Understanding the modulation of specific immune cells within the tumor microenvironment (TME) offers new hope in cancer treatments, especially in cancer immunotherapies. In recent years, immune modulation and resistance to immunotherapy have become critical challenges in cancer treatments. However, novel strategies for immune modulation have emerged as promising approaches for oncology due to the vital roles of the immunomodulators in regulating tumor progression and metastasis and modulating immunological responses to standard of care in cancer treatments. With the progress in immuno-oncology, a growing number of novel immunomodulators and mechanisms are being uncovered, offering the potential for enhanced clinical immunotherapy in the near future. Thus, gaining a comprehensive understanding of the broader context is essential. Herein, we particularly summarize the paradoxical role of tumor-related immune cells, focusing on how targeted immune cells and their actions are modulated by immunotherapies to overcome immunotherapeutic resistance in tumor cells. We also highlight the molecular mechanisms employed by tumors to evade the long-term effects of immunotherapeutic agents, rendering them ineffective.

Ethnomedicinally, more than 2000 plants were found to be used in Nepal. Among them, the red colored rhizome of Angiopteris helferiana and the bark of Saurauia fasciculata have been used widely to treat muscle fatigue, bone pain, fever, postpartum hemorrhage, and thirst by healers in Kaski and Tanahun districts, Nepal. However, scientific evidence towards their traditional uses is lacking till December, 2023. Therefore, we report the phytochemicals, total phenolic content (TPC), total flavonoid content (TFC), total carbohydrate content (TCC), antioxidant and antibacterial activities of A. helferiana and S. fasciculata extracts. Phytochemical analysis indicated that A. helferiana and S. fasciculata extracts were potential sources of chemicals such as phenols, flavonoids, tannins, terpenoids, saponins, and carbohydrates. The TPC, TFC, and TCC of extracts were determined by using an ultraviolet visible spectrophotometer. Among the extracts tested, A. helferiana extracts showed the highest phenolic and carbohydrate contents of 208.33 ± 12.96 mg of gallic acid equivalent/g and 564.16 ± 2.92 mg of D‐glucose equivalent/g of dry extract, respectively. Similarly, S. fasciculata revealed the highest flavonoid content of 30.35 ± 0.1 mg quercetin equivalent/g of dry extract. The extract of A. helferiana and S. fasciculata exhibited potent antioxidant activity by scavenging 2,2‐diphenyl‐1‐picrylhydrazyl radicals with an IC₅₀ of 25.9 µg/ml and 31.07 µg/ml, respectively. The antibacterial activity of the A. helferiana and S. fasciculata extract against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli was determined using an agar‐well diffusion protocol that revealed the potential antibacterial activity of A. helferiana against E. coli. The present study will help validate the traditional uses of A. helferiana rhizomes and S. fasciculata barks as a healing medicine and inspire the researcher towards further research, development, and formulation.

Objective. The red rhizome of Angiopteris helferiana has been used widely to treat muscle fatigue, bone pain, and skin infection in Nepal. However, scientific evidence for its bioactive compounds and their bioactivities was lacking till January, 2024. Therefore, we investigated to validate and advance the further use and development. Methods. Column chromatography, including MCI gel CHP20P, Sephadex LH‐20, ODS, and Silica gel, was used for the isolation of compounds from 70% methanol extract of A. helferiana rhizomes. The isolated compounds were evaluated for their TLC‐based antioxidant and antibacterial activity against Staphylococcus aureus, Klebsiella pneumonia, Escherichia coli, and Pseudomonas aeruginosa by adopting the agar well diffusion protocol. Furthermore, in silico molecular docking against the penicillin binding protein of E. coli (PBP1b, PBP2, and PBP3 TPd) and ADME toxicity of the isolated compounds was predicted. Results and Discussion. Angiopteroside (1) and osmundalactone (2) were isolated for the first time from the red rhizomes of A. helferiana. The structure of the isolated compounds was elucidated on the basis of spectroscopic (¹H‐, ¹³C‐, and ¹³C/DEPT‐NMR) and spectrometric (LC MS/ESI and IR) analyses and comparison with reported literature. Both compounds were inactive towards DPPH scavenging activity. Compound 1 showed poor inhibitory activity against E. coli, with inhibition zone range of 2–7 mm. However, both isolated compounds were found to be resistant against S. aureus, K. pneumonia, and P. aeruginosa. Based on in silico molecular docking forecasting, compound 1 revealed the good binding affinity with PBP1b (−6.5 kcal/mol), PBP2 (−5.8 kcal/mol) and PBP3 TPd (−6.1 kcal/mol) compared to positive control meropenem with PBP1b (−6.6 kcal/mol), PBP2 (−6.9 kcal/mol), and PBP3 TPd (−6.6 kcal/mol). Similarly, compound 2 showed weak preference for PBP1b (−4.3 kcal/mol), PBP2 (−4.4 kcal/mol), and PBP TPd (−4.5 kcal/mol). Compounds 1 and 2 were predicted to be safe in terms of hepatotoxicity, cytotoxicity, mutagenicity, and carcinogenicity, with a potential to induce nephrotoxicity similar to that of meropenem. Conclusion. This study successfully isolates two lactones with antibacterial properties and inspires the researcher to further research, development, and formulation.

