Despite nearly 5000 United States Food and Drug Administration (FDA)-tracked trials, no new FDA- or European Union-approved Coronavirus Disease 2019 (COVID-19) drug was discovered during the COVID-19 pandemic. Fortunately, drugs developed before the pandemic proved highly effective, particularly when used early in vaccinated patients. The most powerful treatments are antivirals targeting the spike structural protein and two non-structural proteins (NSPs), NSP5 (main protease [Mpro]) and NSP12 (RNA-directed RNA polymerase [RdRp]). Notably, two studies published before the pandemic and one shortly after its declaration had already identified these three key targets. New monoclonal antibodies were designed to block the spike protein from binding to the host cell. However, all such antibodies were eventually rendered ineffective by emerging viral variants. Several drugs previously used for Middle East respiratory syndrome, Ebola, respiratory syncytial virus, and other viruses work by disrupting the replication activity of Mpro and RdRp. Convalescent plasma, a treatment used since 1900, showed mixed results. For hyperinflammation, only three rheumatoid arthritis drugs and one glucocorticoid, also used in arthritis treatment, received approval. No new approaches were developed to treat blood clots or improve oxygenation. Despite a wartime-like focus and unprecedented research intensity, no respiratory illness, including COVID-19, has yet been cured. Using a personal database of 3050 therapeutic research papers, along with data from ClinicalTrials.gov and Google Scholar, this review examines approved, promising, and ineffective COVID-19 therapeutics. Potential candidates currently undergoing clinical trials are identified to highlight future therapeutic possibilities and guide ongoing research efforts.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder primarily targeting synovial joints, resulting in pain, stiffness, swelling, and progressive joint destruction. The disease is driven by proinflammatory cytokines such as interleukin (IL)-1β and IL-6, which promote synovial inflammation and cartilage degradation. RA affects not only the joints but also other organs, contributing to systemic complications such as cardiovascular disease, anemia, and osteoporosis. Despite the availability of disease-modifying antirheumatic drugs and biologics, their efficacy is often incomplete and frequently accompanied by adverse effects and high costs. This study presents a detailed overview of the etiology, pathogenesis, clinical manifestations, diagnostic strategies, and current treatment modalities of RA, emphasizing herbal medicine as a complementary approach. Botanicals with immunomodulatory and anti-inflammatory properties offer promising adjunctive benefits in RA management. Natural products such as Curcuma longa, Aloe barbadensis, and Zingiber officinale exhibit significant potential to reduce inflammation, modulate cytokine production, and improve patient outcomes. This review highlights the therapeutic promise of integrating herbal remedies with conventional pharmacological therapies, promoting a more holistic, effective, and safer management of RA.

It is generally reported that neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, pose severe threats to global public health. Traditional therapies for neurodegenerative diseases exhibit low drug delivery efficiency due to the restrictive nature of the blood-brain barrier. Fortunately, nanomedicines can effectively overcome blood-brain barrier through mechanisms such as intercellular penetration and receptor targeting, which have advantages such as controlled release, reduced toxicity, and enhanced efficacy. In this paper, we summarize the latest research progress based on the types of nanomaterials, administration approach, and implications, with the aim of providing insights for optimizing the research and development of nanomedicines for neurodegenerative diseases.

The JN.1 Omicron coronaviruses possess a unique 16MPLF spike insertion that compensates for deletions at positions 24LPP, 31S, 69HV, 145Y, 211N, and V483 in the spike protein. These viruses also exhibit a 3576SGF deletion in the open reading frame (ORF)1ab protein, 26-49 nucleotide deletions in the 3’-untranslated region (UTR), and a 31ERS amino acid deletion in the N protein. In an ongoing analysis of JN.1 lineages, an N30 deletion in the spike was detected. This N30 deletion was found in many subvariants, suggesting viral instability and low penetration. SWISS-MODEL analysis revealed that the 30N deletion mutants exhibit a more compact and symmetrical three-dimensional spike structure. The modeling was performed using templates 7nc8.1.A (88.8% similarity) and 8x4h.1.A (99.07% similarity). In the resulting models, His440 was positioned as the first amino acid to interact with the angiotensin-converting enzyme receptor (ACE). However, the JN.1-derived 8y5j.1.A template showed a flattened trimeric spike with protruding residues engaging the receptor. Moreover, a T44I mutation in the nsp2 ribonucleic acid topoisomerase (XLQ96433), a potential drug target, was identified. The T224I ORF1ab mutation occurred in ~300 subvariants. Further analysis identified several important mutations in the ORF1ab polyprotein. The mutations T19I, S50L, V127F, G339H, K356T, S371F, S373P, S375F, R403S, K417N, V455H, G446S, N460K, S477K, Q493E, and Y505H were identified in the spike protein of JN.1 lineages. Moreover, the mutations P13L, Q229K, and S413R in N protein, A63T in M protein, T223I in ORF3a, and F19L in ORF7b protein were observed within the newly studied JN.1 lineage. A 26-nucleotide deletion in the 3’-UTR was highly prevalent (99%), while a 49-nucleotide deletion was observed less frequently. In addition, mutations in the accessory proteins (A68V in XEC.2, H144Q in XEC.3, and G71R in XEC.5) were found, suggesting that recent mutations are clustered in the NH₂-terminus of the spike protein.

