of neutralizing cell culture-derived HCV in a genotype-independent manner, with 50% inhibitory concentration values in the low nanomolar range. Systemic administration of AvFc in a histidine-based buffer was well tolerated; after 11 doses every other day at 25 mg/kg there were no significant changes in body or liver weights or in blood human albumin or serum alanine aminotransferase activity. Gross necropsy and liver pathology confirmed the lack of toxicity. This regimen successfully prevented genotype 1a HCV infection in all animals, although an AvFc mutant lacking HMG binding activity failed. CONCLUSIONS: These results suggest that targeting envelope HMGs is a promising therapeutic approach against HCV infection, and AvFc may provide a safe and efficacious means to prevent recurrent infection upon liver transplantation in HCV-related end-stage liver disease patients.

Musa acuminata lectin exerts anti-cancer effects on HeLa and EAC cells via activation of caspase and inhibitions of Akt, Erk, and Jnk pathway expression and suppresses the neoangiogenesis in in-vivo models.

In the present study aimed to purify the lectin from the sap of Musa acuminata pseudostem and elucidate the apoptotic and angiogenic molecular mechanism in both in-vitro and in-vivo model. Mannose specific lectin was purified by using mannose affinity column chromatography and analyzed by RP-HPLC, SDS-PAGE, and PAS staining method. Furthermore, the protein was identified by MALDI-MS/MS. MAL effectively agglutinates trypsinized RBCs and showed effective cytotoxicity against various human cancer cell lines. MAL mitigates the cell proliferation, colony formation, cell migration, arrest the cell cycle in the G2/M phase, and induce apoptosis by altering the expression of apoptotic proteins/mRNA level (Bax and Bcl-2) via caspase 8/9, 3 dependent pathway in both in-vitro and in-vivo. Supporting this, in-vivo EAC tumor mice models prove the efficacy of MAL by inducing cell death and inhibiting the neovessel formation by targeting the MVD, inhibition of VEGF secretion, suppressing the expression of MMPs, HIF-1α, Flt-1, Akt, Jnk, and Erk1/2. More importantly, the MAL treatment leads to effective inhibition of tumor growth and an increase in the survivability of EAC mice. Our study summarizes that the MAL having a significant anticancer potential expressively degenerates the tumor development by inducing apoptosis and suppressing neoangiogenesis.