Litchi chinensis is a edible fruits of soapberry family commonly known as lychee; is traditionally used for the treatment of inflammation, headache, and body pain. The present study investigated the toxicity, anti-inflammatory, and analgesic activity of the ethanolic crude extract of Litchi chinensis to support its traditional use in its folk medicine and to screen the phytochemical constituents. 70% ethanolic extract of seeds of Litchi chinensis (LCSE) was prepared and preliminary phytochemical screening was performed. Acute toxicity of LCSE was carried out based on OECD guidelines 423. In vivo anti-inflammatory and analgesic effect of the extract was evaluated using carrageenan-induced paw edema and hot plate methods in Wistar albino rat's model. Results revealed that LCSE contains phenols, tannins, flavonoids, saponins, steroids, and alkaloids. LD50 values were found to be higher than 5000 mg/kg body weight; no any sign of toxicity, behavior changes, moribund, and mortality were observed in LCSE treated animals. Oral administration of LCSE at the dose of 150, 300, and 600 mg/kg produced a significant (p<0.05) dose-dependent inhibition in carrageenan-induced rat paw edema and hot plate. These results suggest that LCSE is non-toxic, and shows potent anti-inflammatory and analgesic activities over Wistar albino rats. These finding demonstrate that lychee seed extract acts as a good therapeutic candidate for the safe anti-inflammatory agents.

Background: Falconeria insignis Royle, a medicinal plant of the Euphorbiaceae family, has been extensively used in Nepal for bacteria-infected wounds, despite the lack of empirical evidence supporting its efficacy. Objectives: This study aims to evaluate the phytopharmaceutical potential of F. insignis leaves and stems in combating oxidative stress and bacterial infections. Methods: Phytoconstituents were characterized using the LC-MS technique. The antioxidant activity was evaluated through DPPH, nitric oxide, hydroxyl radical, and FRAP assays. Furthermore, antibacterial activity was assessed via in vitro disc diffusion and broth dilution assays, along with in silico molecular docking and ADME-toxicity studies. Results: The phenolic compounds identified include gallic acid, chlorogenic acid, and quercetin. Methanolic leaf extract exhibited significant DPPH radical scavenging activity, with an IC ₅₀ of 5.272 ± 0.5 µg/ml, comparable to that of standard ascorbic acid (IC ₅₀ of 4.05 ± 0.3 µg/ml). Additionally, it also demonstrated a pronounced dose-dependent capacity to scavenge nitric oxide, hydroxyl radicals, and reduce ferric ions. Methanolic leaf and ethyl acetate stem extracts showed promising antibacterial activity against Staphylococcus aureus, with a zone of inhibition (ZOI) ranging from 17 to 24 mm and a minimum inhibitory concentration (MIC) of 15.625 µg/ml. In contrast, standard antibiotic meropenem exhibited a ZOI of 24 ± 1.6 mm and MIC of 1.5625 µg/ml. All identified phytoconstituents displayed strong interactions with the catalytic residues SER 403, LYS 406, SER 462, ASN 464, and THR 600 of the penicillin-binding protein, with binding energies of −6.1 to −7.1 kcal/mol, rivaling meropenem (−7.4 kcal/mol). Furthermore, these compounds were forecasted to be safe in terms of hepatotoxicity, with minimal risks of nephrotoxicity. Conclusion: Our findings establish F. insignis as a promising antioxidant and antibacterial crude drug and recommend further cell line and in vivo validations, along with isolation of antibacterial lead compounds.

Background: Crateva unilocularis, Millettia extensa, and Plumbago zeylanica are commonly used traditional medicinal plants in Nepal for treating various skin ailments. Objectives: The ethanol extracts of these plants were analyzed for qualitative and quantitative phytochemical content, antioxidant potential, and anti-tyrosinase activity. Methods: The Folin-Ciocalteu technique was used to measure the total phenolic content, and the aluminum chloride method was used to assess flavonoid content.In vitro antioxidant activity was evaluated via 2,2- diphenyl-1-picrylhyrazyl (DPPH), nitric oxide (NO), and hydrogen peroxide (H₂O₂) assays. A mushroom tyrosinase inhibition assay was employed to assess anti-tyrosinase activity. Molecular docking was performed using the tyrosinase enzyme (PDB ID: 2Y9X) for the five selected phytoconstituents of Millettia extensa. Results: The ethanolic extract of Millettia extensa leaves exhibited high concentrations of phenolic compound (273.85 ± 4.05 mg GAE/g dry extract weight) and flavonoids compound (1787.35 ± 0.22 mg QE/g dry extract weight). The roots of Plumbago zeylanica showed the highest levels of DPPH and NO radical-scavenging activities, with percentages of 95.83% and 43.83%, respectively. Similarly, the stem bark of Crateva unilocularis showed notable H₂O₂ radical scavenging activity (67.81%). Millettia extensa root bark demonstrated the most potent tyrosinase inhibition activity (99.31 ± 0.16), comparable to the standard drug Kojic acid (99.56 ± 0.08). Molecular docking corroborates the in vitro anti-tyrosinase activity, with isoauriculatin and auriculatin demonstrating the highest binding affinities of −9.9 and −9.7 kcal/mol, respectively, compared to Kojic acid (−5.6 kcal/mol). Conclusion: These findings highlight the significant tyrosinase inhibitory potential of Millettia extensa root bark, suggesting further exploration of its cosmetic application and safety evaluation.