Operculina turpethum is widely known for its use in traditional treatment practices to heal several diseases, such as bronchitis, pectoralgia, arthralgia, diarrhea, obesity, helminthiasis, gastropathy, ascites, sporadic fever, leucoderma, inflammation, pruritis, ulcers, erysipelas, tumors, jaundice, hemorrhoids, and ophthalmia. In this study, the antidiarrheal potential of the ethanolic extract of O. turpethum stem was assessed in an animal model, and molecular docking of previously reported stem-derived compounds was performed to determine the possible mechanism of action. The in vivo antidiarrheal effect was assessed using a castor oil-induced mouse model. In silico molecular docking analysis was performed using the ‘Vina Wizard’ program in PyRx 0.8. The stem extracts at 250 and 500 mg/kg produced significant, dose-dependent antidiarrheal activity. Among the four previously isolated compounds, three (22,23-dihydro-α-spinosterol-ß-D-glucoside, paprazine, and sitogluside) showed satisfactory binding affinity against the target M3 muscarinic acetylcholine receptor, comparable to the reference standard drug loperamide. These findings suggest that the O. turpethum stem has significant potential to prevent diarrhea that warrants further phytochemical, pharmacological, and mechanistic investigations.

Alzheimer’s disease (AD), one of the neurodegenerative disorders, is marked by the gradual degeneration of nerve cells in the brain or peripheral nervous system, along with abnormal protein aggregation. While significant efforts have been made to manage AD, a dearth of data remains on candidate phytochemicals and analogs in its treatment. Herein, we present alkaloids derived from the marine algae Jania rubens as potential inhibitors of human acetylcholinesterase (AChE) relevant to AD therapy. Using in silico tools, such as Protox II and SwissADME, 40 isolates were screened for toxicity and absorption, distribution, metabolism, and excretion properties. Molecular docking simulations were performed using PyRx 0.8, AutoDock Vina Wizard, and Discovery Studio 2020. A 50-nanosecond molecular dynamics simulation was performed using the Groningen Molecular Simulation in the LINUX environment and bio-organic molecules force field simulation (CHARMM 36). Ursodeoxycholic acid (AL20), an isolate from J. rubens, exhibited strong inhibitory activity against AChE with a binding energy of −8.5 kcal/mol, surpassing standard anti-Alzheimer drugs donepezil (−8.3 kcal/mol), galantamine (−7.7 kcal/mol), and rivastigmine (−6.4 kcal/mol). However, in silico data revealed a 73% probability of hepatotoxicity for AL20. Thereafter, seven derivatives (AL20A-G) were designed to improve properties for drug likeness. The amide analog, AL20E, showed superior inhibitory activity (−9.0 kcal/mol) and non-toxicity compared to AL20 and the standard drugs. This derivative also demonstrated strong interactions with the AChE enzyme, forming three hydrogen bonds with amino acid residues Pro290, Ser293, and Leu289. The brain or intestinal estimated permeation model predicted favorable gastrointestinal absorption and blood-brain barrier penetration for AL20E, indicating its potential as a central nervous system-active drug. Density functional theory and molecular dynamics analyses confirmed the chemical stability of AL20E, making it a promising candidate for the development of an anti-Alzheimer drug. This study highlights AL20E ([4R]-4-[{3S,7S,8R,9S,10S,13R,14S,17R}-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H cyclopenta{a}phenanthren-17-yl]pentanamide) as a non-toxic, AchE inhibitor with enhanced drug-likeness. This study thereby presents AL20E for consideration as a lead compound in the development of novel Alzheimer’s therapeutics.

The progesterone concentration in endometrial tissue after using vaginal progesterone supplementation is significantly higher than that with IM progesterone administration, whereas; serum progesterone levels are approximately four times higher with IM progesterone compared with vaginal administration. Therefore, serum progesterone cut-off points will differ according to the route of progesterone administration. This study aims to assess the association between serum progesterone levels on the day of frozen embryo transfer (FET) and pregnancy outcomes in artificial FET cycles. This multicenter prospective cohort study, conducted at different centers of Indira IVF Hospitals across India, included 353 women aged 21-40 years who underwent hormone replacement therapy-based FET cycles with intramuscular (IM) progesterone administered up to the day of embryo transfer. The mean serum progesterone level was 31.36 ± 13.78 ng/mL. Participants were categorized into quartiles based on serum progesterone levels: Q1 (<21.7 ng/mL), Q2 (21.7-28.1 ng/mL), Q3 (28.2-40.0 ng/mL), and Q4 (≥40.0 ng/mL). No significant differences in ongoing pregnancy rate (OPR), clinical pregnancy rate (CPR), first-trimester miscarriage rates, or live birth rate (LBR) were observed across the quartiles. Binary logistic regression revealed no statistically significant differences in OPR among the quartiles. Our findings suggest that serum progesterone levels do not significantly influence clinical outcomes, including OPR, CPR, and LBR, in patients undergoing artificial FET cycles with IM progesterone support.